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