Up-regulation of granulomatous inflammation in interleukin-6 knockout mice infected with Rhodococcus aurantiacus.
After intravenous injection of Rhodococcus aurantiacus normal mice develop non-necrotic granulomas, the formation of which is dependent on endogenous interferon-gamma (IFN-gamma). In the early phase of R. aurantiacus infection a high level of endogenous interleukin-6 (IL-6) is detected in the spleen extracts, though its importance is unknown. Using IL-6 knockout (IL-6-/-) mice, we studied the role of IL-6 in granulomatous inflammation induced by R. aurantiacus. The size of granulomas generated in IL-6-/- mice was significantly larger than that of wild-type (IL-6+/+) mice at 2 weeks postinjection (p.i). Moreover, central necrosis of the granuloma was observed in IL-6-/- mice but not in IL-6+/+ controls. Titres of endogenous IFN-gamma and tumour necrosis factor-alpha (TNF-alpha) were markedly increased in the spleens and livers of IL-6-/- mice in comparison with IL-6+/+ mice at days 1 through 3 p.i. In vivo administration of either an anti-IFN-gamma monoclonal antibody (mAb) or anti-TNF-alpha mAb to IL-6-/- mice reduced the number and size of granulomas, and prevented formation of necrotic granulomas. In addition, the production of endogenous IFN-gamma and TNF-alpha in the early phase of R. aurantiacus infection by IL-6-/- mice was suppressed by treatment with recombinant IL-6 (rIL-6). This suppression of IFN-gamma and TNF-alpha production was followed by a reduction in the number and size of central necrotic granulomas at 2 weeks p.i. These findings suggest that overproduction of IFN-gamma and TNF-alpha induces central necrotic granuloma formation in IL-6-/- mice, and that IL-6 down-regulates granulomatous inflammation reaction in response to R. aurantiacus infection by modulating production of IFN-gamma and TNF-alpha.
Yimin
Department of Microbiology, School of Medicine, Hokkaido University, Sapporo, Japan. yimin@med.hokudai.ac.jp
Kohanawa
Masashi
M
Minagawa
Tomonori
T
D000193:Actinomycetales Infections / Q000276:immunology* / Q000473:pathology; D000818:Animals; D000911:Antibodies, Monoclonal / Q000276:immunology; D004797:Enzyme-Linked Immunosorbent Assay / Q000379:methods; D006099:Granuloma / Q000276:immunology* / Q000473:pathology; D007165:Immunosuppression Therapy; D007249:Inflammation / Q000276:immunology / Q000473:pathology; D007371:Interferon-gamma / Q000032:analysis / Q000276:immunology; D015850:Interleukin-6 / Q000032:analysis / Q000276:immunology*; D007700:Kinetics; D008099:Liver / Q000276:immunology / Q000473:pathology; D051379:Mice; D018345:Mice, Knockout; D009336:Necrosis; D012240:Rhodococcus / Q000254:growth & development / Q000276:immunology*; D013154:Spleen / Q000276:immunology; D014409:Tumor Necrosis Factor-alpha / Q000032:analysis / Q000276:immunology; D015854:Up-Regulation / Q000276:immunology
D000911:Antibodies, Monoclonal; D015850:Interleukin-6; D014409:Tumor Necrosis Factor-alpha; D007371:Interferon-gamma