Extracellular Acidosis Regulates the Expression of Inflammatory Mediators in Rat Epithelial Cells

Acidification of the cellular microenvironment is found in different pathological states such as inflammation, ischemia and in solid tumors. It can affect cell function and phenotype, and by this aggravate the pathological process. Epithelial cells are a relevant functional part in several normal organs as well as in tumors and will thus be challenged by the acidic extracellular pH (acidosis). Therefore, the impact of acidosis on the expression of different inflammatory mediators (MCP-1, IL-6, osteopontin, iNOS, TNF-α, and COX-2), as well as the role of different signaling pathways regulating the expression, was studied in epithelial normal rat kidney cells (NRK-52E). Acidosis led to an increase in TNF-α expression but a down-regulation of MCP-1, iNOS and COX-2. Expression of IL-6 was only slightly modulated, while osteopontin was not regulated at all. Since acidosis activates ERK1/2 and p38 signaling in NRK-52E cells, the impact of MAP kinase signaling pathways on the expression of the inflammatory markers was analyzed. At normal pH, blocking ERK1/2 or p38 decreased the level of MCP-1, iNOS and partly TNF-α. However, the effect of acidosis on the expression of inflammatory mediators was not affected by inhibition of the MAP kinase pathways. In conclusion, our results show that an acidic microenvironment affects the transcriptional program of epithelial cells. Low pH mostly reduced the expression of pathological relevant genes and might thus repress inflammatory processes induced by epithelial cells.