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sT2044

Vagus Nerve Released Acetylcholine Can Inhibit Intestinal Inflammation viaCross Talk With Vasoactive Intestinal PeptideEsmerij P. van der Zanden, Cathy Cailotto, Laurens Nijhuis, Guy E. Boeckxstaens, Wouterde Jonge

BACKGROUND AND AIMS Vagus nerve activity attenuates NF-κB activation and productionof pro-inflammatory cytokines by macrophages. In Vitro studies have shown that this ismediated by the vagal neurotransmitter acetylcholine (ACh) via nAChR activation. However,it is unclear whether ACh is the sole mediator of the vagal anti-inflammatory potential. Inthe present study, we questioned whether vagus nerve activity may amplify its anti-inflammat-ory effect via co-release of the neuropeptide vasoactive intestinal peptide (VIP) that has beenshown to have significant immuno-modulatory properties. METHODS Immunohistochemicalstaining or detection for VIP protein was performed on transversal sections of intestinaltissue. Electrical vagal nerve stimulation (VNS) was performed using bipolar electrodes, afterwhich intestinal tissue was analyzed for expression of the VIP receptors VPAC1-2 usingQPCR and normalized to B2M levels. In Vitro, peritoneal mouse macrophages were pretreatedwith ACh and/or VIP for 30 min. ACh (10μM) was applied 30 minutes before VIP (10μM)incubation, followed by 3hrs LPS challenge (10ng/mL), and cytokine levels were determinedusing ELISA. RESULTS VIP-positive fibers were found throughout the plexus and laminapropria. VNS decreased the expression of VPAC2 transcript at the myenteric plexus (downto 4±1.2% of sham stimulation) but increased mucosal VPAC2 transcript (VPAC/B2M(%):0.6± 0.17 (SHAM) vs. 12.48 ± 2.6 (VNS)). Next, we assessed the potential of VIPand ACh to modulate macrophage activation In Vitro. VIP inhibited LPS-induced TNFproduction in a dose dependent fashion in RAW macrophages, down to 52.4+/-4.2% ofcontrol release. ACh pretreatment (30 min) attenuated LPS-induced TNF production downto 59±4.5% confirming previous studies. However, when ACh and VIP (at 10 uM) wereco-administered, LPS induced TNF production was decreased almost down to unstimulatedlevels (25±4.2% of LPS vehicle). CONCLUSION The vagal transmitters ACh and VIP inhibitLPS induced pro-inflammatory cytokine release in macrophages in a cumulative manner.Vagus nerve activity enhances VPAC receptor expression in the mucosa. Hence, VIP co-released after vagus nerve activity may amplify the vagal anti-inflammatory pathway inintestinal inflammation.

T2045

Neuroanatomical Evidence for Activation of Vagal Motor Neurons by IntestinalInflammation in a Model of Postoperative IleusCathy Cailotto, Jan van der Vliet, Sjoerd van Bree, Rene M. van den Wijngaard, Wouter J.de Jonge, Guy E. Boeckxstaens

BACKGROUND and AIM: Postoperative ileus (POI) is characterized by transient hypomotilityof the gastrointestinal tract following abdominal surgery. Recent studies indicated thatinflammation triggered by intestinal handling is the main underlying mechanism. Previously,we demonstrated that electrical stimulation of the vagus nerve suppresses intestinal inflamma-tion via nicotinic receptor activation leading to reduced release pro-inflammatory cytokinesby macrophages. Although this cholinergic anti-inflammatory pathway is proposed to bepart of the so-called vago-vagal “anti-inflammatory reflex”, no neuro-anatomical evidenceis available demonstrating the existence of this hard-wired neurocircuitry. Therefore, theexpression of c-fos, a marker for neuronal activation, was evaluated at different levels ofthis proposed neurocircuitry, in particular in the dorsal motor nucleus of the vagus nerve(DMV) in our POI model. METHODS: A retrograde neuronal tracer (Cholera toxin b, CTb)was injected into the small bowel to label vagal motor neurons in the DMV. After two weeksof recovery, mice underwent intestinal manipulation (IM) or laparatomy (L). 24 hrs aftersurgery, brain and intestinal tissue were collected for immunohistochemical staining of cFos/CTb and leukocytes, respectively. The number of c-fos positive cells was counted in thenucleus of the solitary tract (NTS), DMV and paraventricular nucleus (PVN) on a minimumof 10 sections. If inflammation triggers activation of the anti-inflammatory circuit, co-localization of cFos and CTb should be detected in the DMV. RESULTS: 24hrs post-surgery,the number of neutrophils in the intestinal muscularis was significantly higher after IMcompared to L (19 ± 7 vs 0 ± 0, mean ±SEM; p= 0,02). IM resulted in a significant increasein cFos positive neurons in the NTS (72 ± 13 vs 15 ± 2 (p= 0,002) and DMV (24 ± 3 vs9 ± 2; p= 0,001), but not in the PVN, compared to L. The percentage of c-fos positiveneurons labeled with CTb was significantly higher in IM (32%) compare to L (3%), indicatinginflammation-induced activation of vagal efferents innervating the small intestine. CONCLU-SION: Our data demonstrate that subtle intestinal inflammation triggers cFos expression inthe NTS and DMNV 24 hrs after surgery. We demonstrate c-Fos expression in a large subsetof the vagal motor neurons (32%) connected to the inflamed small intestine. Whether theother c-fos+ neurons innervate the spleen or other organs is currently investigated. Thesefindings for the first time provide neuro-anatomical evidence for the existence of the endogen-ous “anti-inflammatory reflex” and its activation during inflammation.

