peripheral actions of the stress hormone corticotropin releasing hormone (crh): focus on its...
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Peripheral actions of the stress hormone
Corticotropin Releasing Hormone (CRH):
focus on its immunomodulatory effects
ACTH
Glucocorticoid
Hypothalamus
Adrenal cortex
Anterior pituitary
CRH
The Hypothalamic-Pituitary Adrenal (HPA) axis
VP+ +
-
-
Sites of CRH synthesis
BRAIN
IMMUNE SYSTEM
T-lymphocyte
PLACENTA
SPINAL CORD
GI TRACT
LUNG
CRH Receptors
CRH RECEPTOR 1 (CRHR1): Brain, anterior pituitary, immune system, GI tract, adrenal gland, skin
CRH RECEPTOR 2 (CRHR2): Brain, pituitary, immune system, GI tract, adrenal gland, heart, skin, skeletal muscle
CRH AND INFLAMMATION
INFLAMMATIONACTH
CRH
GC PERIPHERAL CRH
Dual effects of CRH on the immune/inflammatory response
* suppressive, by central CRH
*stimulatory, by peripheral CRH
Signaling pathways mediating the immunomodulatory effects of CRH
??
l
Co
ntr
ol
CR
H 1
0-7 M
Ctrl CRH Ctrl CRH
p50 p65
NF-B
n.s.
Ctrl
LPS 10
g/m
lCRH 1
0-7 M
com
petit
or
Mut
ant c
ompe
titor
CRH/hC
RH 10
-6 M
n.s.
NF-B
IB
CO
NT
RO
L
CR
H 1
5min
CR
H 3
0min
Concentration-dependent effects of CRH on MAPK activation in human leukocytes
p38 (5 min) p42/44 (5 min) JNK (30 min)
Con
trol
CR
H (1
0-9M
)C
RH
(10
-8M
)C
RH
(10
-7M
)
TN
F (1
0ng/
ml)
CR
H (1
0-6M
)
Con
trol
CR
H (1
0-9M
)C
RH
(10
-8M
)C
RH
(10
-7M
)
TN
F (1
0ng/
ml)
CR
H (1
0-6M
)
Con
trol
CR
H (1
0-9M
)C
RH
(10
-8M
)C
RH
(10
-7M
)
EG
F (1
0ng/
ml )
CR
H (1
0-6M
)
Is there an important physiological role
for peripheral CRH itself in the regulation
of the inflammatory process ?
The Crh-deficient animal model
Normal lifespanNormal weightNormal food intake
Blunted/absent circadianrhythmicity
Low basal corticosterone
Impaired ACTH and corticosterone responsesto multiple stressors
CRH
ACTH
GC
Muglia et al. Nature, 1995
Sources of peripheral CRH
ACTH
leukocytes
Nerve fibers?
CRHHypothalamus
Pituitary
Adrenals
Inflammatory sites
glucocorticoid
EPINEPHRINE CRH
INFLAMMATION
GLUCOCORTICOID
1 4 8 16 24 300
600
1200
1800
2400IL
-6 (
pg
/mL
)
Time (hr)
Crh+/+ turpentine
Crh-/- turpentine
CYTOKINE RESPONSE TO TURPENTINE
1 4 8 16 24 30 480
100
200
300
400
500
600
AC
TH
(p
g/m
L)
Time (hr)
*
*
Crh +/+ salineCrh+/+ turpentine Crh -/- salineCrh-/- turpentine
1 4 8 16 24 30 480
15
30
45
60
Co
rtic
ost
ero
ne
(ug
/dL
)Time (hr)
HORMONAL RESPONSES TO TURPENTINE
1 2 3 4 5
0.05
0.10
0.15
0.20
0.25
0.30
**
*
*
* #
* #
Fo
od
in
take
(g
r)/m
ou
se w
eig
ht
(gr)
Days following the injection
1 2 3 4 5 6
92
96
100
104
108 *
*
##
#
*
Bo
dy
wei
gh
t (%
of
con
tro
l)
Day following the injection
Crh +/+ salineCrh+/+ turpentine Crh -/- salineCrh-/- turpentine
METABOLIC RESPONSES TO TURPENTINE
SYSTEMIC INFLAMMATION:
Is there an important physiological role
for peripheral CRH itself on the regulation
of the inflammatory process, or its effects
are linked to its role in stimulating the
release of glucocorticoid ?
