MACROPHAGE INFLAMMATORY PROTEIN-2 - CHROMOSOMAL REGULATION IN RAT SMALL-INTESTINAL EPITHELIAL-CELLS

Nonpathogenic, resident bacteria participate in the pathogenesis of in flammation in the small intestine, but the molecular messages produced by such bacteria are unknown, Inflammatory responses involve the recr uitment of specific leukocyte subsets. We, therefore, hypothesized tha t butyrate, a normal bacterial metabolite, may modulate chemokine secr etion by epithelial cells, by amplifying their response to proinflamma tory signals. We studied the expression of the chemokine, macrophage i nflammatory protein-2 (MIP-2) by the rat small intestinal epithelial c ell line, IEC-6. Cells were stimulated with lipopolysaccharide or with interleukin 1 beta (IL-1 beta) and incubated with sodium butyrate, Ac etylation of histones was examined in Triton X acetic acid-urea gels b y PAGE. Unstimulated IEC-6 cells did not secrete MIP-2, However, lipop olysaccharide and IL-1 beta induced MIP-2 expression, Butyrate enhance d MIP-2 secretion both in lipopolysaccharide-stimulated and IL-1 beta- stimulated enterocytes; but butyrate alone did not induce MIP-2 expres sion. Butyrate increased the acetylation of histones extracted from th e nuclei of IEC-6 cells, Furthermore, acetylation of histones (induced by trichostatin A, a specific inhibitor of histone deacetylase) enhan ced MIP-2 expression by cells stimulated with IL-1 beta. In conclusion , trichostatin A reproduced the effects of butyrate on MIP-2 secretion , Butyrate, therefore, increases MIP-2 secretion in stimulated cells b y increasing histone acetylation. We speculate that butyrate carries i nformation from bacteria to epithelial cells. Epithelial cells transdu ce this signal through histone deacetylase, modulating the secretion o f chemokines.