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* Department of Internal Medicine, School of Medicine, Keio University,
Department of Internal Medicine, Kitasato Institute Hospital, and
Department of Immunology, National Institute of Infectious Diseases, Tokyo, Japan
Disorders in enteric bacteria recognition by intestinal macrophages (M
) are strongly correlated with the pathogenesis of chronic colitis; however the precise mechanisms remain unclear. The aim of the current study was to elucidate the roles of M in intestinal inflammation by using an IL-10-deficient (IL-10–/–) mouse colitis model. GM-CSF-induced bone marrow-derived M (GM-M) and M-CSF-induced bone marrow-derived M (M-M) were generated from bone marrow CD11b+ cells. M-M from IL-10–/– mice produced abnormally large amounts of IL-12 and IL-23 upon stimulation with heat-killed whole bacteria Ags, whereas M-M from wild-type (WT) mice produced large amounts of IL-10 but not IL-12 or IL-23. In contrast, IL-12 production by GM-M was not significantly different between WT and IL-10–/– mice. In ex vivo experiments, cytokine production ability of colonic lamina propria M (CLPM) but not splenic M from WT mice was similar to that of M-M, and CLPM but not splenic M from IL-10–/– mice also showed abnormal IL-12p70 hyperproduction upon stimulation with bacteria. Surprisingly, the abnormal IL-12p70 hyperproduction from M-M from IL-10–/– mice was improved by IL-10 supplementation during the differentiation process. These results suggest that CLPM and M-M act as anti-inflammatory M and suppress excess inflammation induced by bacteria in WT mice. In IL-10–/– mice, however, such M subsets differentiated into an abnormal phenotype under an IL-10-deficient environment, and bacteria recognition by abnormally differentiated subsets of intestinal M may lead to Th1-dominant colitis via IL-12 and IL-23 hyperproduction. Our data provide new insights into the intestinal M to gut flora relationship in the development of colitis in IL-10–/– mice.
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