the skin as a mirror of the soul exploring the possible of serotonins

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The skin as a mirror of the soul: exploring the possibleroles of serotonin

Klas Nordlind1, Efrain C. Azmitia2 and Andrzej Slominski3

1Department of Dermatology, Karolinska University Hospital, Solna, Stockholm, Sweden;2Department of Biology and Psychiatry, Center for Neural Science, New York University, New York, USA;3Department of Pathology and Laboratory Medicine, University of Tennessee HSC, Memphis, USA

Correspondence: Klas Nordlind, MD, PhD, Unit of Dermatology and Venereology, Department of Medicine, Karolinska University Hospital,

Solna, SE 171 76 Stockholm, Sweden, Tel.: +46 8 5177 7882, Fax: +46 8 5177 7851, e-mail: [email protected]

Accepted for publication 16 November 2007

Abstract: Serotonin (5-hydroxytryptamine; 5-HT) is an

important mediator of bidirectional interactions between the

neuroendocrine system and the skin. The rate of synthesis of

5-HT from l-tryptophan can be enhanced by brain-derived

neuronal growth factor, cytokines, exposure to ultraviolet lightand steroids. The major source of 5-HT in the skin are

platelets, which, upon aggregation, release this biogenic amine.

Moreover, the epidermal and dermal skin express the enzymes

required for the transformation of tryptophan to 5-HT, and

certain skin cells, such as melanocytes, have been demonstrated

to produce 5-HT. In addition, rodent mast cells produce 5-HT,

but human mast cells have not yet been fully examined in this

respect. Skin cells express functionally active, membrane-bound

receptors for 5-HT, as well as proteins that transport 5-HT.

The interactions of 5-HT with these various proteins determines

the nature, magnitude and duration of serotonergic responses.

The immune and vasculature systems in the skin are traditional

targets for bioregulation by 5-HT. Moreover, recent findings

indicate that keratinocytes, melanocytes and dermal fibroblasts

also respond to this amine in various ways. Thus, mammalian

skin is both a site for the production of and a target forbioregulation by 5-HT. This indicates that agonists and

antagonists directed towards specific 5-HT receptors could be

useful in connection with treatment of skin diseases. Based on

our increasing knowledge concerning these receptors and

their plasticity, future research will focus on the development

of serotonergic drugs that exert metabotrophic effects on

the cells of the skin without affecting the central nervous

system.

Key words: 5-HT – 5-HT receptors – 5-HT transporters – skin

Please cite this paper as: The skin as a mirror of the soul: exploring the possible roles of serotonin. Experimental Dermatology 2008; 17: 301–311.

Introduction

The skin can be considered to be a mirror of the soul.

Light from the outside world passes through the layers of

epidermal cells, the first line of immune defenses, and then

interacts with the neuroendocrine system. The dynamic

interactions between these two extensive systems involve

many molecules (1), among which serotonin (5-hydroxy-

tryptamine; 5-HT) is of major importance.

Synthesised from l-tryptophan, 5-HT was originally named ‘tonin’ on the basis of its capacity to regulate the

tonus of blood vessels (2). Distributed widely throughout

the body, this signal molecule plays important roles in con-

nection with stress responses, appetite, sleep, sexual desire,

memory and behaviour (3). As 5-HT is synthesised in the

skin, its role in cutaneous physiology and pathology, e.g. in

regulation of inflammatory processes, is also receiving more

and more attention.

The broad distribution of 5-HT in living organisms,

including the central and peripheral nervous tissues of

mammals, is indicative of a central role in maintaining

homeostasis (3). 5-HT in the plasma, brain and various

other organs integrates the effects of signals from sensory

and motor systems, as well as endocrine, digestive,

immunological and vascular signals on the various cells

in the human body. Steroids, neuropeptides and growth

factors can also influence production and secretion of

5-HT by serotonergic cells. Consequently, alterations inthe levels of 5-HT in extracellular fluids can alter the

maturation, metabolism, migration and mitosis of its

target cells, including those in both the brain and the

skin.

The purpose of the present review is to highlight the

importance of 5-HT as a signalling substance that mediates

neurocutanous interactions, both at the organ and cellular

levels. In addition, questions regarding 5-HT and the skin

DOI:10.1111/j.1600-0625.2007.00670.x

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ª 2007 The Authors

Journal compilation ª 2007 Blackwell Munksgaard, Experimental Dermatology , 17, 301–311

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are posed and future directions in this important area of

research on skin physiology envisioned.

Synthesis and general and cellulareffects of 5-HT

Synthesis of 5-HT starts with hydroxylation of the l-trypto-

phan at the fifth position on the indole ring to yield 5-hy-

droxytryptophan (TrpOH; Fig. 1). This reaction requires

molecular oxygen and the reducing cofactor 6-tetrahydrobi-

opterin and is catalysed by tryptophan hydroxylase (TPH),

an enzyme encoded by the TPH1 (which is expressed ubiq-

uitously) and TPH2 genes (expressed predominantly in the

brain) (4,5). Thereafter, TrpOH is decarboxylated to pro-

duce 5-HT in a reaction catalysed by the ubiquitously

expressed l-aromatic amino acid decarboxylase (AAD) and

involving the cofactor pyridoxal phosphate. These enzymes

that synthesise 5-HT appeared very early during evolution

(6).

Tryptophan, the amino acid precursor for 5-HT, cap-tures light with great efficiency and is present in the reac-

tive core of chlorophyll (6,7). Consequently, plants have a

highly efficient mechanism for synthesising tryptophan

within chloroplasts and also produce high levels of 5-HT.

This 5-HT serves as a trophic factor involved in root

growth and leaf motility, as well as a potent antioxidant.

Lacking chloroplasts, animals also lack the ability to syn-

thesise tryptophan and must, therefore, obtain this amino

acid from dietary sources (8). Although overall levels of 5-

HT are, therefore, lower, its trophic and antioxidation

functions are similar in animals (7).

In the plasma of mammals, tryptophan is present at

steady state both in the free form (at a concentration of

approximately 12 lm) and tightly bound to serum albumin

(about 61 lm) (9). The free form can enter cells, including

those of the brain. Its level exhibits diurnal and seasonal

variations and is also influenced by diet and stress, as

well as by age and gender. TPH, the rate-limiting enzyme

in 5-HT biosynthesis, has a dissociation constant (Kd) for

tryptophan of approximately 10)8 m, i.e. close to the free

level in serum, so that fluctuations in this free pool can

directly and immediately alter the amount of 5-HT that is

produced.

Tryptophan hydroxylase is expressed by brainstem neu-

rons and in the pineal gland, lung, gut and skin. In the

case of skin, this enzyme is localised in blood vessels, mast

cells, melanocytes, keratinocytes and fibroblasts (10,11),

where 5-HT may function as an antioxidant, as well as

influencing cellular metabolism. Activated T cells also

express TPH1 and the 5-HT they produce is taken by den-

dritic cells, which also receive 5-HT from other sources in

their microenvironment (12).

The mast cells of rodents (13), dogs (14) and guinea pigs

(15) contain 5-HT, whereas the presence of this compound

in human mast cells has only been reported occasionally

(10,16–18). Interestingly, mast cells in the thalamic nucleiof the rat brain, which appear to modulate neuronal

activity, also contain 5-HT (19).

Biochemical and molecular biologicalaspects of 5-HT synthesis in the skin

Tryptophan hydroxylase 1 mRNA with the expected

sequence has been detected in biopsies of normal human

skin, as well as in basal cell carcinomas, normal epider-

mal and follicular melanocytes in culture, melanoma cell

lines, normal neonatal, adult epidermal and follicular

keratinocytes, squamous cell carcinoma cells and follicular

and dermal fibroblasts (20). In addition, aberrant species

of TPH1 mRNA are present in keratinocytes from a

human cell line (HaCaT), melanoma cells (20) and masto-

cytoma cells (21).

