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

Tumor necrosis factor-alpha (TNF-alpha) 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-alpha is responsible for altering vascular permeability and activating infiltrating inflammatory cells, such as monocytes and neutrophils. Interestingly, TNF-alpha has also demonstrated the ability to induce tolerance to subsequent challenges with TNF-alpha 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-alpha 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-alpha during the primary response to LPS. To investigate TNF-a-dependent tolerance, human monocytic THP-1 cells were treated with TNF-alpha-neutralizing antibodies or antagonistic TNF-alpha receptor antibodies before primary LPS stimulation and then monitored for the production of TNF-alpha during the primary and challenge stimulation. During the primary stimulation, anti-TNF-alpha treatment effectively attenuated the production of TNF-alpha and interleukin-1 beta; however, this reduced production did not impact the induction of endotoxin tolerance. These results demonstrate that interfering with TNF-alpha signaling attenuates production of inflammatory cytokines without affecting the induction of tolerance.