phospholipase a -activating protein-an important regulatory...
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Indi an Journal of Experimental Biology Vol. 40, February 2002, pp. 129-138
Review Article
Phospholipase A2-activating protein-An important regulatory molecule in modulating cyclooxygenase-2 and tumor necrosis factor production during
inflammation
Deborah A Ribardo, Johnny W Peterson & Ashok K Chopra*
Department of Microbiology and Immunology, University of Texas Medical Branch, Galveston TX 77555-1070, USA
Inflammation is a complex multifactorial process and a hallmark of many inflammatory diseases. Most of the tissue destruction that occurs in these di seases is the result of an aberrant or often uncontrolled immune response. Factors that play an important role in such diseases include pro- infl ammatory cytokines, complement, and eicosanoids. This review focuses on eicosanoids and their regulation via phospholipase A2-acti vating protein , which could be targeted as a new therapeutic tool to control inflammatory diseases.
Eicosanoids Chronic inflammatory diseases (e.g., rheumatoid
arthritis, asthma, atherosclerosis, inflammatory bowel disease) appear to involve a multitude of signaling pathways, resulting in activation of various cytokines, complement cascades, apoptotic proteins, and eicosanoids l.2. This review focuses primarily on eicosanoids, as these molecules themselves perform a range of diverse functions from immuno/physiolog ical modulation to cell signaling in gastrointestinal and reproductive tracts, as well as in neurological and respiratory functions 1.3. Most eicosanoids are formed from arachidonic acid (AA; Fig. 1), which is a 20 carbon , unsaturated fatty acid found in membrane phospholipids of cells. AA is liberated from phospholipid bilayers by phospholipases, of which there are many types4
• Once liberated, AA becomes the substrate for three primary enzymatic pathways [cyclooxygenase (COX), the lipoxygenase (LOX) and the epoxygenase]5. The COXs result in the production of prostaglandins (PGs), while LOXs are involved in leukotriene (LT) production. Epoxygenase pathway forms epoxyeicosatrieno ic acids (EpETrEs), which have been implicated in calcium mobili zati on and hypertension6
•7
• In add ition , AA can be directly converted into hydroxyeicosatetraenoic acids (HETEs) by nonenzymatic oxidation and have been implicated in s ignal transduction, proliferation and chemotax is8
.9
. PGs and L Ts, collectively designated as eicosanoids, have a profound impact on normal and inflammatory
*Corrcspondent author: Telephone: (409) 747-0578; Fax: (409) 747-6869 E-mail : achoprJ@ utJ1lb.cdu
processes, in conjunction with other signaling molecules such as cytokines and therefore have resulted in rigorous investigation of these molecules. Figure 1 depicts the formation of eicosanoids from membrane phospholipids of eUkaryotic cells with AA as the substrate utilized by different pathways.
Prostaglandins PGs are formed from the substrate AA by the cata
lytic action of several cyclooxygenase enzymes (Fig. I) . The first PG formed is PGG2, which is then converted to PGH2 by prostag landin hydroperoxidase. From thi s branch point of PGH2, most of the other
PGs are formed, namely PGF2a, PGD2 and PGE2 by endoperox ide reductase, endoperoxide 0 and E isomerases, respectively 10. PGE2 is particularly important, since it is a bronchodilator and vasodilator in lungs and stimulates adenylate cyclase with formation of cyclic adenosine monophosphate (cAMP), which stimulates intestinal chloride secretion during noninflammatory and inflammatory diarrhoeas!." . PG E2
also induces bone resorption and is thought to be a central component in rheumatoid arthritis and in uterine contractions I2
-15
. PGE2 has been shown to increase cytosolic PLA2 (cPLA 2) and cyclooxygenase-2 levels and thereby to amplify its own production , a well as to increase synthesis of some inflammatory cy tokines [e.g ., interleukins- l and 6 (IL-l and IL-6) and tumor
necrosis factor alpha (TNFa)], resulting in perpetuation of immune response I6
.17
. In addition, PGE2 levels are elevated in the mucosal tissue of patients with in flammatory bowel diseases [e.g., ulcerati ve colitis (UC) and Crohn's disease (CD)l. as compared to
7
130 INDIAN J EXP BIOL, FEBRUARY 2002
