Stat3 in resident macrophages as a repressor protein of inflammatory response.
Inflammation is counterbalanced by anti-inflammatory cytokines such as IL-10, in which Stat3 mediates the signaling pathway. In this study, we demonstrate that resident macrophages, but not other cell types, are important targets of IL-10 in a murine model of acute peritonitis. Injection of thioglycollate i.p. induced a considerable number of neutrophils and macrophages in the peritoneum, which was significantly augmented in mice with a cell-type specific disruption of the Stat3 gene in macrophages and neutrophils (LysMcre/Stat3flox/- mice). The augmented leukocyte infiltration was accompanied by increased peritoneal levels of TNF-alpha, MIP-2, KC chemokine (KC), and MCP-1/CCL2. Stat3 was tyrosine phosphorylated in peritoneal resident macrophages as well as infiltrating leukocytes in the littermate controls, suggesting that Stat3 in either or both of these cells might play a regulatory role in inflammation. The peritoneal levels of TNF-alpha, MIP-2, KC, and MCP-1 were similarly elevated in LysMcre/Stat3flox/- mice rendered leukopenic by cyclophosphamide treatment as compared with the controls. Adoptive transfer of resident macrophages from LysMcre/Stat3flox/- mice into the control littermates resulted in increases in the peritoneal level of TNF-alpha, MIP-2, KC, and MCP-1 after i.p. injection of thioglycollate. Under these conditions, control littermates harboring LysMcre/Stat3flox/- macrophages exhibited an augmented leukocyte infiltration relative to those received control macrophages. Taken together, these data provide evidence that resident macrophages, but not other cell types, play a regulatory role in inflammation through a Stat3 signaling pathway. Stat3 in resident macrophages appears to function as a repressor protein in this model of acute inflammation.
Matsukawa
Akihiro
A
Department of Pathology and Experimental Medicine, Graduate School of Medical Sciences, School of Medicine, Kumamoto University, Honjo, Kumamoto, Japan. matsu@kaiju.medic.kumamoto-u.ac.jp
Kudo
Shinji
S
Maeda
Takako
T
Numata
Kousuke
K
Watanabe
Hiroyuki
H
Takeda
Kiyoshi
K
Akira
Shizuo
S
Ito
Takaaki
T
D019264:Adoptive Transfer; D000818:Animals; D018925:Chemokines / Q000096:biosynthesis; D016207:Cytokines / Q000096:biosynthesis; D004268:DNA-Binding Proteins / Q000502:physiology*; D007249:Inflammation / Q000517:prevention & control*; D016753:Interleukin-10 / Q000502:physiology; D008264:Macrophages / Q000502:physiology*; D008297:Male; D051379:Mice; D016328:NF-kappa B / Q000378:metabolism; D020556:Neutrophil Infiltration; D009504:Neutrophils / Q000502:physiology; D050796:STAT3 Transcription Factor; D015534:Trans-Activators / Q000502:physiology*
D018925:Chemokines; D016207:Cytokines; D004268:DNA-Binding Proteins; D016328:NF-kappa B; D050796:STAT3 Transcription Factor; C494087:Stat3 protein, mouse; D015534:Trans-Activators; D016753:Interleukin-10