IL-2-deficient mice raised under germfree conditions develop delayed mild focal intestinal inflammation

Abstract

Interleukin-2 (IL-2) amplifies immune stimuli and influences B cell differentiation. IL-2-deficient mice spontaneously develop intestinal inflammation if raised under specific pathogen-free (SPF) conditions. We quantitatively determined the aggressiveness and kinetics of gastrointestinal and hepatic inflammation in the presence or absence of viable bacteria in IL-2-deficient mice. Breeding colonies were maintained under SPF and germfree (GF) conditions. Intestinal tissues, serum, and mesenteric lymph nodes were obtained from mice at different ages for blind histological scoring, immunoglobulin measurements, mucosal T cell infiltration, and cytokine secretion. GF IL-2 −/− mice developed mild, focal, and nonlethal intestinal inflammation with delayed onset, whereas the more aggressive inflammation in SPF IL-2 −/− mice led to their death between 28 and 32 wk. Periportal hepatic inflammation was equal in the presence or absence of bacterial colonization. Intestinal immunoglobulin secretion decreased significantly by 13 wk of age in IL-2 −/− mice in both GF and SPF environments. In contrast to other genetically engineered rodents, IL-2 −/− mice develop mild focal gastrointestinal and active portal tract inflammation in the absence of viable bacteria.

Role of Toll-like receptors in gastrointestinal malignancies

“…Mice deficient in IL-2, IL-10, double knockouts for the T-cell receptor and p53 or tumor growth factor b1 and recombination activating gene 2 develop adenocarcinoma in the small and large intestine. In the absence of bacteria, these mouse models neither develop inflammation nor dysplasia or cancer (Sellon et al, 1998;Schultz et al, 1999;Kado et al, 2001;Engle et al, 2002). Given that H. hepaticus infection induces CAC in recombination activating gene 2-deficient mice, these data support the premise that innate immune responses to commensal bacteria are sufficient to induce inflammation-associated gastrointestinal carcinogenesis (Erdman et al, 2003).…”

NF-κB Is Required Within the Innate Immune System to Inhibit Microflora-Induced Colitis and Expression of IL-12 p40

“…Several reports have suggested that patients are improved by treatment with antibiotics (1,2). Recent data from mouse models demonstrate that experimental colitis is significantly ameliorated in mice raised in germfree condition (3)(4)(5)(6)(7). Furthermore, it has been shown that targeted introduction of proinflammatory microflora can induce colitis in several susceptible strains (8 -10).…”

The +1059G/C polymorphism in the C‐reactive protein (CRP) gene is associated with involvement of the terminal ileum and decreased serum CRP levels in patients with Crohn's disease

“…The evidence for a pathophysiological role of certain luminal bacteria strains in the pathogenesis of CD is supported by a number of animal models. [37][38][39][40][41] CRP itself binds with high avidity to bacteria. 2 Similar to the association of the +1059 G/C polymorphism with ileal disease location, we recently demonstrated that the 1007fs variant in the CARD15 gene encoding NOD2, which recognizes bacterial muramyl dipeptide, is a strong predictor for ileal disease.…”