Maturation of the mucosal immune system underlies colitis susceptibility in interleukin-10-deficient (IL-10−/−) mice

Abstract

Elevated mucosal IL-12/23p40 and IFN-gamma accompany early inflammation in IL-10-deficient (IL-10(-/-)) mice and then later decline while inflammation persists. This report addresses whether this cytokine profile reflects disease progression or inherent, age-related changes in mucosal immunity. IL-10(-/-) and wild-type (WT) mice were maintained in an ultrabarrier facility or transferred to conventional housing at 3, 12, or 30 weeks of age. Weight, stool changes, and histologic features were followed. Lamina propria mononuclear cells were cultured for cytokine analysis by ELISA. Ultrabarrier-housed IL-10(-/-) mice are statistically indistinguishable from WT mice by weight, disease activity index, and histologic inflammation. IL-10(-/-) mice but not WT, transferred at 3 weeks, develop colitis gradually, reaching a significant, sustained maximum by 15 weeks of age. Transfer at 12 weeks induces rapid disease onset in both strains, maximal at 15 weeks of age. Inflammation persists in IL-10(-/-), and WT recover. IL-10(-/-) and WT mice transferred at 30 weeks demonstrate transient diarrhea and weight loss but no chronic inflammation. Probiotics delay symptom onset only in the 12-week-old group. IFN-gamma production from ultrabarrier-housed IL-10(-/-) mice is elevated at 12 weeks of age, and older animals have decreased IFN-gamma and increased IL-4. IL-10 is important for suppressing inflammation after transfer at 3 weeks of age and limiting inflammation after transfer at 12 weeks but has little influence at 30 weeks of age. Colitis onset, progression, and response to probiotic therapy vary with immune system age, suggesting that a distinct, Th1-driven, age-dependent cytokine profile may contribute to increased colitis susceptibility in otherwise healthy mice.

Role of interleukin 10 in murine postoperative ileus

“…Animals used in this study were maintained in ultra-barrier housing until 2 months of age and then transferred to conventional housing, and used experimentally at between 2 and 3 months of age. As reported previously by others and seen here, histologically and molecularly animals within this time frame display no evidence of a basal increase in bowel inflammation 40. Interestingly, in addition to having no basal alterations in 96 inflammatory mediators, the initial 3 h molecular inflammatory responses in wild-type and IL10 –/– mice following surgery were remarkably similar, except only for an enhanced induction of IL1β mRNA, as determined by Taqman microfluidic technology.…”

“…It has been shown experimentally that B6.129P2-IL10tm1Cgn/J mice (IL10 –/– ) in conventional housing develop a sustained colitis between 8 and 10 weeks of age 37 40. Animals used in this study were maintained in ultra-barrier housing until 2 months of age and then transferred to conventional housing, and used experimentally at between 2 and 3 months of age.…”

SAMP1/YitFc mouse strain: A spontaneous model of Crohnʼs disease-like ileitis

“…Similar diversity between early and late cytokine responses has been shown in experimental and clinical IBD. When long‐term studies were performed in IL‐10 −/− colitic mice, a transition from early Th1 to late Th2 responses was found 90. Earlier studies in humans showed that different cytokines predominate in early as opposed to late CD 91.…”

Therapeutic effects of triptolide on interleukin-10 gene-deficient mice with colitis

“…Further studies indicated changes in overall immunologic patterns over time, including a shift from predominantly Th1 to Th2 responses as the inflammatory process matures in intestinal mucosa of CD [23][24][25]. According to previous studies, disease development in elder IL-10 −/− mice with severe colitis and IBD patients was characterized by a complex cytokine pattern, not only with high levels of IFN-γ and IL-12, but also with elevated IL-4 [23][24][25]. In our study, administration of triptolide reduced the production of IL-4 as well as of IFN-γ in colon mucosa.…”