controls, and PGE2 has been shown to potentiate TNFa-induced fluid secretion from human colonic tissues I8-20_ Additional PGs, such as PGh which are derived from PGD2, are also important in inflammation, as they have been implicated in oxidative stress resulting in tissue injur/I.22_
Cyclooxygenases Once AA is liberated from cell membranes, it be
comes the substrate for cyclooxygenases or lipoxygenases to form prostaglandins and leukotrienes, respectively (Fig_ 1). There are two isoforms of cyclooxygenase, constitutive COX-l and inducible COX-2. COX-2-induced PG production has been implicated in inflammation, as elevated levels of this protein have been measured in synovial cells treated with inflammatory mediators from patients with rheumatoid arthritis and in gastric ulcer tissues 23-28. The expression of cox-2 gene appears to be highly regulated by a number of transcription factors, in particular by NF-
B 2729-32 I . . I d· . d d h I f K . . IlItla stu les pOInte towar s t e ro e <0
Eicosanoid Formation from Phospholipids
Phospholipids
[MMmim~ (PLAA~ ,~? ! \i. PLD
PLC PLA 2
DAG .... PA
l Arachidonic Acid (AA)
CYclooxygcrnasc tTl " -g Lipoxygcnasc (COX-I , COX-2) ~ (FLAP)
rIC
'" = I:ol til
Prostaglandins '" Leukotrienes
HETEs EpETrEs
Fig. I-Eicosanoid production cascade originating from phospholipids. [Production of eicosanoids begins with the liberation of arachidonic acid from membrane phospholipids by phospholipase A2 (PLA2), and phospholipases C and D (PLC, PLD). Arachidonic acid is converted to prostaglandins through the cyclooxygenase pathway utilizing cyclooxygenase-I and -2 (COX-lor COX-2) enzymes, to leukotrienes through the lipoxygenase pathway, and to epoxyeicosatrienoic acids (EpETrEs) through the epoxygenase
- pathway. Potential regulator of various phospholipases, phosphoripase A2-activating protein (PLAA). and S-lipoxygenase activating protein (FLAP) leading to leukotriene formation are also indicated. PA=phosphatidic acid. DAG=diacyl glycerol.)
wards the role of PG produced through COX-2, but not COX-I, during the inflammatory processes. However, recent studies have emerged indicating a healing role of PGE2 produced via COX-2 as the use of nonsteroidal, anti-inflammatory drugs (NSAlDS) often cause various untoward side effects on gastrointestinal mucosa33. Transgenic knockout mice with either of the cox genes being deleted have yi elded insight into the mechanisms of eicosanoid production23.34.35. Initial studies have indicated that the first phase of PGD2
production in mast cells of these knockout mice is dependent on COX-I, while the second phase is dependent on COX-2 3 (ref.36).
Phospholipases Phospholipase and eicosanoid production are inex
tricably linked through a pathway originating from AA, which is hydrolyzed from membrane phospholipids by secretory PLA2 (sPLA2) and cytosolic PLA2
(cPLA2) (Fig. 1)1. Among these phospholipases, sPLA2, a 14-kDa type IIa sPLA2, which hydrolyzes phospholipids from the sn-2 position, has been extensively studied. The sPLA2 requires millimolar amounts of calcium for activity and has been linked to many other inflammatory diseases, notably adult respiratory distress syndrome (ARDS)37, rheumatoid arthritis38, and asthma39-41. Recently, cPLA2 (85-110 kDa) has been characterized, and found to preferentially use glycero-phospholipids as a substrate and requires submicromolar amounts of calcium for activit/2. A third PLA2 is calcium independent (iPLA2) and is thought to be responsible for late-phase production of PGs when intracellular calcium level in cells is depleted43-45. Recent studies have indicated that iPLA2
plays an important role in golgi-to-encloplasmic reticulum retrograde membrane-trafficking events46 .
Several groups have reported that sPLA2 is the primary phospholipase involved in PG production in
II 47-5? C I h · . h target ce s -. onverse y, ot er InvestIgators ave suggested that cPLA2 is the predominant phospholipase involved in PG formation I6.29.45.53-57. Contribution of the other phospholipases (PLC and PLD) in PG production has not been as extensively studied58. It is plausible that various phospholipases may be involved in PG production, and the induction of a particular phospholipase is dependent on the cell type involved, the stimulus given, and the activation state of the cell before induction3.42.59-61.