The levels of TPH protein in extracts of skin or of nor-

mal or malignant epidermal keratinocytes and melanocytes

or dermal fibroblasts have been examined with Western

blotting (10,11). The size variability detected in the skin

indicates extensive turnover of this enzyme in this tissue

(11). Immunocytochemical analysis of skin biopsies fixed

in paraformaldehyde or formalin revealed that TPH and

5-HT are localised primarily in normal melanocytes and

malignant melanoma, suggesting that the pathway for5-HT synthesis is expressed predominantly in the melano-

cytic cells of this tissue (11,22). However, more recent

immunofluorescence studies on biopsies of human scalp

detected TPH in the epidermis and adnexal structures as

well (10). Moreover, AAD mRNA was found in epidermal

keratinocytes and melanocytes and the protein itself in

melanocytes (23). In addition, of relevance in this connec-

tion is the observation that the skin is fully capable of

Figure 1. Schematic illustration of the biosynthesis of 5-HT. Starting

from tryptophan, this synthesis proceeds via reactions catalysed by two

enzymes, TPH and l-aromatic AAD. The first of these steps has been

clearly shown to be rate limiting.

Nordlind et al.

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302Journal compilation ª 2007 Blackwell Munksgaard, Experimental Dermatology , 17, 301–311



synthesising 6-tetrahydrobiopterin, the cofactor required

for TPH activity (24).

Of direct relevance to these findings is the detection

of the enzymatic activity of TPH in extracts of skin cells, of

5-HT itself in skin cells and extracts, and of both 5-HTP

and 5-HT in melanoma cell (10,11,20,25). In addition,

positive immunohistochemical staining for 5-HT is exhib-

ited by the epidermal and adnexal compartments and by

mast cells in the skin (10,16,18).

The enzymes required to synthesise 5-HT from trypto-

phan are also present in the skin of rodents (reviewed in

10). For example, the TPH gene (Accession No. AY034600)

is expressed in hamster skin and melanoma cell lines, as

well as in the spleen and liver of this rodent (26). Similarly,

the mouse TPH gene (Accession No. NM_009414) is

expressed in the skin of this animal during all phases of the

hair cycle, with the lowest level being present in the telogen

phase, as well as in cultured mouse follicular melanocytes

and melanoma cells (27).

The TPH expressed in the mouse demonstrates a bandwith the expected molecular weight 53–55 kDa upon Wes-

tern blotting. However, larger and smaller bands were also

detected and it was proposed that the high molecular

weight immunoreactive species reflects ubiquitinated TPH,

whereas the smaller species represent degradation products.

Finally, biochemical assays have documented the conver-

sion of tryptophan to TrpOH in hamster melanoma cells

and, furthermore, 5-HT itself was detected in extracts of

these cells by reverse-phase high-performance liquid chro-

matography (RP-HPLC) and liquid chromatography ⁄ mass

spectrometry (LC ⁄ MS) (26).

Release and reuptake of 5-HT

In the plasma, 5-HT can be taken up into platelets by a

5-HT transporter (5-HTT). This protein, with its 12 mem-

brane-spanning domains, can both release 5-HT and reup-

take this signal molecule (28) although under most

conditions reuptake is favoured. A large number of phar-

macological drugs referred to as specific serotonin reuptake

inhibitors (SSRIs) inhibit the reuptake process (Fig. 2). At

the same time, drugs such as 3,4 methylenedioxymetham-

phetamine (ecstasy) (MDMA) and methylamphetamine are

potent inhibitors of the release of 5-HT from platelets via

5-HTT.Platelet levels of 5-HTT exhibit seasonal variations (29).

Furthermore, genetic polymorphisms in the promoter as

well as in intron regions of the 5-HTT gene render the

individuals involved more prone to stress and depression

(30,31). It has been proposed that the brains of subjects

with inactivating polymorphisms take up lower amounts of

5-HT, but the eventual significance of this process for

peripheral cells is unclear (32).

The release of 5-HT by melanocytes and mast cells may

influence cell communication in the periphery. Although

this release by mast cells has been postulated to involve

intracellular granules and is probably regulated by Ca++

influx, release of cytoplasmic 5-HT through the reuptake

protein is certainly possible and such a process would be

regulated by the concentrations of 5-HT inside and outside

the cell (28,33–35). 5-HT is also released by Merkel cells,

highly specialised cells that receive many axon terminals,

can be activated by mechanical reception and ⁄ or distortion

and indirectly regulate the action of sensory neurons via 5-

HT1A receptors (36,37). Both Merkel cells and their axon

terminals express 5-HTT (37,38).

Serotonin receptors

Free 5-HT can interact with specific cell surface mem-

brane-bound receptors (R) which are classified into seven

general families (39–41). These receptors are coupled toG-proteins and can stimulate (5-HT7R) or attenuate

(5-HT1R) adenylate cyclase activity or enhance the activity

of phosphoinositol (PI)-hydrolases (5-HT2AR). In addi-

tion, 5-HT3R can function as an ion channel. As observed

in the brain (7), 5-HT receptors may act in a competitive

manner. For example, via 5-HT1AR 5-HT can reduce

intracellular levels of cyclic AMP (c-AMP) and calcium-

linked kinase activity, whereas activation of 5-HT7R can

Figure 2. Synthesis, storage, release and reuptake of 5-HT at synaptic

and non-synaptic nerve endings. The actions of 5-HT are regulated by

changes in the local rate of synthesis of this compound in response to

alterations in the availability of tryptophan, molecular oxygen and ⁄ or

reduced biopterin. 5-HT can be released from nerve cells by a Ca ++-

mediated mechanism involving vesicles or by the reverse action of 5-

HTT (28). A large number of drugs designed to interfere with all of the

individual steps involved in local release and reuptake of 5-HT, as well

as binding of this compound to its receptor, have been developed.

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303



increase c-AMP levels. The net result determines the degree

of phosphorylation of the c-AMP response element-binding

protein (p-CREB), an important transcription factor in

connection with development and maintenance of adult

homeostasis (42).

Through their C-terminus and ⁄ or intracellular loops,

several 5-HTR subtypes interact sterically with calmodulin

and such interaction can modulate the phosphorylation

and consequent desensitisation of the activated receptor

(see 41). Interestingly, antagonists of calmodulin ameliorate

the symptoms of skin diseases associated with increased

levels of 5-HT (43). It should here also be mentioned that

S100b protein, a closely related molecule to calmodulin, is

expressed in inflammatory skin diseases and disturbed epi-

dermal maturation (44).

Monoamines, including 5-HT, serve as neuronal growth

factors to induce maturational, protective and metabolic

changes (7,45).

The 5-HT1A receptor has long been shown to produce

trophic changes by acting through a glial-mediated releaseof S100b (7,46,47). S100b containing astrocytes are signifi-

cantly increased in the brains of mice with overexpression

of the 5-HT1A receptor gene (48). Not only does the 5-

HT1AR produce changes in neuronal maturation rate but

serves an antiapoptotic factor (49–51). Activation of the

5-HT1AR in neuronal and hippocampal HN2-5 cells atten-

uates the activation of caspase-3 induced by anoxia, an

effect that is apparently mediated by phospholipase C

(PLC) via a pathway suggested to be dependent on the

extracellular-regulated kinase (ERK) mitogen-activated pro-

tein kinase (MAPK) and protein kinase C (PKC) a (52).

An activation of NF-jb by a 5-HT1AR agonist has also

been shown for activated B and T cell splenocytes, promot-

ing their survival and proliferation (53).

The affinity of 5-HT1AR for 5-HT is sufficiently high for

it to be stimulated by normal daytime circulating levels of

this ligand. Furthermore, expression of this receptor is

down-regulated by prolonged activation (54–56). In con-

trast, the 5-HT2AR is a low-affinity receptor activated only

by high levels of 5-HT (i.e. about 100-fold above normal

circulating levels). Activation of this receptor promotes

hydrolysis of PI and an increase in intracellular Ca++ levels,

thereby stimulating kinase activity, cell division and apop-

tosis (7,57).

