title: Abnormally differentiated subsets of intestinal macrophage play a key role in Th1-dominant chronic colitis through excess production of IL-12 and IL-23 in response to bacteria.
abstract: Disorders in enteric bacteria recognition by intestinal macrophages (Mphi) 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 Mphi in intestinal inflammation by using an IL-10-deficient (IL-10-/-) mouse colitis model. GM-CSF-induced bone marrow-derived Mphi (GM-Mphi) and M-CSF-induced bone marrow-derived Mphi (M-Mphi) were generated from bone marrow CD11b+ cells. M-Mphi from IL-10-/- mice produced abnormally large amounts of IL-12 and IL-23 upon stimulation with heat-killed whole bacteria Ags, whereas M-Mphi 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-Mphi was not significantly different between WT and IL-10-/- mice. In ex vivo experiments, cytokine production ability of colonic lamina propria Mphi (CLPMphi) but not splenic Mphi from WT mice was similar to that of M-Mphi, and CLPMphi but not splenic Mphi from IL-10-/- mice also showed abnormal IL-12p70 hyperproduction upon stimulation with bacteria. Surprisingly, the abnormal IL-12p70 hyperproduction from M-Mphi from IL-10-/- mice was improved by IL-10 supplementation during the differentiation process. These results suggest that CLPMphi and M-Mphi act as anti-inflammatory Mphi and suppress excess inflammation induced by bacteria in WT mice. In IL-10-/- mice, however, such Mphi subsets differentiated into an abnormal phenotype under an IL-10-deficient environment, and bacteria recognition by abnormally differentiated subsets of intestinal Mphi may lead to Th1-dominant colitis via IL-12 and IL-23 hyperproduction. Our data provide new insights into the intestinal Mphi to gut flora relationship in the development of colitis in IL-10-/- mice.
authors.affiliation: Department of Internal Medicine, School of Medicine, Keio University, Japan.
authors.forename: Nobuhiko
authors.initials: N
authors.lastname: Kamada
authors.forename: Tadakazu
authors.initials: T
authors.lastname: Hisamatsu
authors.forename: Susumu
authors.initials: S
authors.lastname: Okamoto
authors.forename: Toshiro
authors.initials: T
authors.lastname: Sato
authors.forename: Katsuyoshi
authors.initials: K
authors.lastname: Matsuoka
authors.forename: Kumiko
authors.initials: K
authors.lastname: Arai
authors.forename: Takaaki
authors.initials: T
authors.lastname: Nakai
authors.forename: Akira
authors.initials: A
authors.lastname: Hasegawa
authors.forename: Nagamu
authors.initials: N
authors.lastname: Inoue
authors.forename: Noriaki
authors.initials: N
authors.lastname: Watanabe
authors.forename: Kiyoko S
authors.initials: KS
authors.lastname: Akagawa
authors.forename: Toshifumi
authors.initials: T
authors.lastname: Hibi
mesh_terms: D000818:Animals; D000942:Antigens, Bacterial / Q000008:administration & dosage; D002454:Cell Differentiation; D002908:Chronic Disease; D003092:Colitis / Q000276:immunology* / Q000473:pathology; D016753:Interleukin-10 / Q000008:administration & dosage / Q000172:deficiency / Q000235:genetics; D018664:Interleukin-12 / Q000096:biosynthesis*; D053759:Interleukin-23; D053760:Interleukin-23 Subunit p19; D007378:Interleukins / Q000096:biosynthesis*; D008264:Macrophages / Q000145:classification / Q000276:immunology* / Q000473:pathology; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D018417:Th1 Cells / Q000276:immunology*
chemical_list: D000942:Antigens, Bacterial; C508841:Il23a protein, mouse; D053759:Interleukin-23; D053760:Interleukin-23 Subunit p19; D007378:Interleukins; D016753:Interleukin-10; D018664:Interleukin-12