Expression of
IL-18 in intestinal epithelial cells (IEC) has been implicated in Th1 cell-mediated chronic intestinal
inflammation and anti-
tumor immunity. However, physiological regulatory factors have not been identified. Besides their effects on proliferation and restitution, immunomodulatory functions have been attributed to
short chain fatty acids (SCFA). We investigated the effect of SCFA (
butyrate,
propionate,
acetate) on expression of
IL-18 in IEC in vitro and in vivo. Expression of
IL-18 mRNA and
protein in human
carcinoma-derived HT-29 and Caco-2 cells was analyzed by reverse transcription-PCR and Western blot. Transcriptional regulation of
IL-18 gene expression was determined by transient transfection of wild-type and mutated
IL-18 promoter. Further, in vivo expression of
IL-18 in the intestine from
butyrate-treated and untreated mice was assessed by immunohistochemistry.
IL-18 mRNA and the
IL-18 protein were expressed in IEC, while
IL-18 secretion was not observed.
Butyrate and
acetate increased intracellular
IL-18 content in a time- and dose-dependent fashion. In contrast to proinflammatory stimuli
butyrate potently activated the
IL-18 promoter, indicating that
IL-18 is regulated at the transcriptional level by SCFA. Furthermore, a 108-bp sequence in the proximal region was identified to be essential for
IL-18 promoter activation by
butyrate. As proof of principle
butyrate effects were confirmed in vivo by demonstration of increased
IL-18 protein expression in IEC from
butyrate-treated mice. In conclusion, SCFA up-regulate
IL-18 protein expression in IEC, suggesting a potential regulatory contribution of these
luminal constituents to T cell mediated inflammatory and neoplastic intestinal conditions.