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

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 B. abortus phagocytosis. During B. abortus 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 B. abortus inside macrophages. We present evidence of the regulatory role played by the c-Fos pathway in proliferation during B. abortus infection; however, this was independent of the anti-Brucella 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 Brucella infection and in bacterial dissemination by macrophages

Activation of NF-kB-Mediated TNF-Induced Antimicrobial Immunity Is Required for the Efficient Brucella abortus Clearance in RAW 264.7 Cells

In this study, we explore the regulatory roles of pro-inflammatory cytokine tumor necrosis factor alpha (TNF) in the innate immunity of macrophages against B. abortus infection. We show that infection of macrophage with B. abortus induces marked expression and secretion of TNF which subsequently binds to TNF receptor 1 (TNFR-1) and activates a downstream signaling cascade of the innate immunity. Blocking of TNF signaling resulted in a notable increase of B. abortus survival which was associated with an increase of anti-inflammatory cytokine interleukin 10 (IL-10), a beneficial effector of Brucella survival, as well as remarkable decrease of reactive oxygen species (ROS) and nitric oxide (NO), antibrucella molecules. However, surprisingly, the interference of TNF did not show any influence on phagolysosome and cell death events. Furthermore, the transcriptional factor NF-kB was found to be a main mediator of TNF signaling when blocking of NF-kB pathway drastically suppressed the TNF-induced brucellacidal effect. Taken together, these findings clearly indicate that the immune cascade activated by TNF/TNFR-1 is required for the sufficient resistance to B. abortus survival in macrophages