Enhanced macrophage responsiveness to lipopolysaccharide and CD40 stimulation in a murine model of inflammatory bowel disease: IL-10-deficient mice.
OBJECTIVE
To elucidate the role of macrophages in the pathogenesis of inflammatory bowel disease, proinflammatory characteristics of macrophages were estimated in a murine model of spontaneous intestinal inflammation.


METHODS
Peritoneal macrophages from IL-10deficient mice were stimulated with lipopolysaccharide (LPS) or an anti-CD40 monoclonal antibody (mAb). Cytokine release was assessed by enzyme-linked immunosorbent assay. CD40 expression was examined by two-color flow cytometric analysis. Induction of suppressor of cytokine signaling 3 (SOCS3) mRNA was evaluated by real-time quantitative RT-PCR.


RESULTS
In the presence of LPS or anti-CD40 mAb, TNF-alpha and IL-12p70 release from macrophages of mutant mice was significantly higher than that from macrophages of wild-type mice. This may be due to the difference in IL-10 production by macrophages, since activated macrophages of wild-type mice produced IL-10 in amounts sufficient to suppress an increased release of cytokines from activated macrophages of mutant mice. LPS and CD40 stimulation induced significantly high level of SOCS3 expression in macrophages of mutant mice in comparison to those of wild-type mice.


CONCLUSIONS
Macrophages from a murine model of inflammatory bowel disease demonstrated enhanced responsiveness to immunological and bacterial stimuli. This suggests significant roles of macrophages in the pathogenesis of inflammatory bowel disease.
Takakura
R
R
Department of Internal Medicine and Molecular Science, Graduate School of Medicine, Osaka University, Suita, Japan.
Kiyohara
T
T
Murayama
Y
Y
Miyazaki
Y
Y
Miyoshi
Y
Y
Shinomura
Y
Y
Matsuzawa
Y
Y
D000818:Animals; D019013:CD40 Antigens / Q000276:immunology* / Q000378:metabolism; D016207:Cytokines / Q000096:biosynthesis; D004195:Disease Models, Animal; D005786:Gene Expression Regulation; D007249:Inflammation / Q000276:immunology; D015212:Inflammatory Bowel Diseases / Q000276:immunology* / Q000473:pathology*; D016753:Interleukin-10 / Q000096:biosynthesis / Q000172:deficiency* / Q000235:genetics / Q000378:metabolism; D008070:Lipopolysaccharides / Q000276:immunology*; D017737:Macrophages, Peritoneal / Q000276:immunology* / Q000378:metabolism; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D011506:Proteins / Q000235:genetics; D012097:Repressor Proteins; D020133:Reverse Transcriptase Polymerase Chain Reaction; D000071223:Suppressor of Cytokine Signaling 3 Protein; D050826:Suppressor of Cytokine Signaling Proteins; D014157:Transcription Factors
D019013:CD40 Antigens; D016207:Cytokines; D008070:Lipopolysaccharides; D011506:Proteins; D012097:Repressor Proteins; C491411:Socs3 protein, mouse; D000071223:Suppressor of Cytokine Signaling 3 Protein; D050826:Suppressor of Cytokine Signaling Proteins; D014157:Transcription Factors; D016753:Interleukin-10