Regulatory Effect of Interleukin-4 in the Innate Inflammatory Response to Rhodococcus aurantiacus Infection in Mice

Interleukin (IL)-4 promotes the regression of granulomas during the late phase of Rhodococcus aurantiacus infection. In this study, the contribution of IL-4 to the initial response against this bacterium was investigated using IL-4-deficient mice. Compared with wild-type (WT) mice, IL-4-deficient mice displayed remarkably lower tumor necrosis factor (TNF)-alpha and IL-6 secretion in the liver, spleen, and blood at the initial phase of infection, along with improved survival. IL-4-deficient mice also showed diminished IL-10 secretion in the spleen and blood; however, hepatic IL-10 levels were similar to those observed in WT animals, and were concomitant with augmented interferon (IFN)-gamma production and decreased bacterial burden in the liver at the early infection phase. Histological examination revealed reduced hepatic granuloma formation in infected IL-4-deficient mice. On challenge with heat-killed R. aurantiacus, IL-4-deficient mouse macrophages showed reduced expression of TNF-alpha, IL-6, and IL-10 at both the gene and protein levels compared with WT mouse cells. These findings indicate that during the initiation of R. aurantiacus-induced inflammation, IL-4 deficiency attenuates cytokine responses in macrophages, which contributes to amelioration in mouse survival and reduction of granulomatous inflammation, and augments a hepatic IFN-gamma response which transiently accelerates bacterial elimination.