title: A regulatory effect of the balance between TNF-alpha and IL-6 in the granulomatous and inflammatory response to Rhodococcus aurantiacus infection in mice.
abstract: 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.
authors.affiliation: 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
authors.lastname: Yimin
authors.forename: Masashi
authors.initials: M
authors.lastname: Kohanawa
mesh_terms: 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
chemical_list: D016207:Cytokines; D015850:Interleukin-6; D012333:RNA, Messenger; D014409:Tumor Necrosis Factor-alpha; D000093242:Interleukin-6 Inhibitors