Proinflammatory effects of TH2 cytokines in a murine model of chronic small intestinal inflammation

Background & Aims: Strict T(H)1 polarization is believed to underlie the pathogenesis of intestinal inflammation in Crohn's disease. In the present study we tested the hypothesis that T(H)2 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 (LP-MCs) were purified and stimulated cytokine secretion was analyzed. Blockade of interferon (IFN)-gamma 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 T(H)1-mediated because up-regulation of IFN-gamma and tumor necrosis factor (TNF) preceded the histologic injury, whereas IFN-gamma 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 (35x) and IL-13 (29x) 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-gamma 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-gamma 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 T(H)1/T(H)2 manipulation may offer a therapeutic advantage for the treatment of Crohn's disease.