T2046

Colitis and Interleukin 17a Enhance Neurite Extension in Adult SympatheticNeurons That Innervate the GutSusan Chisholm, Simrin Nagpal, Alan Lomax

Inflammatory bowel diseases (IBD), such as ulcerative colitis and Crohn's disease, changethe structure and function of the innervation of the gut. They also result in local and systemicelevation of cytokine levels. We hypothesised that elevated circulating cytokines mediatesome of the effects of IBD on gut-projecting sympathetic neurons. Therefore, we examinedwhether dextran sulphate sodium-induced colitis or interleukin (IL)-17A, a cytokine stronglyassociated with IBD, affects the structure of the sympathetic innervation of the gastrointestinaltract. Neurons dissociated from mouse superior mesenteric ganglion (SMG) were plated onlaminin-coated coverslips and cultured in Dulbecco's modified eagle medium for up to 7days in the presence or absence of IL-17A (1 ng/mL). Neurons dissociated from mice withDSS-induced colitis exhibited significantly enhanced neurite extension compared to neurons

S-620AGA Abstracts

from uninflamed control mice. Treatment of SMG cultures from control mice with IL-17Acaused a significant increase in outgrowth and branching of neurites between 1 and 7 daysfollowing the addition of IL-17A to the culture medium. Neurite extension was associatedwith inhibition of voltage-gated Ca2+ current in SMG neurons and could be mimicked bythe N-type Ca2+ channel blocker ω-conotoxin GVIA (30 nM). These effects were notdependent on the presence of glia, as the glial toxin cytosine arabinoside (5 μM) did notinhibit neurite outgrowth in response to IL-17A. The I kappa kinase inhibitor SC-514 (20μM) blocked neurite outgrowth in response to IL-17A, suggesting a role for nuclear factorkappa B (NF-κB) signaling in the regulation of neurite outgrowth from SMG neurons.Interestingly, tumor necrosis factor-alpha (TNF-α; 20 ng/mL), which also activates NF-κBsignaling in SMG neurons, reduced neurite outgrowth from SMG neurons. These data arethe first evidence of a role for IL-17A in modulating the innervation of the gut and suggestthat NF-κB signalling is an important intracellular pathway underlying neuronal plasticityduring IBD.

T2047

Mast Cell Activation by Corticotropin Releasing Factor (CRF) in Guinea Pigand Human IntestineXiyu Wang, Guo-Du Wang, Yun Xia, Wei Ren, Dean J. Mikami, Bradley Needleman, W.S. Melvin, Jackie D. Wood

