Katakura Kyoko, Lee Jongdae, Rachmilewitz Daniel, Li Gloria, Eckmann Lars, Raz Eyal
Department of Medicine, UCSD, La Jolla, California 92093-0663, USA.
J Clin Invest. 2005 Mar;115(3):695-702. doi: 10.1172/JCI22996.
Experimental colitis is mediated by inflammatory or dysregulated immune responses to microbial factors of the gastrointestinal tract. In this study we observed that administration of Toll-like receptor 9 (TLR9) agonists suppressed the severity of experimental colitis in RAG1-/- but not in SCID mice. This differential responsiveness between phenotypically similar but genetically distinct animals was related to a partial blockade in TLR9 signaling and defective production of type I IFN (i.e., IFN-alpha/beta) in SCID mice upon TLR9 stimulation. The addition of neutralization antibodies against type I IFN abolished the antiinflammatory effects induced by TLR9 agonists, whereas the administration of recombinant IFN-beta mimicked the antiinflammatory effects induced by TLR9 agonists in this model. Furthermore, mice deficient in the IFN-alpha/beta receptor exhibited more severe colitis than wild-type mice did upon induction of experimental colitis. These results indicate that TLR9-triggered type I IFN has antiinflammatory functions in colitis. They also underscore the important protective role of type I IFN in intestinal homeostasis and suggest that strategies to modulate innate immunity may be of therapeutic value for the treatment of intestinal inflammatory conditions.
实验性结肠炎是由对胃肠道微生物因子的炎症性或失调的免疫反应介导的。在本研究中，我们观察到给予Toll样受体9（TLR9）激动剂可抑制RAG1-/-小鼠而非SCID小鼠的实验性结肠炎严重程度。表型相似但基因不同的动物之间这种不同的反应性与SCID小鼠中TLR9信号传导的部分阻断以及TLR9刺激后I型干扰素（即IFN-α/β）的产生缺陷有关。添加针对I型干扰素的中和抗体消除了TLR9激动剂诱导的抗炎作用，而在该模型中给予重组IFN-β模拟了TLR9激动剂诱导的抗炎作用。此外，在诱导实验性结肠炎时，缺乏IFN-α/β受体的小鼠比野生型小鼠表现出更严重的结肠炎。这些结果表明，TLR9触发的I型干扰素在结肠炎中具有抗炎功能。它们还强调了I型干扰素在肠道稳态中的重要保护作用，并表明调节先天免疫的策略可能对治疗肠道炎症性疾病具有治疗价值。