HPA axis response 1 hr after LPS or saline
*: P<0.05 between treatments in the same genotype $: P<0.05 between genotypes following the same treatment
0
150
300
450
600
750
900
AC
TH
(p
g/m
l)
0
20
40
60
80
Co
rtic
ost
ero
ne
(g
/dl)
*
$*
* *
Crh+/+
Saline
Crh-/-
SalineLPS LPS
Crh+/+
Saline
Crh-/-
SalineLPS LPS
0
100
200
300
350
AC
TH
(p
g/m
l)
0
10
20
30
40
50
60
Co
rtic
ost
ero
ne
(g
/dl)
HPA axis response 24 hr after LPS or saline
Crh+/+
Saline
Crh-/-
SalineLPS LPS
Crh+/+
Saline
Crh-/-
SalineLPS LPS
$
*
*
*
*
*: P<0.05 between treatments in the same genotype $: P<0.05 between genotypes following the same treatment
Effect of pre-treatment with antalarmin on the HPA axis response 24 hr after LPS
0
8
16
24
32
40
Co
rtic
ost
ero
ne
(g
/dl)
0
75
150
225
300
375
AC
TH
(p
g/m
l)
Vehicle+
LPS
Antalarmin+
LPS
Vehicle+
LPS
Antalarmin+
LPS
* n.s.
Glu
cose
(g
/dl)
1 24
50
100
150
200
250
50
100
150
200
Crh+/+
Crh-/-
Plasma glucose levels 1 and 24 hr after LPS or saline
Time (hr) following the injection
SalineLPS
Crh+/+ Crh-/-
0
2000
4000
6000
basal saline LPS basal saline LPS
Pg/
ml
P<0.01
P<0.01
Plasma epinephrine at basal levels, and 24 hours post-LPS or –saline injection
CRH
GC
Systemic Bacterial Inflammation
LEPTIN
ACTH
CYTOKINES
?
?
???
Decreased food intake / Body weight loss-cachexia
?
Plasma TNF 11/2, 4 hours and 24 hours post-LPS injection
0
5000
10000
15000
20000
25000
30000
11/2 hour
Crh+/+ Crh-/- Crh+/+ Crh-/-
Pg/
ml
Crh-/-Crh+/+
4 hours 24 hours
P<0.01
*
*
* : statistical significance of p<0.01 from TNF levels 4 and 24 hours post-LPS injection between animals of the same genotype
4 hour 24 hour
0
1000
2000
3000
4000
5000
Pg/
ml
Crh+/+ Crh-/- Crh+/+ Crh-/-
Plasma IL-6 4 hours and 24 hours post-LPS injection
CRH
GC
Systemic Bacterial Inflammation
LEPTIN
ACTH
CYTOKINES
?
?
TLRs???
Decreased food intake / Body weight loss-cachexia
?
Increased leptin levels have been reported to exert protective effects
during inflammation
CRH and inflammation-associated processes
• AngiogenesisCRH receptors are found in endothelial cells
CRH causes chemotaxis of endothelial cells in vitro
CRH induces NF-B DNA binding activity in human endothelial cells
• Wound healingCrh-/- mice show altered wound healing
HPA axis, LEPTIN, and LPS
LPS administration results in
* activation of the immune system manifested by increased plasma levels of proinflammatory cytokines, including TNF, IL-1 and IL-6,
*activation of the HPA axis, and * induction of the ob gene, most likely by the action of cytokines on adipocytes.
Plasma leptin 24 hr after LPS or saline
*: P<0.05 between treatments in the same genotype $: P<0.05 between genotypes following the same treatment
05101520253035
Lep
tin
(n
g/m
l)
$
*
*
Crh+/+
Saline
Crh-/-
SalineLPS LPS
25
0
5
10
15
20L
epti
n (
ng
/ml)
Effect of pre-treatment with antalarmin on leptin secretion 24 hrs after LPS
Vehicle+
LPS
Antalarmin+
LPS
*
* P=0.05
Responses of Crh-/- splenocytes to LPS
0
50
100
150
200
250
*
*
TN
F-
(p
g/m
l/m
illi
on o
f p
late
d c
ells
)
control
$
LPSLPS control
Crh+/+ Crh-/- Crh+/+ Crh-/-
TNF-
-actin
A B
0.0
2.5
5.0
7.5
10.0
IL-1
(p
g/m
l/m
illi
on o
f p
late
d c
ells
)
control LPS control LPS
Crh+/+ Crh-/-
* $
Crh+/+Crh-/-
IL-1
-actin
A B
Crh
HT
WTSPL
WT SPL+LPS
CRHKO
Regulation of systemic inflammation by CRH and glucocortioid
What are the target organs / cells?
