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Inhibiting TNF-α signaling does not attenuate induction of endotoxin tolerance

Authors Loosbroock C, Hunter K

Received 27 September 2014

Accepted for publication 20 October 2014

Published 3 December 2014 Volume 2014:7 Pages 159—167

DOI https://doi.org/10.2147/JIR.S75037

Checked for plagiarism Yes

Review by Single-blind

Peer reviewer comments 3

Editor who approved publication: Dr Ning Quan


Christopher Loosbroock, Kenneth W Hunter

Department of Microbiology and Immunology, University of Nevada School of Medicine, Reno, NV, USA

Abstract: Tumor necrosis factor-alpha (TNF-α) is a central mediator of inflammatory responses elicited by Toll-like receptor agonists, such as the Gram-negative bacterial outer membrane antigen lipopolysaccharide (LPS). TNF-α is responsible for altering vascular permeability and activating infiltrating inflammatory cells, such as monocytes and neutrophils. Interestingly, TNF-α has also demonstrated the ability to induce tolerance to subsequent challenges with TNF-α or LPS in monocyte and macrophage cell populations. Tolerance is characterized by the inability to mount a typical inflammatory response during subsequent challenges following the initial exposure to an inflammatory mediator such as LPS. The ability of TNF-α to induce a tolerant-like state with regard to LPS is most likely a regulatory mechanism to prevent excessive inflammation. We hypothesized that the induction of tolerance or the degree of tolerance is dependent upon the production of TNF-α during the primary response to LPS. To investigate TNF-α-dependent tolerance, human monocytic THP-1 cells were treated with TNF-α-neutralizing antibodies or antagonistic TNF-α receptor antibodies before primary LPS stimulation and then monitored for the production of TNF-α during the primary and challenge stimulation. During the primary stimulation, anti-TNF-α treatment effectively attenuated the production of TNF-α and interleukin-1β; however, this reduced production did not impact the induction of endotoxin tolerance. These results demonstrate that interfering with TNF-α signaling attenuates production of inflammatory cytokines without affecting the induction of tolerance.

Keywords: endotoxin tolerance, lipopolysaccharide, tumor necrosis factor-alpha, anti-tumor necrosis factor-alpha, THP-1 cells

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