Inhibition of IL-8 gene expression in Caco-2 cells by compounds which induce histone hyperacetylation.
Ulcerative colitis, an idiopathic inflammatory disease of the colonic mucosa, can be effectively treated by enemas containing short chain fatty acids (SCFA) such as butyrate, propionate, and acetate. The molecular mechanisms that lead to this response have not been well characterized. It is well known that intestinal inflammation leads to an alteration in patterns of epithelial differentiation with an increase in epithelial proliferation and an expansion of cell populations in an undifferentiated state. SCFAs such as butyrate are capable of inhibiting cell proliferation and inducing a differentiated phenotype in vitro. The Caco-2 colon cancer cell line was used to study the effect of SCFAs and the process of cellular differentiation on the expression of the pro-inflammatory cytokine, interleukin 8 (IL-8). SCFAs and trichostatin A, structurally unrelated compounds which both induce histone hyperacetylation, both led to a dose-dependent inhibition of IL-8 gene expression. Furthermore, spontaneous differentiation of Caco-2 cells by growth to a post-confluent state also inhibited the expression of IL-8. A possible mechanism by which SCFAs may be effective in the treatment of ulcerative colitis may be through their ability to increase histone acetylation states and inhibit the production of pro-inflammatory substances by the intestinal epithelium.
Huang
N
N
Department of Internal Medicine, University of Pennsylvania School of Medicine, Philadelphia 19104-6144, USA.
Katz
J P
JP
Martin
D R
DR
Wu
G D
GD
D000107:Acetylation; D002087:Butyrates / Q000494:pharmacology*; D020148:Butyric Acid; D018938:Caco-2 Cells; D002454:Cell Differentiation / Q000187:drug effects; D004791:Enzyme Inhibitors / Q000494:pharmacology; D005786:Gene Expression Regulation / Q000187:drug effects*; D056572:Histone Deacetylase Inhibitors; D006657:Histones / Q000378:metabolism*; D006801:Humans; D006877:Hydroxamic Acids / Q000494:pharmacology; D007375:Interleukin-1 / Q000494:pharmacology*; D016209:Interleukin-8 / Q000235:genetics*; D010641:Phenotype; D011422:Propionates / Q000494:pharmacology*; D013268:Stimulation, Chemical
D002087:Butyrates; D004791:Enzyme Inhibitors; D056572:Histone Deacetylase Inhibitors; D006657:Histones; D006877:Hydroxamic Acids; D007375:Interleukin-1; D016209:Interleukin-8; D011422:Propionates; D020148:Butyric Acid; C012589:trichostatin A