Inflammatory bowel disease (IBD) is clinically classified as ulcerative colitis (UC) and Crohn’s disease (CD). Although the etiology of IBD is very complicated, both genetic and environmental factors are essentially involved. It is generally accepted that IBD is caused by dysregulated hyperreactive immune responses. Specifically, while CD patients are characterized by increased production of Th1 cytokines, such as IFN-γ and TNFα, UC patients display increased levels of IL-4, a cytokine classically associated with Th2 response [1]. Due to a variety of types of inflammation in IBD patients, understanding the inflammatory processes is essential for designing effective strategies for IBD treatment as well as other autoimmune diseases.

In order to investigate the complex immune processes in the etiology and progression of IBD, several mouse models have been established, which reflect at least some of the aspect of human disease [2], [3]. These models include chemical administration models, gene knockout/transgenic models, T-cell transfer models, and infection models.

IL-10 is an immunomodulatory cytokine that downregulates/terminates inflammatory responses [4]. Spontaneous colitis has been observed in several cytokine gene knockouts such as IL-10 as well as IL-2 and TGFβ [2], [3]. Moreover, mutations in human IL-10 and IL-10 receptor genes induce a severe enterocolitis at earlier age [5]. Therefore, IL-10 is one of the most important factors for the homeostasis in the gastrointestinal tract.

IL-4 plays an essential role in promoting T cell growth and differentiation of Th2 cells, and acts as an anti-inflammatory and immunomodulatory factor through its suppression effect for the secretion of proinflammatory cytokines [6]. IL-13 is a cytokine with similar properties to IL-4 and these cytokines share IL-4 receptor alpha chain (IL-4Rα) as their receptor subunit [7]. Functional importance of IL-4/IL-13 signaling through IL-4Rα has been demonstrated in the mucosal sites. In intestinal helminth infection, the induced type 2 immune responses including IL-4 and IL-13, mediate host protection through enhanced tissue repair, the control of inflammation and worm expulsion [8]. On the other hand, IL-4/IL-13 have been reported to be involved in the pathogenesis of IBD. IL-4 plays a role not only for promoting Th2 immune responses but also Th1 responses, which involve the early induction and/or sustained production of IFNγ in infection and autoimmunity [9]. In IL-10-/- mice, IL-4 is required for the induction of spontaneous colitis [10], and IL-4 exacerbates disease severity in dextran sulphate sodium (DSS)-induced colitis [11]. IL-13 also plays either pathogenic or protective roles dependent of the different conditions [12], [13], suggesting the importance of types of inflammation for disease therapies.

During the establishment of BALB/c background IL-4Rα and IL-10 double knockout (IL-4Rα × IL-10 KO) mice by crossing IL-4Rα-/- mice and IL-10-/- mice, we frequently observed spontaneous rectal prolapse in their double KO mice. Their rectal prolapse was caused by the strong inflammation in their cecum and colon, and its incidence in IL-4Rα × IL-10 mice was much higher than that in their littermates and parental controls. In this paper, we investigated causes and pathologies of the spontaneous colitis in BALB/c IL-4Rα × IL-10 KO mice. We hope that these mice are potentially beneficial for clarifying causes and control of colitis and intestinal inflammation in patients as a more susceptible murine model.