PLA2 has been implicated in a number of inflammatory processes throughout the body. affecting the circulatory system (e.g., ARDS, acute lung injury), the skin and muscular systems (e.g., edema, acute
RIBAROO el 01. : PHOSPHOLIPASE ArACTIVATING PROTEIN 131
synovitis), gastrointestinal tract (e.g., IBO, peritonitis), and the immune system (e.g., chemotaxis, phagocytosis) (Fig. 2)37.62.69. PLA2 is also activated by a number of proinflammatory cytokines (e.g., IL-l, TNF) and by other mediators (e.g., lipopolysaccharide [LPS], and peptidoglycan), which are major constituents of gram-negative and gram-positive organisms. The activation of PLA2 by these mediators has been demonstrated in a number of studies both in tissue culture and in animal models and appears to be a highly regulated process39AOA9.59.70.7 1. Although in-
volvement of PLA2 has been demonstrated in a number of inflammatory diseases, the enzyme also plays an important role in normal cell physiology72. Figure 2 depicts the role of PLA2 in evoking different diseases in humans.
Melittin and phospholipase Aractivating protein (PLAA)
The importance of eicosanoid production (particularly that of PG) in inflammation has led to the search for regulators of this pathway. Two central targets for regulation have been the COXs (COX-l & COX-2) and the phospholipases33.73 . Although naturally occurring regulators are found for both, they are nonspecific and often cause unwanted side effects. This is typified by aspirin, a non-specific regulator of both COXs that can cause intestinal bleeding, indicating the relative importance for normal physiological functions of blocking all forms of PG production74. There are various phospholipases that can release AA for PG production, and elevated levels of PLA2 have been
Immune Chemotaxis
Adhesiveness
Lysosomal Enzyme Release Phagocytosis
Superoxide Generation
Bactericidal Activity
MuscularlSkeletaVSkin Hypexemia Edema
Acute synovitis
Synovial Hyperplasia
Microabscess Formation
CirculatorylRespiratory Acute Lung Injury
ARDS
Hypotension
Increased Vascular Permeability
Myocardial Depression
Pulmonary Hypertension
Gastrointestinal
Acute Pancreatitis
Peritonitis
Inflammatory Bowel Disease
Fig. 2-Major organ systems in which PLA2 has been implicated as an important factor in causing disease/inflammatory response. [PLA2 has been implicated as an important factor in causing many diseases. It is a central component of the inflammatory response including those in the circulatory/respiratory (AROS, myocardial depression), gastrointestinal (lBO, peritonitis), muscular/skeletal/skin (edema, microabscess formation) and immune systems (chemotaxis, phagocytosis)].
found in inflamed ti ssue of IBO patients, in synovial fluid of patients with arthritis and in blood of those with acute pacreatitis, AROS, bacterial peritonitis and septic shock37.66.67.7s. Therefore, it has been thought that regulation of COX-2 alone might reduce the detrimental effects of PG production , while not eliminating all of its beneficial properties via production from other phospholipases (e.g., PLC & PLO).
Melittin-Various venoms found in nature (e.g., snake & bee venom) have high levels of PLA2 enzyme, albeit of different types4. In bee venom, a peptide regulator of PLA2 is also present, which is thought to prevent activation of the enzyme until injected into its host76. This peptide, referred to as melittin, contains 26 amino acids (aa) and comprises 50% of the dry weight of bee venom. Melittin is a basic amphipathic polypeptide with a cluster of positively charged aa at its C-terminal end77 . Melittin also contains both linear and helical conformations, which enable it to insert into lipid bilayers78.79. It is highly hemolytic, causing lysis of red blood cells (RBCs) and may be one of the components responsible for allergic reactions to insect stings8o.82 . Melittin is widely thought to be an sPLA2 activator83.89; however it has been recently demonstrated melittin to be a noncompetitive inhibitor of PLA2 and an activator of PL076.89. Interestingly, downstream effects of melittin (e.g., eicosanoid and cytokine production) in eukaryotic cells, have not been thoroughly investigated so far90• Our laboratory has shown that synthetic melittin causes increase in the abundance of message for both TNFa and COX-2, as measured by Northern blot analysis, and an increase in TNFa antigen levels based on enzyme-linked immunosorbant assay91 .92 PGE2 levels were also increased in macrophages treated with melittin, and this effect was mediated by a variety of phospholipases (PLA2, PLC, PLO)90.
