Inhibition of transmembrane TNF-? shedding by a specific antibody protects against septic shock.

ABSTRACT: Transmembrane TNF-? (tmTNF-?) and secretory TNF-? (sTNF-?) display opposite effects in septic shock. Reducing tmTNF-? shedding can offset the detrimental effects of sTNF-? and increase the beneficial effect of tmTNF-?. We previously developed a monoclonal antibody that is specific for tmTNF-? and does not cross-react with sTNF-?. In this study, we show that this antibody can specifically suppress tmTNF-? shedding by competing with a TNF-? converting enzyme that cleaves the tmTNF-? ectodomain to release sTNF-?. This tmTNF-? antibody significantly inhibited LPS-induced secretion of interleukin (IL)-1?, IL-6, interferon-?, and nitric oxide by monocytes/macrophages, and protected mice from septic shock induced by lipopolysaccharide (LPS) or cecal ligation and puncture, while reducing the bacterial load. The mechanism associated with the protective effect of this tmTNF-? antibody involved promotion of LPS-induced toll-like receptor 4 (TLR4) internalization and degradation by recruiting Triad3A to TLR4. Moreover, the tmTNF-? antibody inhibited LPS-induced activation of nuclear factor-?B and interferon regulatory factor 3 pathways by upregulating expression of A20 and monocyte chemotactic protein-induced protein 1. Similarly, treatment of macrophages with exogenous tmTNF-? suppressed LPS/TLR4 signaling and release of proinflammatory cytokines, indicating that increased levels of tmTNF-? promoted by the antibody contributed to its inhibitory effect. Thus, use of this tmTNF-? antibody for specific suppression of tmTNF-? shedding may be a promising strategy to treat septic shock.

SUBMITTER: Li C 

PROVIDER: S-EPMC6683172 | biostudies-literature | 2019 Aug

REPOSITORIES: biostudies-literature