A small compound that inhibits lipopolysaccharide-induced tumor necrosis factor-α production

Lipopolysaccharide (LPS) is critically involved in the inflammatory responses via generation of several pro-inflammatory cytokines. Since tumor necrosis factor-α (TNF-α) is one of the major pro-inflammatory cytokines which is induced by LPS treatment, the development of molecules capable of modulating LPS-induced TNF-α production is an issue of concern. We identified a novel synthetic compound that inhibits LPS-induced TNF-α production in human peripheral blood mononuclear cells (PBMCs). The active compound SM-7409 inhibited LPS-induced TNF-α production in a concentration-dependent manner, showing maximal activity at 5 μM. SM-7409 inhibited LPS-induced TNF-α mRNA transcript accumulation and protein expression. We also found that SM-7409 strongly inhibits LPS-induced extracellular signal-regulated protein kinase activity in PBMCs. Moreover, we found that SM-7409 strongly inhibits the LPS-induced other pro-inflammatory cytokines, such as interleukin (IL)-1β and IL-8 in PBMCs. SM-7409 also dramatically inhibits the LPS-induced TNF-α production in neutrophils. Taken together, our results demonstrate that SM-7409 is a synthetic compound that inhibits LPS-induced TNF-α production, and thus SM-7409 should be useful for the development of chemotherapies targeting LPS-mediated inflammatory responses.