Effects of p38MAPK isoforms on renal mesangial cell inducible nitric oxide synthase expression.

Several related isoforms of p38MAPK have been identified and cloned in many species. Although they all contain the dual phosphorylation motif TGY, the expression of these isoforms is not ubiquitous. p38alpha and -beta2 are ubiquitously expressed, whereas p38gamma and -delta appear to have more restricted expression. Because there is evidence for selective activation by upstream kinases and selective preference for downstream substrates, the functions of these conserved proteins is still incompletely understood. We have demonstrated that the renal mesangial cell expresses the mRNA for all the isoforms of p38MAPK, with p38alpha mRNA expressed at the highest level, followed by p38gamma and the lowest levels of expression by p38beta2 and -delta. To determine the functional effects of these proteins on interleukin (IL)-1beta-induced inducible nitric oxide synthase (iNOS) expression, we transduced TAT-p38 chimeric proteins into renal mesangial cells and assessed the effects of wild-type and mutant p38 isoforms on ligand induced iNOS expression. We show that whereas p38gamma and -delta had minimal effects on iNOS expression, p38alpha and -beta2 significantly altered its expression. p38alpha mutant and p38beta2 wild-type dose dependently inhibited IL-1beta-induced iNOS expression. These data suggest that p38alpha and beta2 have reciprocal effects on iNOS expression in the mesangial cell, and these observations may have important consequences for the development of selective inhibitors targeting the p38MAPK family of proteins.