Butyrate and trichostatin A attenuate nuclear factor κB activation and tumor necrosis factor α secretion and increase prostaglandin E₂ secretion in human peripheral blood mononuclear cells

Abstract 

The effects of short-chain fatty acids (butyrate, propionate, and acetate) and trichostatin A (TSA), a typical histone deacetylase inhibitor, on tumor necrosis factor (TNF)-α secretion and nuclear factor κB (NF-κB) activation in peripheral blood mononuclear cells induced with lipopolysaccharide were evaluated in relation to prostaglandin E₂ (PGE₂) secretion. Treatment of cells with butyrate; tributyrin, a prodrug of butyrate; propionate; acetate; and TSA down-regulated TNF-α secretion but all up-regulated PGE₂ secretion. Butyrate, propionate, and TSA inhibited NF-κB activation. The effects of the cyclooxygenase-nonspecific inhibitor, indomethacin; the cyclooxygenase-2 selective inhibitor, N-[2-(cyclohexyloxy)-4-nitro-phenyl] methanesulfonamide; and the general lipoxygenase inhibitor, nordihydroguaiaretic acid, varied in cells treated with each short-chain fatty acids. N-[2-(cyclohexyloxy)-4-nitro-phenyl] methanesulfonamide inhibited the effect of propionate on TNF-α secretion, and nordihydroguaiaretic acid inhibited that of acetate. The results showed that butyrate, propionate, and TSA inhibited TNF-α production via PGE₂ secretion and down-regulated NF-κB activation by lipopolysaccharide. These data suggest that the mechanism of butyrate and propionate action is through histone deacetylation and acetate through lipoxygenase activation in the regulation of proinflammatory responses in cells.

Abbreviations: COX, cyclooxygenase, HDAC, histone deacetylase, IL, interleukin, LOX, lipoxygenase, LPS, lipopolysaccharide, NDGA, nordihydroguaiaretic acid, NF-κB, nuclear factor κB, NS398, N-[2-(cyclohexyloxy)-4-nitro-phenyl] methanesulfonamide, PBMCs, peripheral blood mononuclear cells, PGE₂, prostaglandin E₂, SCFAs, short-chain fatty acids, TNF, tumor necrosis factor, TSA, trichostatin A

Keywords: Short-chain fatty acids, Tumor necrosis factor α, Nuclear factor κB, Prostaglandin E₂, Histone deacetylase inhibitor, Human peripheral blood mononuclear cells