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

Huynh T Hop,Hong H Chang,Lauren T Arayan,Alisha W B Reyes,Suk Kim,Wongi Min,Tran X N Huy,Hu J Lee,Man H Rhee

doi:10.3389/fcimb.2017.00437

Abstract

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.

Highlights

Brucella spp. are facultative intracellular Gram-negative bacteria that cause brucellosis in a variety of mammalian hosts including humans with more than 500,000 new cases annually (Hop et al, 2015)
This study is aimed to provide new evidences in the host-Brucella interaction by investigating the immune signaling pathways that are activated by pro-inflammatory cytokine tumor necrosis factor (TNF) during B. abortus infection in macrophages
The anti-inflammatory cytokine, interleukin 10 (IL-10) was most known to support the persistence of Brucella within phagocytes (Fernandes and Baldwin, 1995; Xavier et al, 2013); the increase of IL-10 in this context is suspected to be responsible for the enhanced number of bacteria

Summary

Introduction

Brucella spp. are facultative intracellular Gram-negative bacteria that cause brucellosis in a variety of mammalian hosts including humans with more than 500,000 new cases annually (Hop et al, 2015). Identification of host-bacterial interaction could be useful to design rational approaches for brucellosis elimination (Xavier et al, 2013). Pro-inflammatory cytokine tumor necrosis factor (TNF) is an important regulator of host responses to microbial challenges (Liew et al, 1990; Ziltener et al, 2016). This cytokine amplifies and coordinates pro-inflammatory signals that lead to the expression of effector molecules resulting in the modulation of the diverse aspects of innate immunity against infection.

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