Several structure and function studies on melittin have revealed that the C-terminal end is predominantly responsible for its biological activit/3.9s . Likewise, the positively charged residues of melittin can interact with negatively charged groups on Lipid A (the toxic moiety of LPS), reducing melittin' s hemolytic activity and the pyrogenicity of Lipid A in rabbits96• Interestingly, we showed that melittin reduced PGE2 levels in LPS-stimulated macrophages by approximately 50%91. The exact mechanism by which melittin reduces PGE2 production in LPS-stimulated cells is currently unknown, but it has been postulated that melittin could prevent binding of LPS to its receptor, thereby interfering with the activation of
132 INDIAN J EXP BIOL, FEBRUARY 2002
signal transduction cascades that LPS would normally be ini tiati ng96• Based on these reports76,96, melittin would be expected to antagonize the effect of LPS on PLA2 activ ity and subsequent PGE2 production, hinting at another mechanism by which melittin reduces LPS induced PGE2 production.
Phospholipase Ar activaling protein (PLAA) Since melitt in seemed to be an important molecule for regu lating phospholipase ac tivity in insects and reptil es and cou ld increase PGE2 and expression of genes encoding TNFa and COX-2 in eukaryotic cells, a mammalian homologue was also thought to exist. Analysis of synovia l fluid from rheumatoid arthriti s patients indicated the presence of a protein wi th homology to melittin97.99. This protein was al so present in murine smooth muscle cells and bovine endothelial cell sloo.lol and was designated as phospholipase Ar activating protein (PLAP). Due to confusion between PLAP's acronym and placenta l alkaline phosphatase, phospholipase Aracti vating protein has recently been redesignated as PLAA91 . Cloning and subsequent purification of murine PLAA fro m a murine BC3H 1 cell line usi ng anti-melittin antibodies resulted in identification of a 28-kDa pOlypeptide lO2 . Injection of partially purified PLAA into rabbit joints caused acute inflammatory arthritis with increased synovial fluid and influx of polymorphonuclear cells (PMNs) and monocytes. Eicosanoid production was also increased in joints injected with PLAA in a dose-dependent fashion97 . Treatment of human neutrophils with 28 kDa PLAA increased neutrophil aggregation, degranulation, superoxide production and release of lysosomal enzymes I03,104. In addition to rheumatoid arthritis, the level of PLAA was shown to be increased by monosodium urate crystals, the etiological agent of goUt'°5, and in bronchial lavage fluid in asthmatics4o. Additional studies utilizing numerous proinflammatory cytokines (e.g., IL-1~ and TN Fa) indicated that these agents did indeed increase PLAA production in T cells and epithelial cellslo6.108. PLAA' s ability to increase the formation of proinflammatory cytokines, illustrated the cyclic relationship between cytokine formation and arachidonic acid metabolism. Initial increase in cytokine production elevates PLAA production, which would, in turn, upregu late cytokine
d . 109 I dd" . fI pro uctlOn . n a Itlon to prom ammatory cyto-kines, bacterial products such as LPS and cholera toxin (CT) were also found to increase expression of I 91,110 BI k' I ' b ' I p aa gene . oc mg p aa gene expressIOn y uti -
izing an antisense oligonucleotide reduced AA production in LPS- and CT-treated cell s9 1.99 , In our labo-
ratory, it has been shown that PLAA is not restricted to inflammatory conditions, Oxytocin. an important hormone required for stimu lation of uterine contractions during pregnancy, medi ates its effect via the production of PGE215, Oxytocin also caused an increase in expression of plaa gene in Chinese hamster ovary (CHO) cell s transfected wi th oxytocin receptor (unpubli shed data), In additi on, like LPS and CT, plaa anti sense oligonucleotide reduced PGE2 production in oxytoci n-treated cells, Subsequently, it was reported that PLAA regu lated the lower molecular weight type II sPLA2 but not the hi gher molecular weight cPLA287. Our studies showed rapid induction (withi n 30 min) of genes encodi ng PLAA in LPS-, TNFaand IL-J ~-stimu l ated macrophages91. The level of cPLA2 was also increased rapid ly (30-60 min), with a concomitant increase in PLA2 act ivity and PGE2 production91, The levels of sPLA2 and COX-2 were increased in LPS-stimulated macrophages at a later time point of 4-24 hr, suggesting their role in late PGE2