Background and Aims: Stress in animal models accelerates large intestinal transit and evokesa diarrheal state. Action of CRF at its receptors in the brain and within the colon itselfunderlie the effects of stress on motility and secretion (Stengel A, Taché Y. Annu Rev Physiol.2009; 71:219-39). We aimed to investigate CRF's role in degranulation of mast cells inguinea pig ileum and human jejunum preparations from fresh segments of jejunum discardedduring Roux-En-Y gastric bypass surgeries. Methods: Double staining immunohistochemistry,measurement of short-circuit current (Isc) in Ussing chambers, ELISA for detection ofhistamine release and intracellular electrophysiological recording in intestinal muscle werethe main methods. Results: Immunostaining found expression of the CRF1 receptor subtype(CRF-R1) colocalized with immunoreactivity for mast cell tryptase in more than 70% ofmucosal and submucosal mast cells in the guinea pig ileum and human jejunum preparations.Immunoreactivity for the CRF2 receptor subtype was found only occasionally in associationwith mast cells, smooth muscle and enterocytes. Bath application of 200nM CRF stimulatedrelease of histamine release from both guinea pig and human preparations. The CRF-R1receptor antagonist NBI27814 (10μM), but not the CRF-R2 antagonist astressin 2B (2μM),suppressed CRF-evoked histamine release in each of 4 guinea pig ileum and colon prepara-tions and each of 3 human preparations. Application of the mast cell secretagogue, compound48/80 (60μg/ml), evoked release of histamine from guinea pig and human preparations.The presence of NBI27814 had no effect on stimulation of histamine release by compound48/80 in either guinea pig or human intestine. Pre-incubation with the mast cell stabilizerdoxantrazole (30μM) abolished the stimulatory action of CRF or compound 48/80 onhistamine release for guinea pig and human preparations. Application of CRF (200-500 nM)in serosal compartment of the Ussing chambers evoked small increases in Isc for guinea pigcolon and human preparations. Application of CRF (200-500nM) while recording intracellul-arly in circular smooth muscle fibers increased the frequency of spontaneously occurringexcitatory and inhibitory junction potentials, which presumably reflected stimulation ofexcitatory and inhibitory musculomotor neurons. Application of NBI127814, but not astres-sin2 B, suppressed this action of CRF. Conclusion: The results suggest that CRF activationof enteric mast cells might have a significant role in stress-evoked alterations of intestinalfunction. Acknowledgment: Supported by NIH RO1 DK37238, RO1 DK06825 and KO8DK060468.

T2048

Anxiety Exaggerates the Immune Response to Bacterial Antigen Exposure inPatients With Functional Gastrointestinal DisordersBirgit Adam, Tobias Liebregts, Montri Gururatsakul, Nick Talley, Guido Gerken, GeraldHoltmann

Background: Transient infection and persisting immune activation are known to play a rolein the pathogenesis of functional gastrointestinal disorders (FGID) (Mearin et al. Gastroenter-ology 2005; Liebregts et al. Gastroenterology 2007). Although clinical observations suggestthat psychological disorders are important risk factors for the manifestation of post- infectiousFGID (Gwee et al. Lancet 1996), very little is known about the role of psychological co-morbidity for cellular immune activation in FGID. We hypothesized that the cellular immuneresponse is significantly modulated by the presence or absence of psychological co-morbidit-ies. We therefore aimed (1) to characterize peripheral blood mononuclear cell (PBMC)mediated cytokine production and (2) the cellular immune response to bacterial antigenstimulation in FGID patients with and without clinical significant anxiety or depression.Methods: A total of 93 consecutive patients with either irritable bowel syndrome (IBS)(n=45; A-IBS: 15, D-IBS: 18, C-IBS: 13) or functional dyspepsia (FD)(n=48) according to ROMEII criteria were enrolled. PBMC were isolated by density gradient centrifugation and culturedfor 24 hours in RPMI 1640 supplemented with 10% FCS. Basal and E. coli LPS (1ng/ml)stimulated cytokine production (TNF-α, IL-1β, IL-10) was measured by enzyme-linkedimmunosorbent assay (ELISA). Utilizing the Hospital Anxiety and Depression Scale (HADS)2 subscales of anxiety and depression were calculated. Responders who score ≥11 on eithersubscale were considered having a clinically relevant psychological disorder. Results: Majoranxiety was found in 23 patients (12IBS;11FD) and depression was found in 19 patients(9IBS;10FD). While baseline cytokine levels did not differ between FGID patients with orwithout anxiety, LPS stimulated TNF-α (1597.2±104.2pg/ml vs. 1044.2±63.0pg/ml;p<0.001), IL-1β (3005.7±227.9pg/ml vs. 1961.5±98.6pg/ml;p<0.001) and IL-10(1630.9±106.2pg/ml vs. 987.4±68.6pg/ml;p<0.001) levels were significantly higher in IBSpatients with concomitant anxiety. Similar results were found for patients with FD. LPS-induced IL-1β (2636.4±208.5pg/ml vs. 1639.5± 127.3pg/ml;p<0.001) and IL-10(1588.4±204pg/ml vs. 907.7±87.3pg/ml;p=0.01) levels were significantly higher in FDpatients with compared to patients without anxiety. No significant differences were observed

between FGID patients with and without depression. Conclusions: Anxiety, but not depres-sion predisposes for an exaggerated cellular immune response to bacterial antigen stimulation.This mechanism may help to explain the increased incidence of post-infectious FGID inpatients with pre-existing psychological disorders.