Certain evidence indicates that these receptors areinvolved in physiological functions of the skin. For example,

cultures of human skin and skin cells express receptors for

5-HT (10,58,59), as well as the mRNA species that code for

5-HT1A, -1B, -2A, -2B, -2C and -7 (59). Additional investi-

gations in situ have demonstrated expression of

5-HT1AR by basal epidermal melanocytes and of 5-HT2AR

in the epidermis of normal and eczematous human skin

(58). Moreover, 5-HT3 is expressed in the proliferative basal

layer of the epidermis. In general, with the exception of the

immunocytochemical detection of 5-HT3R, the in situ find-

ings are consistent with molecular analyses in vitro.

Other factors that influence theaction of 5-HT

The functioning of the 5-HT system is also influenced by

cytokines. The enzyme indoleamine 2,3-dioxygenase is

expressed by a variety of cells, including macrophages and

dendritic cells derived from monocytes, and is induced

preferentially by the Th1-type cytokine interferon (IFN)-c.

This enzyme reduces intracellular levels of both tryptophan

and 5-HT, which contributes to the cytostatic and antipro-

liferative activity of IFN-c (60). Treatment of cancer

patients with cytokines is often associated with depression

that is proposed to be caused by the potent reduction of

cellular levels of tryptophan and can be alleviated by treat-

ment with SSRIs (61).

In addition, pro-inflammatory cytokines are known toalter the metabolism and release of 5-HT in the central

nervous system by rapidly regulating neuronal 5-HTT

activity via p38 MAPK-linked pathways (62). Significantly,

interleukin (IL)-1b receptors and 5-HT2CR demonstrate

identical distributions in the medial hypothalamus (63).

The possibility of a reciprocal relationship between IL-1

and 5-HT is of interest in the context of our observation

of immunohistochemical staining for 5-HT2CR in Langer-

hans-like cells of the murine skin (64).

The brain-derived neuronal growth factor (BDNF) pro-

duced by the brain promotes the survival and sprouting of

local 5-HT neurons (65,66). Furthermore, reduction of the

plasma level of tryptophan gives rise to a significant

increase in the plasma level of BDNF (67). The authors

propose that peripheral changes in BDNF levels may reflect

central processes, as rapid passage of this factor across the

blood-brain barrier is mediated by a saturable transport

system with high capacity, so that the levels of this com-

pound in the serum and cerebrospinal fluid are similar.

Moreover, nerve growth factor (NGF), which possesses a

structure similar to that of BDNF, stimulates release of

5-HT by mast cells in the rat peritoneum designed to ame-

liorate inflammation and hasten tissue repair (68). Another

member of the NGF family, neurotrophin 3 (NT-3), does

not induce synthesis of 5-HT in suspension of mast cells(69).

In addition, stress activates the hypothalamic–pituitary–

adrenal (HPA) axis, which results in elevated levels of cir-

culating glucocorticoids (70), that stimulate the synthesis

and turnover of 5-HT (71,72). Treatment with dexametha-

sone, a synthetic adrenal steroid, enhances the level of the

TPH protein in brainstem neurons (73). In the periphery

of patients exhibiting elevated serum levels of cortisol, the

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ª 2007 The Authors




turnover of 5-hydroxyindole acetic acid (5-HIAA) and

5-HT is abnormally rapid (74). Furthermore, 5-HT1AR lev-

els decrease acutely in connection with stress, a phenome-

non that is either because of the direct action of cortisol

on gene transcription (75) and ⁄ or feedback inhibition (55).

Chronic stress may have impact on the skin barrier,

thereby worsening inflammatory skin diseases such as ato-

pic eczema (76). As 5-HT1AR is expressed in the outer part

of the epidermis (58), a change of this receptor in chronic

stress or during application of glucocorticoids might mod-

ulate the protective function of this barrier. Finally, expo-

sure to ultraviolet light enhances the serum concentration

of 5-HT via a mechanism that remains to be elucidated

(77).

Actions of 5-HT in the skin

Addition of 5-HT to the medium of cultures of skin cells

exerts variable effects on the proliferation of these cells (59).

This factor stimulates the growth of dermal fibroblasts in adose-dependent manner, whereas in the case of

immortalised epidermal melanocytes, 5-HT stimulates

growth in the absence of melanocyte growth factors, but

inhibits cell proliferation when these factors are present. It

has been proposed that these differing effects reflect the

influence of 5-HTR on both cell proliferation and apoptosis.

Moreover, in a human melanoma cell line, 5-HT inhibits

melanogenesis (78), whereas inhibitors of 5-HT uptake pre-

vent the melanisation of melanoma cells (79). These find-

ings suggest that 5-HT affects melanocyte behaviour (10).

The biosynthetic enzyme TPH was shown earlier to be

present in mouse mastocytoma (80) and later, 5-HT1AR

was found to be expressed in human mastocytoma (Ritter

et al., unpublished observations). In addition, 8-hydroxy-2-

di-n-propylamino-tetralin (8-OH-DPAT), an agonist of

5-HT1AR, reduces the spontaneous release of histamine

from a human mast cell line (HMC)-1. Moreover, 5-HT

and the 5-HT1A and 5-HT2A receptors, and 5-HTT, are all

expressed in benign compound nevi, dysplastic nevi and

malignant melanoma (Naimi-Akbahr et al., unpublished

observations).

The mRNA species coding for the 5-HT2B and 5-HT7

receptors have been demonstrated to be present in samples

of mouse and hamster skin (81). In the case of mouse skin,

expression of these transcripts varies during the cycle of hair growth, being expressed in anagen, but not in telogen

skin (81,82). 5-HT2BR mRNA was found in mouse and

hamster melanomas, as well as in immortalised mouse fol-

licular melanocytes, whereas the mRNA for 5-HT7R tran-

script was detected in hamster melanomas, but not in

cultured mouse melanocytes or melanoma cells (81).

I-A antigen positive cells in murine epidermis demon-

strate positive immunohistochemical staining for 5-HT2CR

(64). Interestingly, this is the same type of 5-HT receptor

that predominates in human skin (59). In addition, 5-HT,

also at near-physiological concentrations, modulates cell

proliferation in cultures of murine keratinocytes (83),

whereas the metabolites NAS and 5-methoxytryptamine

(5-MT) stimulate and inhibit melanoma cell proliferation,

respectively, only at close to mm concentrations (84).

Degradation of serotonin in the skin

Monoamine oxidase (MAO), which is also expressed in

mammalian skin (10), deaminates 5-HT to yield 5-hydrox-

yindole acetaldehyde, which is then transformed to

5-HIAA and 5-hydroxytryptophol (5-HTPOL) (as demon-

strated by LC ⁄ MS analyses of rodent skin extracts) (27,85).

Inhibition of MAO by pargyline attenuates the production

of 5-HIAA and 5-HTPOL in rodent skin, thereby confirm-

ing the involvement of this enzyme in this production.

While both 5-HIAA and 5-HTPOL are formed in mouse

skin (27), 5-HIAA is the major degradation product in ratskin, where the level of 5-HTPOL is below the limit of

detection (85).

Detection of 5-HT and 5-HIAA in human HaCaT kerati-

nocytes (20) suggests that similar metabolism of 5-HT

occurs in human skin. Moreover, the presence of 5-meth-

oxytryptamine (5-MT) in both human (25) and rodent

(86) skin indicates direct or indirect metabolism of 5-HT

to 5-MT. In addition, certain findings suggest that human

and rodent skin transform 5-HT to melatonin via a

sequence of reactions (87–89).

Skin pathology: role of 5-HT in skininflammation

Analysis by HPLC has revealed that serum levels of 5-HT

in patients with allergic contact eczema are elevated (90),

whereas immunohistochemical examination demonstrated

that melanocytes expressing 5-HT in the inflamed skin of

these patients are abnormally elongated. In contrast, 5-HT

levels in murine skin undergoing contact allergic reactions

are the same as in control skin although the platelets of the

allergic animals do exhibit elevated immunohistochemical

staining for 5-HT (91). Other immunohistochemical stud-

ies have demonstrated elevated expression of 5-HT in the

epithelial and adnexal structures of skin suffering from pso-riasis (92) or chronic eczema (93), but no such increase in

the mast cells in these same samples.

