The Key Role of c-Fos for Immune Regulation and Bacterial Dissemination in Brucella Infected Macrophage

Abstract

The cellular oncogene c-Fos (c-Fos) is a component of activator protein 1 (AP1), a master transcriptional regulator of cells. The suppression of c-Fos signaling by siRNA treatment resulted in significant induction of TLR4, which subsequently activates p38 and ERK1/2 mitogen-activated protein kinases (MAPKs) and enhances F-actin polymerization, leading to an increase in <i>B. abortus</i> phagocytosis. During <i>B. abortus</i> infection, c-Fos signaling is induced, which activates the downstream innate-immunity signaling cascade for bacterial clearance. The inhibition of c-Fos signaling led to increased production of interleukin 10 (IL-10), which partially suppressed lysosome-mediated killing, resulting in increased survival of <i>B. abortus</i> inside macrophages. We present evidence of the regulatory role played by the c-Fos pathway in proliferation during <i>B. abortus</i> infection; however, this was independent of the anti-<i>Brucella</i> effect of this pathway. Another finding is the essential contribution of c-Fos/TRAIL to infected-cell necrosis, which is a key event in bacterial dissemination. These data provide the mechanism via which c-Fos participates in host defense mechanisms against <i>Brucella</i> infection and in bacterial dissemination by macrophages.