T2049

Hydrogen Sulfide Ameliorates Murine Experimental Colitis Through SpecificEffects on Diverse Classes of Infiltrating Immune CellsKimberly A. Zins, Tamas Ordog, Michael R. Bardsley, Gianrico Farrugia, Michael D.Levitt, Arne Slungaard, Joseph H. Szurszewski, David R. Linden

Background: Hydrogen sulfide (H2S) has both pro- and anti-inflammatory effects. Aim: Toquantify the effect of H2S on the immune cells in normal mouse colonic tissue and duringacute and chronic colitis. Methods: In a 3x2 designed experiment mice either remainednaïve or received an enema of TNBS 24h or 6d prior to tissue collection and either receivedNaHS injections (100 mmol/kg, daily, i.p.) or served as control for NaHS injection. Colonswere dissected into mucosal/submucosal and external muscle layers, separately digested tosingle cells, and stained with one of 5 different combinations of a total of 21 antibodies(7 per experiment) targeting standard cell surface lineage marker proteins. Non-immuneantibodies of matching isotypes coupled to the same fluorochromes were used as controls.50,000 cells in each sample were analyzed by multiparameter flow cytometry with gatingstrategies to identify 20 cell types. Data are presented as the mean±SEM proportion of totalcells and analyzed by two-way ANOVA with TNBS treatment and NaHS as independentvariables. Results: In the mucosa of mice naïve to TNBS, five days of NaHS treatmentincreased the proportion of myeloid dendritic cells and eosinophils from 0.08±0.03% and0.79±0.06% to 0.40±0.06% and 1.3±0.1%, respectively (N=3, P<0.05). In the externalmuscle layers of mice naïve to TNBS, NaHS treatment increased the proportion of CD19+B cells from 0.21±0.07% to 1.4±0.8% (N=4-6; P<0.05). NaHS treatment reduced the weightloss of TNBS-treated mice (85±2% vs 93±3% of basal weight, N=10-12; P<0.05) and alsothe proportion of CD45+ cells in the mucosa at the 6 d time point (17±2% vs. 12±2%, N=10-12; P<0.05) but not at 24 h. NaHS treatment reduced the proportion of mast cells (at24 h: 0.29±0.07% vs 0.08±0.04%, N=9; P<0.05; at 6 d: 0.23±0.07% vs 0.02±0.01%, N=6-10; P<0.05). The proportion of natural killer cells was reduced at the 6d time point(1.62±0.04% vs 0.5±0.2%, N=3; P<0.05). In the external muscle layers NaHS treatmentincreased the proportion of B cells and T cells and decreased the proportion of natural killercells and eosinophils at the 6d timepoint. Conclusion: H2S released from NaHS upregulatessome immune cell types in normal animals but is strongly anti-inflammatory in the TNBSmodel of murine colitis. The anti-inflammatory action of H2S is complex and involvesmultiple cell types in both the mucosa and the muscle layers. Supported by a grant fromthe Minnesota Partnership for Biotechnology and Medical Genomics, and NIH grantsDK76665, DK58185.

T2050

Immunophenotypic Characterization of the Cellular Infiltrate During MurineExperimental Colitis Using Multiparameter Flow CytometryKimberly A. Zins, Tamas Ordog, Michael R. Bardsley, Gianrico Farrugia, Joseph H.Szurszewski, David R. Linden