Is there a role for CRH and/or glucocorticoid on theregulation of innate immunity?
What is the contribution of the above hormonesin the metabolic changes triggered by inflammation?
Immunomodulatory neuropeptides (*acting through GPCRs)
INFLAMMATIONINFECTION
ObesityDiabetesAtherosclerosisCNS disease
Appetite controlBody weight regulationCachexia of chronic diseases
Cytokines and Related peptides
Jie ZhaoLilian vanVlerkenChristina ChandrasMaria VenihakiJerome Gay
Joseph MajzoubChildren’s Hospital Endocrine Division, Boston
Harris PothoulakisEfi Kokkotou
Beth Israel Hospital, Boston
Yassemi KoutmaniDespina XanthakiChristina ChandrasMaria VenihakiDevelopmental Biology Section, Foundation for Biomedical Research, Academy of Athens (IIBEAA)
Reduced toxin A-associated histologic damage Reduced toxin A-associated histologic damage and inflammation in CRH deficient miceand inflammation in CRH deficient mice
Crh +/+
Crh - / -
+, ++ significantly different (p<0.05, 0.01) from WT toxin A treated mice
Epithelial damage Epithelial damage Congestion & edemaCongestion & edema PMNPMN
His
tolo
gic
scor
es
0.0
0.5
1.0
1.5
2.0
+
+ +
Toxin A modulation of plasma corticosterone Toxin A modulation of plasma corticosterone in CRH deficient micein CRH deficient mice
* significantly different (p<0.05,p<0.001) from their respective Crh +/+ counterparts (4 hours)
0
10
20
30
40
50
Crh +/+ Crh -/- Crh +/+ Crh -/-
Time 0 4 hours
**
pla
sma
cort
icos
tero
ne
(g/
dl) buffer
toxin A
0
20
40
60
80
100
120
140
Inte
stin
al f
lui d
sec
reti
o n (
mg /
cm)
Control
TxA
TxA + antalarmin
* significantly different (p<0.05) from controls ; ++ significantly different (p<0.01) from Tx A
*
+ ++ +
TxA + -helical CRH
CRH receptor antagonists reduce CRH receptor antagonists reduce toxin A-induced ileal fluid secretion toxin A-induced ileal fluid secretion
LEPTIN and HPA axis
Leptin, the product of the ob gene, interacts reciprocally with the hypothalamic-pituitary adrenal (HPA) axis:
Glucocorticoid, stimulates the expression of the ob gene in adipocytes.
Administration of leptin increases CRH and ACTH secretion, while it decreases glucocorticoid release in rodents.
0
0.5
1
1.5
2
2.5
3
3.5
lung thymus peritoneal leukocytes pituitary
mR
NA
exp
ress
ion
(d
ensi
omet
ric
un
its)
Crh+/+ saline
Crh+/+ LPS
Crh-/- saline
Crh-/- LPS
p<0.05
p<0.01
p<0.05
p<0.05
TLR4 expression in Crh+/+ and Crh-/- tissuesfollowing LPS or saline administration
LPS
LPS LBP
LPS
CYTOPLASM
TLR4 MD-2
MyD88
IRAK
TRAF6
JNK p38 ERK1
/2
M A P K
IKK/ß
NIK
IB P P
P NF-B
P P
IB
NUCLEUS
TRANSCRIPTION FACTORS
c-Jun c-Fos CREB Elk1
Transcription Transcription NF-B
P
CD14
80
85
90
95
100
105
110
d - 1 d0 24h 48htime
Wei
ght v
aria
tion
(%
of
d-1)
Crh+/+ controls
Crh+/+ TNBS
Crh-/- controls
Crh-/- TNBS
***
****
A
B
0
1
2
3
4
5
24h 48h
Foo
d in
take
(g) Crh+/+ controls
Crh+/+ TNBS
Crh-/- controls
Crh-/- TNBS
Total p38
Con
trol
TNFα
(10n
g/µl
)
CR
H (1
0-6 M
)
Con
trol
TNFα
(10n
g/µl
)
CR
H (1
0-6 M
)
Phospho-p38
CRH
CYTOPLASM
CRHR
JNK p38 ERK1
/2
M A P K
IKK/ß
NIK
IB P P
P NF-B
P P
IB
NUCLEUS
TRANSCRIPTION FACTORS
c-Jun c-Fos CREB Elk1
Transcription Transcription NF-B
P
G
?
?
CRH
intestine
CRHCRH
CRH
CRH
Inflammatory stimulus
CRH deficient
inflammation
CRH2CRH2
Inflammatorystimulus
CRH IBD?
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