Cells that express 5-HT1AR and stain positively for tryp-

tase are diminished in number in association with allergic

contact eczema (58,94) and psoriasis (95), whereas the

number of dermal cells expressing 5-HT2AR and CD3 is

enhanced in connection with both of these inflamma-

tory conditions, as well as with atopic dermatitis (96).


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Moreover, 5-HT1AR is also expressed in the apical region

of the epidermis, where it might play a role in establishing

the skin barrier, and on melanocytes (Fig. 3). 5-HT2CR-

and I-A positive cells, are increased in number in the

epidermis of Balb ⁄ C mice with contact eczema and, fur-

thermore, an agonist of 5-HT2CR aggravates a contact

allergic reaction in the same strain of mice (64). In addi-

tion, eczematous human skin contains abnormally large

numbers of dermal cells that express 5-HTT, CD3, CD56

as well as exhibiting epidermotropism (94,96). An increase

in the number of 5-HTT-positive mononuclear cells has

also been observed in patients with psoriasis, both in the

affected and unaffected skin, in comparison with normal

skin (unpublished observations).

Biological effects of 5-HT in connectionwith skin inflammation

It is questioned which cells that are in control of skin

immunity under physiological circumstances (97). Never-

theless, 5-HT mediates important signals in connection

with immune responses (98). Specifically, 5-HT participates

in the activation of T cells and natural killer cells by mac-

rophages; the initiation of delayed-type hypersensitivity responses; the production of a variety of chemotactic fac-

tors; and the modification of innate immune responses.

Both mast cells and platelets produce 5-HT that may help

initiate contact hypersensitivity in normal mice (99). The

chemoattractive potency of 5-HT for eosinophils in differ-

ent mammalian species is probably mediated via the

5-HT2AR and can be blocked by cyproheptadine (100).

The enhancement of mast cell migration and adherence

that occurs in response to activation of 5-HT1AR by 5-HT

does not involve degranulation. This more pronounced

migration is associated with polymerisation of actin and

suggests that 5-HT promotes inflammation by recruiting

mast cells to the site of tissue injury (101).

5-HT receptors also play a role in certain reactions of

the skin to light. For example, cis-urocanic acid, produced

in response to sunlight, exerts its immunosuppressive

effects via binding to both a specific receptor and the struc-

turally similar 5-HT2AR. This immunosuppression might

have an impact on the development of skin cancer

(102,103). However, it has also been proposed that cis-uro-

canic acid and 5-HT mediate UVB-induced immunomodu-

lation via independent pathways (104).

Earlier, 5-HT1AR was reported to be involved in skin

inflammation in rats (105). Thus, topical or oral adminis-

tration of buspirone, an unselective agonist of this receptor,

diminishes the severity of contact allergy in these experi-

mental animals. In addition, tandospirone, an agonist of

this same receptor, reduces the stress level and attenuatesitching in patients with atopic dermatitis (106). Treatment

with antagonists of 5-HT2AR reduces the severity of con-

tact allergic reactions in mice (107) and the same effect can

be achieved by systemic or topical administration of spiper-

one (108). In addition, ketanserin, a 5-HT2R antagonist,

inhibits the established (109), but not challenge-induced

(110) phases of allergic contact dermatitis evoked by nickel

in humans.

When injected intradermally, 5-HT gives rise to pruri-

tus in human skin (111–113), a response that may be

mediated via different receptors. For instance, ondanse-

tron, an antagonist of 5-HT3R, reduces the severity of

this pruritus (112). Furthermore, the 5-HTT inhibitor

paroxetine has been used in the treatment of pruritus

associated with malignant disease and its antipruritic

action is connected with down-regulation of 5-HT3R

expression (114).

The 5-HT2AR is present on primary sensory afferents

in rat skin (115) and cutaneous 5-HT2AR is at least par-

tially responsible for mediating scratching in mice (113).

Primary nerve afferents are proposed to be targets for

mediators released by cutaneous cells in response to

stimulation by 5-HT. Nonetheless, intradermal injection

of 5-HT into rats elicits enhanced c- fos-like immunoreac-

tivity in superficial lamina at the lateral aspect of the dor-sal horn, in a manner similar to the immunoreactivity

evoked by capsaicin (116).

Neither the 5-HT2 nor 5-HT3 receptors are involved in

scratching of itches caused by allergic skin dermatitis in

rats (117). On the contrary, acute scratching induced by

5-HT is mediated by peripheral 5-HT2 receptors. In con-

trast to histamine, intradermal injection of 5-HT induces

itching in normal, but not inflamed skin (118).

5-HT1AR

Figure 3. Expression of the 5-HT1AR in the apical epidermis,

melanocytes (arrowhead points at a typical cell) and mast cells (arrow)

of atopic eczematous human skin.

Nordlind et al.

ª 2007 The Authors




Interestingly, the scratching behaviour induced in hair-

less (HR-1) mice by 5-HT is more intense than in other

mouse strains, such as NC ⁄ Nga (119,120) and Balb ⁄ C

(120) mice. In addition, HR-1 mice scratch themselves

more in response to exposure to compound 48 ⁄ 80 than do

NC ⁄ Nga mice (120).

Inhibitors of 5-HTT exert various side effects on the skin

including spontaneous bruising, pruritus, urticaria, angio-

edema, erythema multiforme, the Steven–Johnson syn-

drome, toxic epidermal necrolysis, erythema nodosum,

alopecia, hypertrichosis, leukocytoclastic vasculitis and

acneiform eruption (121). In addition, flares of psoriasis

vulgaris (122,123) have been described in patients adminis-

tered such compounds. Delayed hypersensitivity has also

been noted (124).

Major remaining questions

(1) The serotonergic system displays a high degree of plas-

ticity and novel receptors for 5-HT might have importantfunctions. Does 5-HT evoke pharmacological responses by

immune cells in the skin that are similar to the response of

neuronal cells?

(2) The serotonergic system might be a double-edged

sword, even when the same receptor such as 5-HT1AR is

involved, modulating the barrier provided by the skin and,

at the same time, possibly promoting inflammation by pro-

longing the lifespan of inflammatory cells such as mast

cells. In this context, the possible ability of SSRI com-

pounds to affect the frequency of apoptosis among immune

cells might be of interest, in connection with the treatment

of cutaneous inflammations. There is a need for study

of signalling pathways for the different 5-HT receptor

subtypes in various immune cells, and in particular, to

establish any relationship with S100b function in the skin.

(3) Through evolution, has the serotonergic system been

adjusted to the development of the entire immune system,

or fine-tuned to innate immunity? In this sense, is there

any difference between neuronal cells and the immune cells

in the skin?

(4) As for other mediators of pruritus, it would be of

interest to determine whether serotonergic compounds

affect sensory afferents directly and ⁄ or via their actions on

other types of skin cells. In this respect, an in vitro system

using human spinal ganglia might be of high interest. Thisquestion is especially interesting in the light of the fact that,

depending on the strain and species, 5-HT can promote or

antagonise the development of pruritus. In this connection,

in vitro studies on human spinal ganglia might provide

valuable information.

(5) The use of different fixation procedures (125) may

explain the varying reported findings concerning the con-

tent of 5-HT in human mast cells. However, during the

process of evolution, a substantial decrease in this content

appears to have occurred and it would be interesting to

examine this phenomenon in more detail.

(6) Is there any relationship between the state of

maturity of mast cells and the level at which they express

5-HT1AR? Which subpopulations of mast cells can store

and secrete 5-HT?

(7) Assessment of serotonergic transmission in the

periphery is problematic. At present, measurement of

5-HIAA levels in the urine is regarded as optimal in this

respect, but development of more direct approaches would

be of value.

