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-α acetylation. Using acetylation of tubulin-α as a biomarker, we have examined the influence of acetate in the large intestine. Because of high concentrations of acetate in fecal material, tubulin-α 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-α acetylation. Flagellin stimulation activates nuclear factor-κB, 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-α 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-α acetylation in epithelial cells of the colonic mucosa.
Department of Gastroenterology and Hepatology, Graduate School of Medicine, Nagoya University, Nagoya, Aichi, Japan.
Kazuhiro
K
Ishiguro
Department of Gastroenterology and Hepatology, Graduate School of Medicine, Nagoya University, Nagoya, Aichi, Japan.
Takafumi
T
Ando
Department of Gastroenterology and Hepatology, Graduate School of Medicine, Nagoya University, Nagoya, Aichi, Japan.
Osamu
O
Maeda
Department of Gastroenterology and Hepatology, Graduate School of Medicine, Nagoya University, Nagoya, Aichi, Japan.
Osamu
O
Watanabe
Department of Gastroenterology and Hepatology, Graduate School of Medicine, Nagoya University, Nagoya, Aichi, Japan.
Hidemi
H
Goto
D000085:Acetates / Q000494:pharmacology*; D000107:Acetylation / Q000187:drug effects; D000818:Animals; D002460:Cell Line; D003106:Colon / Q000187:drug effects / Q000276:immunology / Q000378:metabolism; D048049:Extracellular Signal-Regulated MAP Kinases / Q000378:metabolism; D005408:Flagellin / Q000276:immunology; D006801:Humans; D016209:Interleukin-8 / Q000096:biosynthesis* / Q000235:genetics; D007413:Intestinal Mucosa / Q000187:drug effects / Q000276:immunology / Q000378:metabolism; D008297:Male; D051379:Mice; D011485:Protein Binding; D012333:RNA, Messenger / Q000235:genetics / Q000378:metabolism; D015398:Signal Transduction; D016176:T-Lymphocyte Subsets / Q000187:drug effects / Q000276:immunology / Q000378:metabolism; D014404:Tubulin / Q000378:metabolism*; D050807:ets-Domain Protein Elk-1 / Q000378:metabolism
D000085:Acetates; D016209:Interleukin-8; D012333:RNA, Messenger; D014404:Tubulin; D050807:ets-Domain Protein Elk-1; D005408:Flagellin; D048049:Extracellular Signal-Regulated MAP Kinases