1α,25(OH)2-Vitamin D3 stimulates intestinal cell p38 MAPK activity and increases c-Fos expression

In intestinal cells, as in other target cells, the steroid hormone 1α,25(OH)2-Vitamin D3 (1α,25(OH)2D3) regulates gene expression via the specific intracellular Vitamin D receptor and induces fast non-transcriptional responses involving stimulation of transmembrane signal transduction pathways. We have previously shown that the hormone activates the extracellular signal-regulated mitogen-activated protein (MAP) kinase isoforms ERK1 and ERK2 in rat intestinal cells. In the present study, we have demonstrated that 1α,25(OH)2D3 also induces the phosphorylation and activation of p38 MAPK in these cells. The hormone effects were time and dose-dependent, with maximal stimulation at 2 min (+3-fold) and 1 nM. 1α,25(OH)2D3-dependent p38 phosphorylation was suppressed by SB 203580, a selective inhibitor of p38 MAPK. Ca2+ chelation with EGTA, inhibition of the c-Src-tyrosine kinase family with PP1 or protein kinase A (PKA) with Rp-cAMP, attenuated hormone activation of p38 MAPK. The physiological significance of 1α,25(OH)2D3-dependent activation of ERK1/2 and p38 MAP kinases was addressed by monitoring c-Fos expression. Incubation of intestinal cells with the hormone was followed by a rapid induction of c-Fos expression which was blocked by SB 203580 and partially suppressed by the ERK1/2 inhibitor PD 98059. Our results suggest that 1α,25(OH)2D3 activates p38 MAPK, involving Ca2+, c-Src and PKA as upstream regulators, and that p38 MAPK has a central role in hormone-induction of the oncoprotein c-Fos in rat intestinal cells.