(8) Mouse strains in which the genes encoding 5-HT

receptors and ⁄ or 5-HTT have been ‘knocked out’ provide

valuable insights into inflammatory skin conditions. It

would be of interest to investigate the effects of serotoner-

gic agents on the development of melanoma or other skin

tumors in these animals. However, the fundamental differ-

ences between murine and human skin, as well as the fact

that mice have fur and are also a nocturnal species, whilehuman skin is continuously exposed to solar radiation,

should not be forgotten.

Figure 4. Postulated involvement of 5-HT in the biology and

pathology of the skin. 5-HT is synthesized by epidermal melanocytes

(me), Merkel cells (Me) and inflammatory cells such as mast cells (M) in

the skin. An additional important source of dermal 5-HT is via release

from platelets. Through its effects on keratinocytes (KC), melanocytes

and mast cells via the 5-HT1AR, 5-HT may influence the differentiation

and life-span, as well as dendricity, of various types of skin cells.

Human melanocytes also express 5-HT2CR (unpublished results).

Activation of 5-HT2AR on T lymphocytes (T) probably renders these cells

more mobile, allowing them to pass through the basal membrane.

Furthermore, this same receptor, together with 5-HT1AR and 5-HT7R,is expressed on vessels and fibrocytes (FC). 5-HT2CR is expressed by

Langerhan’s cells (LC), where it participates significantly in determining

dendriticity. 5-HTT is also expressed on Langerhan’s cells (95), as well as

on T lymphocytes and Merkel cells, and may, via uptake of 5-HT into

these cells, exert an important influence on their susceptibility to

apoptosis. Dendritic cells in the epidermis may also take up 5-HT from

the epidermis. The 5-HT2AR present on sensory afferent nerves may

influence nerve transmission and play a role in connection with pruritus.

5-HT3R is expressed by basal keratinocytes and has been reported to be

involved in the proliferation of these cells.


ª 2007 The Authors


307



(9) As 5-HT1AR is expressed by mast cells and melano-

cytes, it would be of interest to look for possible interac-

tions between 5-HT and oncogenes such as c-kit.

Future perspectives: use of drugs

The serotonergic system delivers relatively high concentra-

tions of bioactive molecules to a variety of specific and

well-defined targets (Fig. 4). Development of novel seroto-

nergic drugs that are more specific for individual 5-HT

receptors represents an intriguing approach to the treat-

ment of inflammatory dermatoses and skin tumors. More-

over, seasonal variations in 5-HTT activity (which is higher

in winter), that might alter the lifespan of inflammatory

cells in the skin, as well as genetic polymorphisms in the

5-HTT gene and ⁄ or alternative splicing of the primary

transcript, might be of significance in connection with the

development of such pathological states.

Our understanding of the 5-HT receptors, their signal

transduction in neuronal and other cells, and the func-tional consequences of their interactions with accessory

proteins needs to be improved. Therapeutic strategies

should aim at developing drugs that disrupt or reinforce

such interactions in the skin, while exhibiting fewer side

effects than those in association with treatment involving

classical agonists- or antagonists-based thought to act on

the brain.

Serotonergic drugs are commonly administered systemi-

cally, but topical treatment might also be beneficial, as has

already been demonstrated in the case of agonists of

5-HT1AR. In this respect, novel serotonergic agents which

penetrate across the blood-brain barrier poorly might be

useful, as the side effects of such drugs would be expected

to be less severe.

References

1 Slominski A, Wortsman J. Neuroendocrinology of the skin. Endo-

crine Rev 2000: 21: 457–487.

2 Whitaker-Azmitia P M. The discovery of serotonin and its role in

neuroscience. Neuropsychopharmacology 1999: 21 (Suppl. 2): 2S–

8S.

3 Azmitia E C. Serotonin neurons, neuroplasticity, and homeostasis

of neural tissue. Neuropsychopharmacology 1999: 21 (Suppl. 2):

33S–45S.

4 Mockus S M, Vrana K E. Advances in the molecular character-

ization of tryptophan hydroxylase. J Mol Neurosci 1998: 10:

163–179.

5 Zhang X, Beaulieu J M, Sotnikova T D, Gainetdinov R R, Caron M

G. Tryptophan hydroxylase-2 controls brain serotonin synthesis.

Science 2004: 305: 217.

6 Azmitia E C. Serotonin and brain: evolution, neuroplasticity, and

homeostasis. Int Rev Neurobiol 2007: 77: 31–56.

7 Azmitia E C. Modern views on an ancient chemical: serotonin

effects on cell proliferation, maturation, and apoptosis. Brain Res

Bull 2001: 56: 413–424.

8 Lieberman H R, Corkin S, Spring B J, Wurtman R J, Growdon J H.

The effects of dietary neurotransmitter precursors on human

behavior. Am J Clin Nutr 1985: 42: 366–370.

9 Blomstrand E, Mo ¨ ller K, Secher N H, Nybo L. Effects of carbohy-

drate ingestion on brain exchange of amino acids during sustained

exercise in human subjects. Acta Physiol Scand 2005: 185: 203–

209.

10 Slominski A, Wortsman J, Tobin D J. The cutaneous serotoniner-

gic ⁄ melatoninergic system: securing a place under the sun. FASEBJ 2005: 19: 176–194.

11 Slominski A, Pisarchik A, Johansson O et al. Tryptophan hydroxy-

lase expression in human skin cells. Biochim Biophys Acta 2003:

1639: 80–86.

12 O’Connell P J, Wang X, Leon-Ponte M, Griffiths C, Pingle S C,

Ahem G P. A novel form of immune signaling revealed by trans-

mission of the inflammatory serotonin between dendritic cells and

T cells. Blood 2006: 107: 1010–1017.

13 Edvinsson L, Cervos-Navarro J, Larsson L I, Owman C, Ronnberg A

L. Regional distribution of mast cells containing histamine, dopa-

mine, or 5-hydroxytryptamine in the mammalian brain. Neurology

1977: 27: 873–883.

14 Kastengren Fro ¨ berg G, Lindberg R, Ritter M, Nordlind K. Expres-

sion of serotonin and its 5-HT1A receptor in canine cutaneous

mast cell tumors. Submitted.15 Lehtosalo J I, Uusitalo H, Laakso J, Palkama A, Ha ¨ rko ¨ nen M. Bio-

chemical and immunohistochemical determination of 5-hydroxy-

tryptamine located in mast cells in the trigeminal ganglion of the

rat and guinea pig. Histochemistry 1984: 80: 219–223.

16 Zochodne D W, Theriault M, Sharkey K A, Cheng C, Sutherland

G. Peptides and neuromas: calcitonin gene-related peptide, sub-

stance P, and mast cells in a mechanosensitive human sural neu-

roma. Muscle Nerve 1997: 20: 875–880.

17 Lefebvre H, Compagnon P, Contesse V et al. Production and

metabolism of serotonin (5-HT) by the human adrenal cortex:

paracrine stimulation of aldosterone secretion by 5-HT. J Clin

Endocrinol Metab 2001: 86: 5001–5007.

18 Kushnir-Sukhov N M, Brown J M, Wu Y, Kirshenbaum A, Metcalfe

D D. Human mast cells are capable of serotonin synthesis and

release. J Allergy Clin Immunol 2007: 119: 498–499.19 Kova cs P, Hernadi I, Wilhelm M. Mast cells modulate maintained

neuronal activity in the thalamus in vivo. J Neuroimmunol 2006:

171: 1–7.

20 Slominski A, Pisarchik A, Semak I et al. Serotoninergic and mel-

atoninergic systems are fully expressed in human skin. FASEB J

2002: 16: 896–898.

21 Sakowski S A, Geddes T J, Thomas D M, Levi E, Hatfield J S, Kuhn

D M. Differential tissue distribution of tryptophan hydroxylase iso-

forms 1 and 2 as revealed with monospecific antibodies. Brain Res

2006: 1085: 11–18.

22 Johansson O, Liu P Y, Bondesson L et al. A serotonin-like immuno-

reactivity is present in human cutaneous melanocytes. J Invest

Dermatol 1998: 111: 1010–1014.

