Selective activation of the p38 MAPK pathway by synthetic monophosphoryl lipid A.

摘要: TLR4 stimulation by lipopolysaccharide can cause both MAL/MyD88- and TRAM/TRIF (Toll IL-1 receptor domain-containing adaptor-inducing IFNβ)-dependent signaling events. Monophosphoryl lipid A (MPLA), a low toxicity derivative of endotoxic lipopolysaccharide, enhances antibody responses, T cell expansion, recall responses against antigens without causing excessive inflammatory side effects. Previously, we proposed that TRIF-biased activation MPLA is responsible for its reduced while retaining potent adjuvant However, some TRIF-associated genes, such as MCP-1, are only weakly expressed, MyD88-associated anti-inflammatory cytokines, tumor necrosis factor α interleukin-10, strongly activated after despite weak NF-κB but strong IRF3 activation. We now report synthetic derivatives retained TRIF bias compared with diphosphoryl A, indicating change in single phosphoryl group sufficient stimulation. extend our previous observations showing sMLA induces p38 MAPK JNK activation, resulting high IP-10 (interferon-inducible protein 10), α, interleukin-10 MCP-1 transcript levels. Results this study identify novel biochemical mechanism regulation sMLA-induced gene expression.