S1724 P53 Deficiency is Protective Against Acute Intestinal Damage Through Increased Interleukin-6 Production in a Mouse Model of Acute Colitis

Abstract

in other genes that mediate innate immunity compared to, and/or impacted upon, the colitis that resulted from loss of TLR5. We hypothesized that acute neutralization of the antiinflammatory cytokine IL-10 might provide a relatively uniform means of revealing how alteration in innate immunity might predispose to development of immunologically-mediated colitis. Methods: A number of knockout mouse strains on the C57BL/6 background including mice deficient in TLR5 (from Drs. Akira and Flavell), TLR4, IPAF (cytosolic flagellin receptor) and various double-KO were bred from mice that had been embryonically rederived into mice purchased from Jackson labs (AKA “Jacksonized”). Such mice were treated weekly for 4 weeks with 1 mg/mouse of an IL-10 receptor neutralizing antibody; a protocol known to cause colitis in WT mice only if they had been previously colonized with Helicobacter. One week after the last injection of IL-10R mAb, mice were euthanized, colitis assayed and a variety of cytokines measured. Results: Anti-IL-10R mAb treatment led to severe intestinal inflammation in 2 independently generated strains of mice deficient in TLR5 but not in their WT littermates. Administration of IL-10R mAb did not cause colitis in mice lacking Ipaf or TLR4. Further, use of TLR4/5-DKO mice indicated the severe colitis in TLR5KO mice treated with IL-10R mAb did not require TLR4. The susceptibility of these mice to this colitis model did not correlate with presence of Helicobacter species, which was present in all strains tested. Conclusion: Regardless of whether they harbor microbiota that predisposes to spontaneous colitis, loss of TLR5 uniformly predisposes mice to colitis that results from loss of IL-10.