23 Gillbro J M, Marles L K, Hibberts N A, Schallreuter K U. Autocrine

catecholamine biosynthesis and the beta-adrenoceptor signalpromote pigmentation in human epidermal melanocytes. J Invest

Dermatol 2004: 123: 346–353.

24 Schallreuter K U, Schulz-Douglas V, Bunz A, Beazley W, Korner C.

Pteridines in the control of pigmentation. J Invest Dermatol 1997:

109: 31–35.

25 Slominski A, Semak I, Pisarchik A, Sweatman T, Szczesniewski A,

Wortsman J. Conversion of l-tryptophan to serotonin and

melatonin in human melanoma cells. FEBS Lett 2002: 511: 102–

106.

Nordlind et al.

ª 2007 The Authors




26 Slominski A, Pisarchik A, Semak I, Swetaman T, Szczesniewski A,

Wortsman J. Serotoninergic system in hamster skin. J Invest Der-

matol 2002: 119: 934–942.

27 Slominski A, Pisarchik A, Semak I et al. Characterization of the

serotoninergic system in the C57BL ⁄ 6 mouse skin. Eur J Biochem

2003: 270: 3335–3344.

28 Gu X F, Azmitia E C. Integrative transporter-mediated release from

cytoplasmic and vesicular 5-hydroxytryptamine stores in cultured

neurons. Eur J Pharmacol 1993: 235: 51–57.29 Callaway J, Storvik M, Halonen P, Hakko H, Ra ¨ sa ¨ nen P, Tiihonen J.

Seasonal variations in (3H) citalopram platelet binding between

healthy controls and violent offenders in Finland. Hum Psychophar-

macol 2005: 20: 467–472.

30 Lesch K P, Gutknecht L. Pharmacogenetics of the serotonin trans-

porter. Prog Neuropsychopharmacol Biol Psychiatry 2005: 29:

1062–1073.

31 Wendland J R, Martin B J, Kruse M R, Lesch K -P, Murphy D L.

Simultaneous genotyping of four functional loci of human

SLC6A4, with a reappraisal of 5-HTTLPR and rs25531. Mol Psychi-

atry 2006: 11: 224–226.

32 Kaiser R, Muller-Oerlinghausen B, Filler D et al. Correlation

between serotonin uptake in human blood platelets with the

44-bp polymorphism and the 17-bp variable number of tandem

repeat of the serotonin transporter. Am J Med Genet 2002: 114:323–328.

33 Berger U V, Gu X F, Azmitia E C. The substituted amphetamines

3,4-methylenedioxy-methamphetamine, methamphetamine, p-

chloroamphetamine and fenfluramine induce 5-hydroxytryptamine

release via a common mechanism blocked by fluoxetine and

cocaine. Eur J Pharmacol 1992: 215: 153–160.

34 Battaglino R, Fu J, Spate U et al. Serotonin regulates osteoclast dif-

ferentiation through its transporter. J Bone Miner Res 2004: 19:

1420–1431.

35 Turetta L, Donella-Deana A, Folda A, Bulato C, Deana R. Charac-

terisation of the serotonin efflux induced by cytosolic Ca2+ and

Na+ concentration increase in human platelets. Cell Physiol Bio-

chem 2004: 14: 377–386.

36 He L, Tuckett R P, English K B. 5-HT2 and 3 receptor antagonists

suppress the response of rat type I slowly adapting mechanorecep-tor: an in vitro study. Brain Res 2003: 969: 230–236.

37 Tachibana T, Endoh M, Fujiwara N, Nawa T. Receptors and trans-

porter for serotonin in Merkel cell-nerve endings in the rat sinus

hair follicle. An immunohistochemical study. Arch Histol Cytol

2005: 68: 19–28.

38 Hansson S R, Hoffman B J. Transient expression of a functional

serotonin transporter in Merkel cells during late gestation and early

postnatal rat development. Exp Brain Res 2000: 130: 401–409.

39 Peroutka S J. Receptor ‘families’ for 5-hydroxytryptamine. J Cardio-

vasc Pharmacol 1990: 16 (Suppl. 3): S8–S14.

40 Hoyer D, Hannon J P, Martin G R. Molecular, pharmacological and

functional diversity of 5-HT receptors. Pharmacol Biochem Behav

2002: 71: 533–554.

41 Bockaert J, Claeysen S, Be camel C, Dumuis A, Marin P. Neuronal

5-HT metabotropic receptors: fine-tuning of their structure, signal-ing, and roles in synaptic modulation. Cell Tissue Res 2006: 326:

553–572.

42 Levine A A, Guan Z, Barco A, Xu S, Kandel E R, Schwartz J H.

CREB-binding protein controls response to cocaine by acetylating

histones at the fosB promoter in the mouse striatum. Proc Natl

Acad Sci USA 2005: 102: 19186–19191.

43 Ashkenazy-Shahar M, Beitner R. Serotonin decreases cytoskeletal

and cytosolic glycolytic enzymes and the levels of ATP and glucose

1,6-biphosphate in skin, which is prevented by the calmodulin

antagonists thioridazine and clotrimazole. Biochem Mol Med

1997: 60: 187–193.

44 Wolf R, Lewerenz V, Buchau A S, Walz M, Ruzicka T. Human

S100A15 splice variants are differentially expressed in inflamma-

tory skin diseases and regulated through Th1 cytokines and

calcium. Exp Dermatol 2007: 16: 685–691.

45 Emerit M B, Riad M, Hamon M. Trophic effects of neurotransmit-

ters during brain maturation. Biol Neonate 1992: 62: 193–201.

46 Whitaker-Azmitia P M, Murphy R B, Azmitia E C. Stimulation ofastroglial 5-HT1A receptors releases the serotonergic growth fac-

tor, protein S-100, and alters astroglial morphology. Brain Res

1990: 528: 155–158.

47 Wilson C C, Faber K M, Haring J H. Serotonin regulates synaptic

connections in the dentate molecular layer of adult rats via

5-HT1a receptors: evidence for a glial mechanism. Brain Res 1998:

782: 235–239.

48 Deng D R, Djalali S, Holtje M et al. Embryonic and postnatal devel-

opment of the serotonergic raphe system and its target regions in

5-HT1A receptor deletion or overexpressing mouse mutants. Neu-

roscience 2007: 147: 388–402.

49 Azmitia E C, Dolan K, Whitaker-Azmitia P M. S-100b but not NGF,

EGF, insulin or calmodulin is a CNS serotonergic growth factor.

Brain Res 1990: 516: 354–356.

50 Fricker A D, Rios C, Devi L A, Gomes I. Serotonin receptor activa-tion leads to neurite outgrowth and neuronal survival. Mol Brain

Res 2005: 138: 228–235.

51 Druse M J, Tajuddin N F, Gillespie R A, Le P. Effects of ethanol

and the serotonin(1A) agonist ipsapirone on the expression of the

serotonin(1A) receptor and several antiapoptotic proteins in fetal

rhombencephalic neurons. Brain Res 2006: 1092: 79–86.

52 Adayev T, Ray I, Sondhi R, Sobocki T, Banerjee P. The G protein-

coupled 5-HT1A receptor causes suppression of caspase-3 through

MAPK and protein kinase Ca. Biochim Biophys Acta 2003: 1640:

85–96.

53 Abdouh M, Albert P R, Drobetsky E, Filep J G, Kouassi E. 5-HT1A-

mediated promotion of mitogen-activated T and B cell survival and

proliferation is associated with increased translocation of NF-kap-

pabeta to the nucleus. Brain Behav Immun 2004: 18: 24–34.

54 Sibug R M, Compaan J C, Meijer O C, Van der Gugten J, OlivierB, De Kloet E R. Flesinoxan treatment reduces 5-HT1A receptor

mRNA in the dentate gyrus independently of high plasma cortico-

sterone levels. Eur J Pharmacol 1998: 353: 207–214.

