IL-6 is known to play a crucial role in the pathogenesis of chronic intestinal
inflammation by modulating T cell functions. In this study, we investigated the role of gp130, the common signal transducer for all
IL-6 cytokines, in a murine model of acute T cell independent
colitis to better characterize the impact of gp130 on innate immune cells and the early stages of
inflammation. Experimental
colitis was induced by
dextran sulfate sodium treatment of mice with inducible systemic deletion of gp130 (MxCre/gp130(-/-)), macrophage/neutrophil-specific gp130-deficiency (LysCre/gp130(-/-)), or bone marrow chimeric mice and compared with wild-type controls (gp130(f/f)). Systemic deletion of gp130 (MxCre/gp130(-/-)) protected mice from severe
colitis and wasting and attenuated the mucosal inflammatory infiltrate as well as local
cytokine,
chemokine, and adhesion molecule expression. Experiments in newly generated macrophage/neutrophil-specific gp130-deleted animals (LysCre/gp130(-/-)) and gp130 bone marrow chimeric mice, revealed a dual mechanism of proinflammatory effects mediated by gp130. Leukocyte recruitment was impaired in gp130-deleted animals and gp130-deleted recipients of wild-type bone marrow, demonstrating a central role of gp130-dependent signals in nonmyeloid cells for directing leukocytes to sites of
inflammation, which was further confirmed in a model of sterile
peritonitis. In contrast, macrophage/neutrophil-specific gp130 deficiency delayed and attenuated the disease but only marginally affected the inflammatory infiltrate, indicating a defective activation of mucosal leukocytes. We provide evidence that
IL-6 cytokines acting via gp130 are required in the acute stages of intestinal
inflammation by modulating the dynamics of innate immune cell recruitment and activation.