Background: Trinitrobenzene sulfonic acid (TNBS) is a common model of experimentalcolitis used to study plasticity in gut neuromuscular function. The immune cells present inthe muscle and mucosal layers during TNBS colitis are not known. Aim: Characterize theimmune cells present in mouse colonic tissue before and after TNBS administration. Methods:The colons of C57Bl/6 male mice (controls, 24h and 6d after TNBS) were dissected intomucosal/submucosal and external muscle layers, separately digested to single cells, andstained with one of 5 different combinations of 21 monoclonal antibodies (7 per experiment)targeting standard cell surface lineage marker proteins. Non-immune antibodies of matchingisotypes coupled to the same fluorochromes were used as controls. 50,000 cells in eachsample were analyzed by multiparameter flow cytometry with gating strategies to identify20 cell types. Data are presented as the mean±SEM proportion of total cells. Results: In themucosa, the frequency of neutrophils changed from 0.16±0.01% in controls to 12±4% and2.3±1.5% at 24h and 6d, respectively (P<0.01, ANOVA). Mast cells showed a similar pattern(control: 0.05±0.01%, 24h: 0.29±0.07%, 6d: 0.23±0.07%; P<0.01). Eosinophils, basophilsand natural killer cells were increased at 24h and further increased at 6d post-TNBS. Thefrequency of T cells and B cells, as well as naïve dendritic cells of myeloid origin, wasincreased only at the 6d time point. The proportions of other cell types including macrophageswere unchanged in the mucosa during the course of inflammation. In the external musclelayers, the frequency of neutrophils increased from 0.06±0.03% in control muscle to 23±7%at 24h and 5.02±0.03% at 6d (P<0.01, ANOVA). Natural killer cells, eosinophils andbasophils were increased at the 24h time point and further increased at 6d post-TNBS.Unlike in the mucosa, macrophages in the muscle were also increased at both time points.The proportion of T cells in the muscle layer was increased only at the 6d time point. Othercell types, including mast cells, dendritic cells and B cells were unchanged in the musclelayers during the course of inflammation. Conclusion: There was dynamic ongoing regulationof immune cell infiltration in both the mucosa and the muscularis of the colon duringTNBS-induced inflammation involving a large number of cell types. Multiparameter immuno-phenotyping is a promising tool to uncover the roles of specific immune cell types inneuromuscular dysfunctions in experimental colitis. Supported by a grant from the MinnesotaPartnership for Biotechnology and Medical Genomics, and NIH grants DK76665, DK58185.

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T2051

Genotoxic Effects of Inflammation on Cacna1c Gene in Colonic SmoothMuscle CellsKuicheon Choi, Sankar Mitra, Sushil K. Sarna

Background and aims: DNA damage/repair is ongoing in every cell of an organism. However,adverse environmental factors, such as inflammation and toxins, may alter the balancebetween DNA damage and repair, which predisposes specific genes to aberrant transcription.Methods: We investigated the DNA damage and repair mechanisms in relation to transcriptionof Cacna1C encoding Cav1.2 (L-type) calcium channels by inducing colonic inflammationwith 68 mg/kg intraluminal TNBS. Muscularis extrenae tissues were collected on days 1, 3,5, 7, 28 and 56 post-inflammation. Results: The mRNA of the pore-forming Cacna1Cdecreased significantly from day 1 to day 7 of inflammation: the peak suppression occurredon day 3 (46±10% of control, p<0.005). Methylation-specific PCR showed no change inthe methylation status of the Cacna1C promoter (-2910/+263) following inflammation.Therefore, we hypothesized that genotoxicity of its promoter sequence by inflammation maycontribute to the suppression of Cacna1C. Long-extension PCR (LX-PCR) showed that DNAintegrity of the Cacna1C promoter region on day-3 of inflammation decreased to 30 ± 9.5% (p<0.05) of that prior to inflammation; it recovered partially on day-7 post-inflammation(67 ± 11.6 %, p<0.05). By contrast, inflammation did not impair integrity of the housekeepingβ-actin gene. Global analysis of AP sites on DNA and immunohistochemistry for γ-H2AXon muscularis externa confirmed the occurrence of both base excision and double strandbreak DNA. TNBS challenge increased the expression of GADD45G, a marker for DNAdamage (420 ± 8 % on day-7). The expression of HMOX1, a marker for oxidative stress,increased by 784±10% on day-3 of inflammation, but it returned to basal level on day-7(180±30%). TNBS challenge suppressed the transcription factor Nrf2 (NF-E2 p45-relatedfactor 2) a and b in muscularis externa, which persisted for 56 days. The expression ofDNA- damage repair genes, such as MBD4, MPG, NTHL1, SOD1, LIG4, RAD52 and XRCC6,involved in base excision or strand break increased significantly (3- to 9- fold on day 7).Daily i.p. administration of 5mg/kg sulforaphane, an nrf activator, for 3 days before TNBSchallenge protected DNA integrity and suppression of Cacna1C . Conclusion: We concludethat oxidative stress during inflammation suppresses the expression of transcription factorNrf2 to facilitate DNA damage. Imbalance between DNA damage/ repair mechanisms contrib-utes to suppression of the pore-forming subunit Cacna1C, which suppresses smooth musclecontractility. The persistent suppression of Nrf2 may predispose selective genes to aberranttranscription in response to subsequent adverse stimuli.