55 Huang J, Azmitia E C. Homologous regulation of 5-HT1A receptor

mRNA in adult rat hippocampal dentate gyrus. Neurosci Lett

1999: 270: 5–8.

56 Subhash M N, Srinivas B N, Vinod K Y, Jagadeesh S. Modulation

of 5-HT1A receptor mediated response by fluoxetine in rat brain.

J Neural Transm 2000: 107: 377–387.

57 Go ¨ oz M, Go ¨ oz P, Luttrell L M, Raymond J R. 5-HT2A receptor

induces ERK phosphorylation and proliferation through ADAM-17

tumor necrosis factor-alpha-converting enzyme (TACE) activation

and heparin-bound epidermal growth factor-like growth factor

(HB-EGF) shedding in mesangial cells. J Biol Chem 2006: 28:

21004–21012.58 Lundeberg L, El-Nour H, Mohabbati S, Morales M, Azmitia E,

Nordlind K. Expression of serotonin receptors in allergic contact

eczematous human skin. Arch Dermatol Res 2002: 294: 393–398.

59 Slominski A, Pisarchik A, Zbytek B, Tobin D J, Kauser S, Wortsman

J. Functional activity of serotoninergic and melatoninergic systems

expressed in the skin. J Cell Physiol 2003: 196: 144–153.

60 Schrocksnadel K, Wirleitner B, Winkler C, Fuchs D. Monitoring

tryptophan metabolism in chronic immune activation. Clin Chim

Acta 2006: 364: 82–90.


ª 2007 The Authors


309



61 Capuron L, Ravaud A, Neveu P J, Miller A H, Maes M, Dantzer R.

Association between decreased serum tryptophan concentrations

and depressive symptoms in cancer patients undergoing cytokine

therapy. Mol Psychiatry 2002: 7: 468–473.

62 Zhu C B, Blakely R D, Hewlett W A. The proinflammatory cyto-

kines interleukin-1 beta and tumor necrosis factor-alpha activate

serotonin transporters. Neuropsychopharmacol 2006: 31: 2121–

2131.

63 Hassanain M, Bhatt S, Zalcman S, Siegel A. Potentiating role ofinterleukin-1b (IL-1 b) and IL-1 b type 1 receptors in the medial

hypothalamus in defensive rage behavior in the cat. Brain Res

2005: 1048: 1–11.

64 El-Nour H, Boman A, Lundeberg L, Abramowski D, Holst M, Nord-

lind K. The expression and functional significance of the serotoner-

gic2C receptor in murine contact allergy. Exp Dermatol 2007: 16:

644–650.

65 Mamounas L A, Altar C A, Blue M E, Kaplan D R, Tessarollo L,

Lyons W E. BDNF promotes the regenerative sprouting, but not

survival, of injured serotonergic axons in the adult rat brain. J Neu-

rosci 2000: 20: 771–782.

66 Tobias C A, Shumsky J S, Shibata M et al. Delayed grafting of

BDNF and NT-3 producing fibroblasts into the injured spinal cord

stimulates sprouting, partially rescues axotomized red nucleus neu-

rons from loss and atrophy, and provides limited regeneration. ExpNeurol 2003: 184: 97–113.

67 Neumeister A, Yuan P, Young TA et al. Effects of tryptophan

depletion on serum levels of brain-derived neurotrophic factor in

unmedicated patients with remitted depression and healthy sub-

jects. Am J Psychiatry 2005: 162: 805–807.

68 Kawamoto K, Aoki J, Tanaka A et al. Nerve growth factor acti-

vates mast cells through the collaborative interaction with lyso-

phosphatidylserine expressed on the membrane surface of

activated platelets. J Immunol 2002: 168: 6412–6419.

69 Metz M, Botchkarev V A, Botchkareva N V et al. Neurotrophin-3

regulates mast cell functions in neonatal mouse skin. Exp Dermatol

2004: 13: 273–281.

70 Goldstein D S, Kopin I J. Evolution of concepts of stress. Stress

2007: 10: 109–120.

71 Azmitia E C, McEwen B S. Corticosterone regulation of tryptophanhydroxylase in midbrain of the rat. Science 1969: 166: 1274–

1276.

72 Abumaria N, Rygula R, Havemann-Reinecke U et al. Identification

of genes regulated by chronic social stress in the rat dorsal raphe

nucleus. Cell Mol Neurobiol 2006: 26: 145–162.

73 Azmitia E C, Liao B, Chen Y S. Increase of tryptophan hydroxylase

enzyme protein by dexamethasone in adrenalectomized rat mid-

brain. J Neurosci 1993: 13: 5041–5055.

74 Mitani H, Shirayama Y, Yamada T, Kawahara R. Plasma levels of

homovanillic acid, 5-hydroxyindoleacetic acid and cortisol, and

serotonin turnover in depressed patients. Prog Neuropsychophar-

macol Biol Psychiatry 2006: 30: 531–534.

75 Ou X M, Storring J M, Kushwaha N, Albert P R. Heterodimeriza-

tion of mineralocorticoid and glucocorticoid receptors at a novel

negative response element of the 5-HT1A receptor gene. J BiolChem 2001: 276: 14299–14307.

76 Aioi A, Okuda M, Matsui M, Tonogaito H, Hamada K. Effect of

high population density environment on skin barrier function in

mice. J Dermatol Sci 2001: 25: 189–197.

77 Roberts J E. Light and immunomodulation. Ann NY Acad Sci

2000: 917: 435–445.

78 Slominski A, Tobin D J, Shibahara S, Wortsman J. Melanin pigmen-

tation in mammalian skin and its hormonal regulation. Physiol Rev

2004: 84: 1155–1228.

79 McEwan M, Parsons P G. Inhibition of melanization in human mel-

anoma cells by a serotonin uptake inhibitor. J Invest Dermatol

1987: 89: 82–86.

80 Kojima M, Oguro K, Sawabe K et al. Rapid turnover of tryptophan

hydroxylase is driven by proteasomes in RBL2H3 cells, a serotonin

producing mast cell line. J Biochem 2000: 127: 121–127.

81 Slominski A, Pisarchik A, Wortsman J. Expression of genes coding

melatonin and serotonin receptors in rodent skin. Biochim Biophys

Acta 2004: 1680: 67–70.82 Slominski A, Wortsman J, Plonka P M, Schallreuter K U, Paus R,

Tobin D J. Hair follicle pigmentation. J Invest Dermatol 2005: 124:

13–21.

83 Maurer M, Opitz M, Henz B M et al. The mast cell products hista-

mine and serotonin stimulate and TNF-alpha inhibits the prolifera-

tion of murine epidermal keratinocytes in situ. J Dermatol Sci

1997: 16: 79–84.

84 Slominski A, Pruski D. Melatonin inhibits proliferation and melano-

genesis in rodent melanoma cells. Exp Cell Res 1993: 206: 189–

194.

85 Semak I, Korik E, Naumova M, Wortsman J, Slominski A. Sero-

tonin metabolism in rat skin: characterization by liquid chroma-

tography-mass spectrometry. Arch Biochem Biophys 2004: 421:

61–66.

86 Slominski A, Baker J, Rosano T G et al. Metabolism of serotonin toN-acetylserotonin, melatonin, and 5-methoxytryptamine in hamster

skin culture. J Biol Chem 1996: 271: 12281–12286.

87 Gaudet S J, Slominski A, Etminan M, Pruski D, Paus R, Namboodiri

M A. Identification and characterization of two isozymic forms of

arylamine N-acetyltransferase in Syrian hamster skin. J Invest

Dermatol 1993: 101: 660–665.

88 Kobayashi H, Kromminga A, Dunlop T W et al. A role of melato-

nin in neuroectodermal–mesodermal interactions: the hair follicle

synthesizes melatonin and expresses functional melatonin recep-

tors. FASEB J 2005: 19: 1710–1712.

89 Slominski A, Fischer T W, Zmijewski M A et al. On the role of

melatonin in skin physiology and pathology. Endocrine 2005: 27:

137–148.

