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A Regulatory Effect of the Balance between TNF- and IL-6 in the Granulomatous and Inflammatory Response to Rhodococcus aurantiacus Infection in Mice¹

Department of Immunology and Microbiology, School of Medicine, Hokkaido University, Sapporo, Japan

After i.v. inoculation with Rhodococcus aurantiacus, wild-type (WT) mice develop nonnecrotic, epithelioid granulomas. Because a high level of TNF- is observed during the initial phase postinfection, we examined the extent to which TNF- contributes to granulomatous inflammation using TNF- gene-deficient (TNF-^–/–) mice. Despite a lack of R. aurantiacus proliferation, TNF-^–/– 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-^–/– mice. Pretreatment of TNF-^–/– mice with rTNF- failed to restore this granuloma formation but accelerated bacterial removal and cellular recruitment. This rTNF- administration also attenuated IL-6 production, resulting in increased survival rates of TNF-^–/– mice. Heat-killed R. aurantiacus induced in vitro enhanced mRNA expression and production of IL-6 in macrophages and DCs from TNF-^–/– mice when compared with WT controls, and treatment of TNF-^–/– mouse cells with rTNF- decreased the IL-6 secretion. Moreover, anti-TNF- or anti-IL-6 treatment increased IL-6 or TNF- production by WT mouse cells, respectively. These data suggest that the production of TNF- and IL-6 can be negatively regulated by each other. Administration of rIFN- to TNF-^–/– mice caused immature granulomas in livers, and treatment with both rTNF- and rIFN- led to the formation of mature granulomas. Overall, TNF- appears crucial for bacterial clearance, cellular recruitment, and granuloma formation. The balance between TNF- and IL-6 during the early phase of infection controls the development of the inflammatory response to R. aurantiacus infection.

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