RESUMEN

AIM: Paracrine interaction between macrophages and adipocytes in obese visceral fat tissues is thought to be a trigger of chronic inflammation. The immunomodulatory effect of the short chain fatty acid, butyric acid, has been demonstrated. We hypothesize that sodium butyrate (butyrate) attenuates inflammatory responses and lipolysis generated by the interaction of macrophages and adipocytes. METHODS: Using contact or transwell co-culture methods with differentiated 3T3-L1 adipocytes and RAW264.7 macrophages, we investigated the effects of butyrate on the production of tumor necrosis factor alpha (TNF-α), monocyte chemoattractant protein 1 (MCP-1), interleukin 6 (IL-6), and the release of free glycerol, free fatty acids (FFAs) into the medium. We also examined the activity of nuclear factor-kappaB (NF-κB) and the phosphorylation of mitogen-activated protein kinases (MAPKs) in co-cultured macrophages, as well as lipase activity and expression in co-cultured adipocytes. RESULTS: We found increased production of TNF-α, MCP-1, IL-6, and free glycerol, FFAs in the co-culture medium, and butyrate significantly reduced them. Butyrate inhibited the phosphorylation of MAPKs, the activity of NF-κB in co-cultured macrophages, and suppressed lipase activity in co-cultured adipocytes. Lipase inhibitors significantly attenuated the production of TNF-α, MCP-1 and IL-6 in the co-culture medium as effectively as butyrate. Butyrate suppressed the protein production of adipose triglyceride lipase, hormone sensitive lipase, and fatty acid-binding protein 4 in co-cultured adipocytes. Pertussis toxin, which is known to block GPR41 completely, inhibited the antilipolysis effect of butyrate. CONCLUSION: Butyrate suppresses inflammatory responses generated by the interaction of adipocytes and macrophages through reduced lipolysis and inhibition of inflammatory signaling.

Asunto(s)

Adipocitos/efectos de los fármacos , Butiratos/farmacología , Inflamación/prevención & control , Lipólisis/efectos de los fármacos , Macrófagos/efectos de los fármacos , Células 3T3-L1 , Adipocitos/metabolismo , Adipocitos/patología , Animales , Línea Celular , Quimiocina CCL2/biosíntesis , Quimiocina CCL2/genética , Técnicas de Cocultivo , Proteínas de Unión a Ácidos Grasos/biosíntesis , Ácidos Grasos no Esterificados/metabolismo , Inflamación/patología , Mediadores de Inflamación/metabolismo , Interleucina-6/biosíntesis , Interleucina-6/genética , Lipasa/antagonistas & inhibidores , Lipasa/metabolismo , Sistema de Señalización de MAP Quinasas/efectos de los fármacos , Macrófagos/metabolismo , Macrófagos/patología , Ratones , Comunicación Paracrina/efectos de los fármacos , Toxina del Pertussis/farmacología , ARN Mensajero/genética , ARN Mensajero/metabolismo , Factor de Transcripción ReIA/metabolismo , Factor de Necrosis Tumoral alfa/biosíntesis , Factor de Necrosis Tumoral alfa/genética

RESUMEN

In inflammatory bowel diseases, interleukin-1ß production is accelerated. Butyrate, a short chain fatty acid, plays an important role in inflammatory bowel diseases. We investigated the effect of butyrate on interleukin-1ß production in macrophage and elucidated its underlying mechanism. We stimulated THP-1 cells, a human premonocytic cell line, by lipopolysaccharide alone and by butyrate with lipopolysaccharide. Butyrate with lipopolysaccharide increased interleukin-1ß production more than lipopolysaccharide alone. Butyrate with lipopolysaccharide increased caspase-1 activity more than lipopolysaccharide alone. As for the phosphorylation pathway, PD98059 (ERK1/2 inhibitor), SB203580 (p38 MAPK inhibitor), SP600125 (JNK1/2 inhibitor) decreased caspase-1 activity and interleukin-1ß production to approximately 50% of the controls. Pertussis toxin (G protein-coupled signal transduction pathway inhibitor) also reduced interleukin-1ß production to approximately 50%. Butyrate with lipopolysaccharide increased reactive oxygen species levels more than lipopolysaccharide alone. The addition of N-acetyl L-cysteine reduced reactive oxygen species levels to a level similar to that of lipopolysaccharide alone. Butyrate with lipopolysaccharide increased nitric oxide production more than lipopolysaccharide alone, and the addition of N-acetyl L-cysteine reduced the elevated amount of nitric oxide. In conclusions, butyrate enhances interleukin-1ß production by activating caspase-1, via reactive oxygen species, the phosphorylation of MAPK, and G protein mediated pathways in lipopolysaccharide stimulated THP-1 cells.