T2052

Adoptive Transfer of Macrophage From Mice With Depression-Like BehaviorConfers Susceptibility to Colitis in Naive MiceJean-Eric Ghia, Patricia Blennerhassett, Waliul I. Khan, Stephen M. Collins

Aims: Inflammatory bowel diseases (IBDs) are idiopathic chronic relapsing intestinal inflam-matory conditions. While depression is common in IBD, its cellular basis is unknown. Theprimary aim of this study was to identify the cellular locus of susceptibility to colitis inmice with depression. Methods: Chronic colitis was established using 3 cycles of DSS inC57BL/6 mice. 7 days after the last cycle, depression was induced by reserprine(1μg/dayfor 14 days via an intra-cerebral-ventricular cannula) in healthy and vagotomized mice.Behavior was assessed by the tail suspension-test. Separate sets of mice were given theantidepressant desipramine (DMI, 15mg/kg, ip) starting two days after the surgery. Pro-inflammatory cytokine were evaluated in cultured peritoneal macrophages when stimulatedwith LPS (150 ng/ml). Naive M-CSF-deficient mice (op/op) were injected with 2.5x106 non-stimulated peritoneal macrophages from vagotomized, depressed mice (DM) treated or notwith DMI or sham mice. 5% DSS was administered to induce colitis in recipient mice.Disease severity, F4/80 staining, inflammation were evaluated clinically and by myeloperoxid-ase activity (MPO) in colonic tissue. C-reactive protein (CRP), IL-1β and IL-6 were determinedby ELISA. Results: Vagotomy reactivated inflammation in mice with quiescent colitis. Depres-sion reactivated colitis and this was prevented by DMI but only in mice with intact vagi.Macrophages isolated from vagotomized-mice or from DM showed a selective increase ofIL-1β and IL-6 (+126%, 425% and +84%, +360% respectively) release when stimulatedwith LPS, but this was not seen in macrophages isolated from DM-DMI-treated. This beneficialeffect was absent in vagotomized DM-DMI-treated. Op/op appeared less vulnerable to colitiscompared to wild-type mice; adoptive transfer of macrophages from non-DM to op/opincreased significantly the level of CRP +27%, MPO +28%, IL-1β +42% and IL-6 +31%.These parameters were significantly increased by 61%, 149%, 95%, 151% respectively whentransferred with macrophages issued from DM. Op/op mice that received macrophagesfrom DM-DMI treated showed a significant decrease of all parameters. The inflammatoryparameters were significantly increased when transferred with macrophages issued fromvagotomized-mice. Conclusion: The macrophage is the critical cell involved in the susceptibil-ity of depressed mice to colitis by virtue of its dysregulated cytokine secretion.These resultsprovide a basis for developing new approaches to the management of IBD patients with co-existing depression by rebalancing cytokine production by the cell.

T2053

Mechanisms Involved in the Immune Regulation of Intestinal PermeabilityRex Sun, Justin DeVito, Jennifer A. Stiltz, Thomas A. Wynn, Kathleen B. Madden, JosephF. Urban, Aiping Zhao, Terez Shea-Donohue

Introduction: Nematode infection upregulates IL-4 and IL-13 and induces a STAT 6 depend-ent increase in intestinal permeability. IL-4 is critical for the proliferation in mast cells,which release tryptase that binds to PAR-2. Activation of PAR-2 is linked to reduced barrierfunction in a number of pathologies. Of interest is that IL-13 also increases intestinalpermeability, but does not contribute to mastocytosis. The biological effects of IL-13 andIL-4 are considered to be overlapping as they are mediated through a shared receptorsubunit, the IL-4Rα chain, which can dimerize with the γc to bind IL-4 or the IL-13Rα1chain to bind IL-13. Aim: To determine the mechanisms of IL-4 versus IL-13 mediated

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