production and the role of cPLAz in early PGEz sy nthesis91 . Add itional studies using an ti sense plaa oligonucleotide revealed that it reduced expression of the gene encod ing cPLA2 indicating a direct role of PLAA in regulating cPLA291. Regulation of other phospholipases (e.g., PLC, PLD) by PLAA is currently unknown . These observations do not all ow the assumption that whenever PGs are increased, the expression of the plaa gene is increased as well. Studies with the cytotoxic enterotoxin (Act) of Aeromonas hydrophila, which leads to in testinal and nonintestinal infections, revealed that PG production could proceed independently of PLAA production, as Act did not cause increased expression of plaa gene, while still stimulating PG production in macrophages III,
We cloned and sequenced human plaa eDNA from a human monocytic cell line U937, which encoded an 82-kDa polypeptide, with 95 and 81 % conservation at the aa level with rat and murine PLAA, respectivel/9. The 28-kDa murine polypeptide originally described \o2 could have been a degradation product of PLAA99. It is noteworthy that rat and human PLAA had 738 aa residues, while murine PLAA contained 646 aa residues99, Analysis of the sequence of PLAA revealed that it contained 4 WD (Trp-Asp) repeats si milar to members of ~-transducin famjly of signaling molecules, three different protein kinase do-
. 11 2 d h mams ,an t us PLAA may act as an effector G-protein" 3, Whether PLAA would act as a signaling molecule or directly interact with PLA2 and other phospholipases to regulate their activity is not known,
RIBARDO et al.: PHOSPHOLIPASE A2-ACTIVATING PROTEIN 133
Both sPLA2 and PLAA have been implicated in a number of other cell fun cti ons, including golgi tubulation and retrograde traffi cking, peroxi somal motility in CHO cells , and calcium oscillations/amylase secretion in rat pancreatic acini 11 4-11 6. Our laboratory has
previously demonstrated PLAA antigen in inflamed colonic ti ssue from dextran sulfate sodium (OSS) treated mice ll7 . Mice fed OSS for 7 and 14 days exhibited significant increase in PLAA antigen levels, as determined by immunohistochemistry compared to untreated mice, with the majority of PLAA localized in monocytes and granulocytes. Likewise, Northern blot analysis of tissue from these mice revealed elevated levels of plaa mRNA compared to control mice ll7 . Biopsy specimens from patients with CO and UC also demonstrated increased PLAA levels compared to normal patient colonic tissues ll7 . However, it is not known whether PLAA plays any role in other types of inflammatory processes, but the possibility is worthy of further study. We believe PLAA to be a global regulatory protein involved in modulating phospholipase levels in various diseases. For example, serum and bronchoalveolar lavage fluid contain increased levels of PLA2 in AROS patients37.118. We
have shown that alveolar macrophages stimulated with LPS, TNFa and IL-l~ increased abundance of p/aa mRNA (unpublished results). Likewise, the serum level of PLA2 is elevated in patients with atherosclerosis68. 119. Compared to non-transgenic litter
mates, transgenic mice overexpressing the gene encoding PLA2 are prone to develop atherosclerosis when fed a high fat and high cholesterol diet69. In addition, we observed elevated levels of plaa mRNA in LPS-stimulated human endothelial cells , suggesting that PLAA has a role in modulating PLA2 levels in cardiovascular diseases (unpublished results) . Fluorescence in situ hybridization mapping has localized p/aa gene on human chromosome 9p21 , a region frequently deleted in various cancers 112. These data may suggest a possible tumor suppressor role for this gene as well.
Ability of plaa gene to be upregulated rapidly after induction, and its homology with numerous G protein ~-subunits, which regulate the activities of many cellular enzymes ll3 , prompted us to determine whether PLAA requires phosphorylation for its activity. Indeed, our data suggested that phosphorylation could be needed for PLANs function, as is the case with many other intermediate signaling molecules91 .
