Proinflammatory effects of T_H2 cytokines in a murine model of chronic small intestinal inflammation

Background & Aims: Strict T_H1 polarization is believed to underlie the pathogenesis of intestinal inflammation in Crohn’s disease. In the present study we tested the hypothesis that T_H2 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 T_H1-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 T_H2 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 T_H1 and T_H2 pathways mediate Crohn’s-like ileitis and suggest that combined T_H1/T_H2 manipulation may offer a therapeutic advantage for the treatment of Crohn’s disease.

Abbreviations used in this paper:  IFN, interferon , IL, interleukin , LPMC, lamina propria mononuclear cell , MAb, monoclonal antibody , MLN, mesenteric lymph node , PCR, polymerase chain reaction , TNF, tumor necrosis factor