90 Lundeberg L, Liang Y, Sundstrom E et al. Serotonin in human

allergic contact dermatis: an immunohistochemical and high-per-formance liquid chromatographic study. Arch Dermatol Res 1999:

291: 269–274.

91 El-Nour H, Lundeberg L, Boman A et al. Study of innervation, sen-

sory neuropeptides, and serotonin in murine contact allergic skin.

Immunopharmacol Immunotoxicol 2005: 27: 67–76.

92 Huang J, Li G, Xiang J, Yin D, Chi R. Immunohistochemical

study of serotonin in lesions of psoriasis. Int J Dermatol 2004:

43: 408–411.

93 Huang J, Li G, Xiang J, Yin D, Chi R. Immunohistochemical study

of serotonin in lesions of chronic eczema. Int J Dermatol 2004:

43: 723–726.

94 El-Nour H, Lundeberg L, Abdel-Magid N, Lonne-Rahm S -B, Azmi-

tia E C, Nordlind K. Serotonergic mechanisms in human allergic

contact dermatitis. Acta Derm Venereol (Stockh) 2007: 87: 390–

396.95 Nordlind K, Thorslund K, Lonne-Rahm S et al. Expression of sero-

tonergic receptors in psoriatic skin. Arch Dermatol Res 2006: 298:

99–106.

96 Lonne-Rahm S B, Rickberg H, El-Nour H, Marin P, Azmitia E C,

Nordlind K. Neuroimmune mechanisms in patients with atopic der-

matitis during chronic stress. J Eur Acad Dermatol (in press).

97 Schroder J M, Reich K, Kabashima K et al. Who is really in control

of skin immunity under physiological circumstances – lymphocytes,

dendritic cells or keratinocytes? Exp Dermatol 2006: 15: 913–929.

Nordlind et al.

ª 2007 The Authors




98 Mo ¨ ssner R, Lesch K -P. Role of serotonin in the immune system

and in neuroimmune interactions. Brain Behav Immun 1998: 12:

249–271.

99 Geba G P, Ptak W, Anderson G M et al. Delayed-type hypersensitiv-

ity in mast cell-deficient mice. J Immunol 1996: 157: 557–565.

100 Boehme S A, Lio F M, Sikora L et al. Cutting edge: serotonin is a

chemotactic factor for eosinophils and functions additively with

eotaxin. J Immunol 2004: 173: 3599–3603.

101 Kushnir-Sukhov N M, Gilfillan A M, Coleman J W et al. 5-hydroxy-tryptamine induces mast cell adhesion and migration. J Immunol

2006: 177: 6422–6432.

102 Walterscheid J P, Nghiem D X, Kazimi N et al. Cis-urocanic acid, a

sunlight-induced immunosuppressive factor, activates immune sup-

pression via the 5-HT2A receptor. Proc Natl Acad Sci USA 2006:

103: 17420–17425.

103 Ullrich S E. Sunlight and skin cancer: lessons from the immune

system. Mol Carcinog 2007: 46: 629–633.

104 Woodward E A, Pre ˆ le C M, Finlay-Jones J J, Hart P H. The receptor

for cis-urocanic acid remains elusive. J Invest Dermatol 2006: 126:

1191–1193.

105 McAloon M H, Chandrasekar A, Lin Y -J, Hwang G C, Sharpe R J.

Buspirone inhibits contact hypersensitivity in the mouse. Int Arch

Allergy Appl Immunol 1995: 107: 437–438.

106 Hashizume H, Takigawa M. Anxiety in allergy and atopic dermati-tis. Curr Opin Allergy Immunol 2006: 6: 335–339.

107 Ameisen J C, Meade R, Askenase P W. A new interpretation of

the involvement of serotonin in delayed-type hypersensitivity. Sero-

tonin-2 receptor antagonists inhibit contact sensitivity by an effect

on T cells. J Immunol 1989: 142: 3171–3179.

108 Sharpe R J, Chandrasekar A, Arndt K A, Wang Z S, Galli S J. Inhi-

bition of cutaneous hypersensitivity in the mouse with systemic or

topical spiperone: topical application of. spiperone produces local

immunosuppression without inducing systemic neuroleptic effects.

J Invest Dermatol 1992: 99: 594–600.

109 Bondesson L, Nordlind K, Mutt V, Lide n S. Inhibitory effect of

vasoactive intestinal polypeptide and ketanserin on established

allergic contact dermatitis in man. Acta Derm Venereol (Stockh)

1996: 76: 102–106.

110 Lundeberg L, Mutt V, Nordlind K. Inhibitory effect of vasoactiveintestinal peptide on the challenge phase of allergic contact dermati-

tis in humans. Acta Derm Venereol (Stockh) 1999: 7: 178–182.

111 Fjellner B, Hagermark O ¨ . Pruritus in polycythemia vera: treatment

with aspirin and possibility of platelet involvement. Acta Derm

Venereol (Stockh) 1979: 59: 505–512.

112 Weisshaar E, Ziethen B, Gollnick H. Can a serotonin type 3(5-HT3)

receptor antagonist reduce experimentally-induced itch. Inflamm

Res 1997: 46: 412–416.

113 Yamaguchi T, Nagasawa T, Satoh M, Kuraishi Y. Itch-associated

response induced by intradermal serotonin through 5-HT2 recep-

tors in mice. Neurosci Res 1999: 35: 77–83.

114 Greaves M W. Itch in systemic disease: therapeutic options. Der-

matol Ther 2005: 18: 323–327.

115 Carlton S M, Coggeshall R E. Immunohistochemical localization of5-HT2A receptors in peripheral sensory axons in rat glabrous skin.

Brain Res 1997: 763: 271–275.

116 Nojima H, Simons C T, Cuellar J M, Crastens M I, Moore J A,

Carstens E. Opioid modulation of scratching and spinal c-fos

expression evoked by intradermal serotonin. J Neurosci 2003: 23:

10784–10790.

117 Nojima H, Carstens E. 5-hydroxytryptamine (5-HT)2 receptor

involvement in acute 5-HT-evoked scratching but not in allergic

pruritus induced by dinitrofluorobenzene in rats. J Pharmacol Exp

Ther 2003: 306: 245–252.

118 Thomsen J S, Sonne M, Benfeldt E, Jensen S B, Serup J, Menne T.

Experimental itch in sodium lauryl sulphate-inflamed and normal

skin in humans: a randomized, double-blind, placebo-controlled

study of histamine and other inducers of itch. Br J Dermatol 2002:

146: 792–800.119 Takano N, Arai I, Hashimoto Y, Kurachi M. Evaluation of antipru-

ritic effects of several agents on scratching behavior by NC ⁄ Nga

mice. Eur J Pharmacol 2004: 495: 159–165.

120 Takubo M, Ueda Y, Yatsuzuka R, Jiang S, Fujii Y, Kamei C. Char-

acteristics of scratching behavior induced by some chemical media-

tors in hairless mice. J Pharmacol Sci 2006: 100: 285–288.

121 Krasowska D, Szymanek M, Schwartz R A, My¢sli¢nski W. Cutane-

ous effects of the most commonly used antidepressant medica-

tion, the selective serotonin reuptake inhibitors. J Am Acad

Dermatol 2007: 56: 848–853.

122 Hemlock C, Rosenthal J S, Winston A. Fluoxetine-induced psoriasis.

Ann Pharmacother 1992: 26: 211–212.

123 Osborne J M, Stafford L, Orr K G. Paroxitene-associated psoriasis.

Am J Psychiatry 2002: 159: 2113.

124 Mera M T, Perez B V, Ferna ndez R O, Iglesias J F. Hypersensitivityto paroxetine. Allergol Immunopathol (Madr) 2006: 34: 125–126.

125 Csaba G, Kova cs P, Pa llinger E . Hormones in the nucleus. Immuno-

logically demonstrable biogenic amines (serotonin, histamine) in

the nucleus of rat peritoneal mast cells. Life Sci 2006: 78: 1871–

1877.


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