Suppressive action of acetate on interleukin-8 production via tubulin-α acetylation

Acetate is the major short-chain fatty acid produced by commensal bacteria in the gut and is known as a nutrient source for epithelial cells of the mucosa. Acetate also suppresses interleukin (IL)-2 production in T cells by inhibiting nuclear factor of activated T cells (NFAT) nuclear translocation via tubulin-alpha acetylation. Using acetylation of tubulin-alpha as a biomarker, we have examined the influence of acetate in the large intestine. Because of high concentrations of acetate in fecal material, tubulin-alpha acetylation is dominant in the proximal large intestine relative to other sections of the large intestine and is induced in epithelial cells of the colonic mucosa. Flagellin stimulation induces IL-8 production in epithelial cells and acetate suppresses this IL-8 production via tubulin-alpha acetylation. Flagellin stimulation activates nuclear factor-kappa B, CREB and AP-1, but not NFAT. Of these transcription factors, acetate specifically inhibits AP-1 activation. Acetate impairs flagellin-induced activation of the Rap1-MEK-ERK-Elk-1 pathway with acetylation of tubulin-alpha that is bound to Rap1, resulting in reduced expression of c-Fos, a subunit of AP-1. These findings reveal a novel action of acetate via tubulin-alpha acetylation in epithelial cells of the colonic mucosa.