title: Inhibiting TNF-α signaling does not attenuate induction of endotoxin tolerance.
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.
authors.affiliation: Department of Microbiology and Immunology, University of Nevada School of Medicine, Reno, NV, USA.
authors.forename: Christopher
authors.initials: C
authors.lastname: Loosbroock
authors.affiliation: Department of Microbiology and Immunology, University of Nevada School of Medicine, Reno, NV, USA.
authors.forename: Kenneth W
authors.initials: KW
authors.lastname: Hunter
keywords: THP-1 cells; anti-tumor necrosis factor-alpha; endotoxin tolerance; lipopolysaccharide; tumor necrosis factor-alpha