Gastroenterology

Gastroenterology

Volume 128, Issue 3, March 2005, Pages 654-666
Gastroenterology

Basic-alimentary tract
Proinflammatory effects of TH2 cytokines in a murine model of chronic small intestinal inflammation

https://doi.org/10.1053/j.gastro.2004.11.053Get rights and content

Background & Aims: Strict TH1 polarization is believed to underlie the pathogenesis of intestinal inflammation in Crohn’s disease. In the present study we tested the hypothesis that TH2 cytokines also may participate in disease development in SAMP1/YitFc mice that spontaneously develop terminal ileitis with perianal manifestations. Methods: Cytokine messenger RNA (mRNA) expression was studied by real-time polymerase chain reaction (PCR). Lamina propria mononuclear cells (LPMCs) were purified and stimulated cytokine secretion was analyzed. Blockade of interferon (IFN)-γ or interleukin (IL)-4 was performed by using specific neutralizing monoclonal antibodies (MAbs). CD4+/IL-4-secreting lymphocytes were purified from SAMP1/YitFc mesenteric lymph nodes (MLNs) and their ability to induce ileitis was tested after transfer to SCID recipients. Results: Initiation of ileitis in SAMP1/YitFc mice was TH1-mediated because up-regulation of IFN-γ and tumor necrosis factor (TNF) preceded the histologic injury, whereas IFN-γ neutralization prevented the development of chronic inflammation (P < .005) by interfering with the expansion of lymphocytes. In contrast, the establishment of chronic ileitis coincided with significant increases in IL-5 (35×) and IL-13 (29×) mRNA expression (P < .005), as well as in TH2 cytokine secretion by lamina propria lymphocytes (P < .05 vs. AKR controls). IL-4 blockade diminished IFN-γ mRNA expression and significantly ameliorated the severity of established ileitis (P < .05) by decreasing the histologic indices for villous distortion and active inflammation. In addition, IL-4 augmented the in vitro IFN-γ secretion by lymphocytes, whereas IL-4-secreting CD4+ lymphocytes were sufficient for adoptively transferring ileitis to SCID recipients. Conclusions: Our results indicate that both TH1 and TH2 pathways mediate Crohn’s-like ileitis and suggest that combined TH1/TH2 manipulation may offer a therapeutic advantage for the treatment of Crohn’s disease.

Section snippets

Animals

SAMP1/YitFc mice were maintained under specific pathogen-free conditions at the Animal Facility of the University of Virginia. AKR and SCID (C3HSmn.C-Prkdcscid/J) mice were purchased from Jackson Laboratories (Bar Harbor, ME). All protocols were approved by the Animal Care and Use Committee of the University of Virginia.

Treatments

For IFN-γ neutralization, 3-week-old SAMP1/YitFc mice were treated weekly for 5 weeks with tail-vein injections of .5 mg of anti-mouse IFN-γ MAb (clone XMG-6, kindly provided by

Increased expression of TH2 cytokines in the terminal ileum of SAMP1/YitFc mice with chronic ileitis

To investigate the possible role of TH2 cytokines in the pathogenesis of chronic ileitis, we first performed quantitative mRNA analysis of cytokine gene expression in the terminal ileum of SAMP1/YitFc mice with long-standing inflammation (>30 weeks) in comparison with age-matched AKR controls and noninflamed SAMP1/YitFc cecal tissue. No significant differences in ileal IFN-γ or TNF expression between AKR and SAMP1/YitFc mice were observed in our study (data not shown). However, our results

Discussion

In the present study we report that both TH1- and TH2- mediated pathways contribute to the pathogenesis of ileitis in the SAMP1/YitFc mouse, a murine model of CD. We show that TH1 and TH2 cytokines participate in different stages of ileitis development and affect diverse components of the inflammatory response. We show that, during chronic ileitis, IFN-γ and IL-4 are not mutually exclusive but can act synergistically. Finally, we show that IL-4-producing Th lymphocytes are sufficient for the

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    Supported by US Public Health Service/National Institutes of Health grants DK-42191, DK-44540, DK-55812 (to F.C.), and the University of Virginia Digestive Health Research Center (1P30DK67629). G.B. is a recipient of a Research Fellowship Award from the Crohn’s and Colitis Foundation of America.

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