Since PLAA contains a region of homology (38-42% at the aa level) with melittin, we sYllthesi zed a PLAA peptide (aa residues 503-538) containing this region and determined whether the 36 aa PLAA synthetic peptide would increase the expression of genes encoding TNFa or COX-2. Synthetic PLAA peptide, like melittin, increased the expression of genes encoding both TNFa and COX-2 in macrophages92. Given that pattially puri
fied murine PLAA (28 kDa) also increased TN Fa and IL-l production in human monocytes, this region of PLAA having homology to melittin appears to be responsible for the activation of proinflammatory cytokine production 101.109. As PLAA's role was predominantly thought to be the regulation of PLA2, its effect on proinflammatory cytokine production and cox-2 gene expression was somewhat surprising. However, due to its similarity with a number of G-proteins lI3, PLAA could be directly increasing expression of these mediators, or more likely, acting as a signaling molecule to activate both PLA2 and downstream signaling molecules, which ultimately increase expression of genes encoding TNFa and COX-2. It is plausible that activation of PLA2 by Gp subunits could phosphorylate lipocortin, which removes an inhibitory constraint from PLA2, resulting in its activation l20. However, detailed biochemical mechanism(s) leading to PLA2 activation by PLAA needs further studies.
More detailed analysis of PLAA peptide revealed that C-terminal region of this peptide (aa 515-538) was predominantly involved in TNFa and COX-2 production in macrophages. The N-terminal region of PLAA peptide (aa 503-526) caused only modest increase in expression of genes encoding TNFa and COX-292 • Whether this residual effect of N-terminal peptide is the result of overlapping aa residues between N- and C-terminal peptides or whether aa residues outside this overlapping region are contributing to the biological effect of N-terminal PLAA peptide remains to be determined.
A model summarizing the recent advances in our studies on inflammatory cascade is depicted in Fig. 3. This figure outlines the various effects that inflammatory mediators, such as LPS, have on downstream signaling cascades. All of these signaling events culminate in the nucleus to regulate transcription of udditional inflammatory mediators, such as cytokines and enzymes involved in eicosanoid production. The production of eicosanoids is also outlined, with subsequent secretion into surrounding cells and tissues where they can act as a catalyst for additional recruitment of inflammatory cells and further tissue damage.
134 INDIAN J EXP BIOL, FEBRUARY 2002
CDl4
P,+AA G) <i)PLA 2, PLC, PLD?
PLW~~X_2 Kinases --+ Phospholipases !0
NF-KB @
PGs @
++-__ {TNF } IL-I
13 PGs ---'----
Fig. 3 - Activation of signaling cascades by LPS lead ing to in
nammation. I ( I) - Bi nding of LPS to macrophages via C D 14 and
Toll-like receptors. (2) - Activation of kinases (tyros ine, ser
ine/threonine, mi togen acti vated protein kinases) . (3) - Act iva ti on
of transcription fac tor NF-KB and translocation to the nucleus.
(4) - NF-kB lead ing to activation of genes encod ing proinnamma
tory cytokines (TNFu, IL- I ~) and COX-2 . (5) - Secreti on of
TNFu and IL- I ~ from cells lead ing to ti ssue damage.
(6) - Partic ipatory ro le of COX-2 in producing PGE2 from AA.
(7) - Rapid induc tion of PLAA afte r LPS stimul at ion of macro
phages. (8) - PLAA leading to ac tivation of various phospholi
pases. (9) - Phospholipases c leave phospho lipids from cell membranes re leasing AA, a substrate for PG production (step 10).
( IO)-Produc ti on of PGs. ( I I)- Binding o f released PLAA to
cells. ( 12) - Acti vation of phospholipases by PLAA leading to
release of AA . (13) - AA lead ing to production of PG E2 via COX
pathway.( 14) Activation of genes encoding TNFu and COX-2 by PLAA.]
Thus it appears that phospholipase Aractivating protein (PLAA) could be a target for the development of new therapeutic approaches to regulate phospholipases and subsequent PG production without the harmful side effects caused by currently used drugs. The ability of PLAA peptide analogs to downregulate PG production would limit the amount of inflammation and tissue destruction that occurs in patients with inflammatory diseases, and therefore, provide novel targets to control these di seases.
Acknowledgement The authors wish to express their gratitude to Mar
delle Susman for her editorial assistance. We thank AI Copeland from the Department of Internal Medicine, and M.S. Soloff and V. Chopra from the Department of Obsterics and Gynecology for their studies with oxytocin on CHO cells and with endothelial cells. D.A. Ribardo was supported by The James W . McLaughlin Fellowship Fund. Thi s work was supported by grants from the National Institutes of
Health , Crohn' s and Colitis Foundation of America, and The American Heart Association, USA.
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