Aim: Inoculation of wild-type (WT) mice with gram-positive bacterium Rhodococcus aurantiacus induces Th1-type granulomatous inflammation, in which interleukin (IL)-4 promotes the regression of granulomas during the late phase of infection. As IL-4 plays diverse roles in disease pathogenesis, we investigated the effect of IL-4 in the innate response to this bacterium infection by using IL-4-deficient mice.

Methods: After intravenous inoculation with 1 x 10⁸ CFU of bacteria, mouse survival rates, bacteria load in organs, local and systemic cytokine production, and morphological changes in liver were assessed. Following stimulation with heat-killed R. aurantiacus, cytokine production in mouse peritoneal macrophages was also examined.

Results: Compared to WT mice, IL-4-deficient mice showed the decreased production of TNF-α and IL-6 in the spleen, liver and blood during the early phase of infection, as well as low bacterial load in the liver and improvement in survival rate. IL-4-deficient mice also showed diminished IL-10 secretion in the spleen and blood, whereas their hepatic IL-10 levels were similar to those observed in WT mice, which were concomitant with the augmented hepatic IFN-γ production. Moreover, histological studies revealed reduction in hepatic granuloma formation at day 14 post-infection in IL-4-deficient mice. Upon stimulation with heat-killed R. aurantiacus, macrophages from IL-4-deficient mice showed lower expression of TNF-α, IL-6, and IL-10 at both the gene and protein levels than WT mouse cells.

Conclusions: These findings indicate that IL-4 deficit attenuates cytokine responses in macrophages but augments the IFN-γ response during the initial stage of R. aurantiacus infection, which together contribute to amelioration of mouse survival, rapid bacterial elimination in liver at the early phase, and reduction of granulomatous inflammation. We previously demonstrated that the early IFN-γ response to R. aurantiacus is induced in mouse natural killer cells. This study thus identifies the essential effect of IL-4 on regulating the activation and function of immunocompetent cells, including macrophages and natural killer cells, during the initial phase of systemic R. aurantiacus infection.