Up-regulation of granulomatous inflammation in interleukin-6 knockout mice infected with Rhodococcus aurantiacus.

Abstract

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.