A regulatory effect of the balance between TNF-alpha and IL-6 in the granulomatous and inflammatory response to Rhodococcus aurantiacus infection in mice.
After i.v. inoculation with Rhodococcus aurantiacus, wild-type (WT) mice develop nonnecrotic, epithelioid granulomas. Because a high level of TNF-alpha is observed during the initial phase postinfection, we examined the extent to which TNF-alpha contributes to granulomatous inflammation using TNF-alpha gene-deficient (TNF-alpha(-/-)) mice. Despite a lack of R. aurantiacus proliferation, TNF-alpha(-/-) mice displayed high mortality rates within 5 days postinfection, as well as a high level of IL-6 in their spleens. Histological examination showed an absence of granuloma formation in TNF-alpha(-/-) mice. Pretreatment of TNF-alpha(-/-) mice with rTNF-alpha failed to restore this granuloma formation but accelerated bacterial removal and cellular recruitment. This rTNF-alpha administration also attenuated IL-6 production, resulting in increased survival rates of TNF-alpha(-/-) mice. Heat-killed R. aurantiacus induced in vitro enhanced mRNA expression and production of IL-6 in macrophages and DCs from TNF-alpha(-/-) mice when compared with WT controls, and treatment of TNF-alpha(-/-) mouse cells with rTNF-alpha decreased the IL-6 secretion. Moreover, anti-TNF-alpha or anti-IL-6 treatment increased IL-6 or TNF-alpha production by WT mouse cells, respectively. These data suggest that the production of TNF-alpha and IL-6 can be negatively regulated by each other. Administration of rIFN-gamma to TNF-alpha(-/-) mice caused immature granulomas in livers, and treatment with both rTNF-alpha and rIFN-gamma led to the formation of mature granulomas. Overall, TNF-alpha appears crucial for bacterial clearance, cellular recruitment, and granuloma formation. The balance between TNF-alpha and IL-6 during the early phase of infection controls the development of the inflammatory response to R. aurantiacus infection.
Yimin
Department of Immunology and Microbiology, School of Medicine, Hokkaido University, Kita 15, Nishi 7, Kita-ku, Sapporo 060-8638, Japan. yimin@med.hokudai.ac.jp
Kohanawa
Masashi
M
D000193:Actinomycetales Infections / Q000235:genetics / Q000276:immunology* / Q000401:mortality; D000818:Animals; D002478:Cells, Cultured; D016207:Cytokines / Q000096:biosynthesis / Q000235:genetics / Q000378:metabolism; D015536:Down-Regulation / Q000235:genetics / Q000276:immunology; D005260:Female; D006099:Granuloma / Q000235:genetics / Q000276:immunology* / Q000382:microbiology* / Q000401:mortality; D007249:Inflammation / Q000235:genetics / Q000276:immunology / Q000382:microbiology / Q000401:mortality; D015850:Interleukin-6 / Q000096:biosynthesis / Q000502:physiology*; D007700:Kinetics; D008099:Liver / Q000276:immunology / Q000378:metabolism / Q000382:microbiology / Q000473:pathology; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D012333:RNA, Messenger / Q000096:biosynthesis; D012240:Rhodococcus / Q000254:growth & development / Q000276:immunology*; D013154:Spleen / Q000276:immunology / Q000378:metabolism / Q000382:microbiology / Q000473:pathology; D014409:Tumor Necrosis Factor-alpha / Q000172:deficiency / Q000235:genetics / Q000502:physiology*; D000093242:Interleukin-6 Inhibitors
D016207:Cytokines; D015850:Interleukin-6; D012333:RNA, Messenger; D014409:Tumor Necrosis Factor-alpha; D000093242:Interleukin-6 Inhibitors