Inhibition of p38MAP kinase potentiates the JNK/SAPK pathway and AP-1 activity in monocytic but not in macrophage or granulocytic differentiation of HL60 cells.

Monocytic differentiation of HL60 cells induced by 1,25-dihydroxyvitamin D(3) (1,25 D(3)) has been recently shown (Exp Cell Res 258, 425, 2000) to be enhanced by an exposure to SB203580 or to SB202190, specific inhibitors of p38MAP kinase, with concomitant up-regulation of the c-jun N terminal kinase (JNK) pathway. In the present study we inquired if this enhancement and the JNK up-regulation are limited to 1,25 D(3)-induced differentiation, or if they occur more generally in HL60 cell differentiation. We found that dimethylsulfoxide (DMSO)-induced differentiation, and to a lesser extent tetradecanoylphorbol acetate (TPA)-induced macrophage differentiation were also potentiated by the p38MAPK inhibitors, but that granulocytic differentiation in response to all-trans retinoic acid (RA) was not. The enhancement of differentiation by p38MAPK inhibitors was accompanied by an activation of the JNK MAPK pathway, as shown by the phosphorylation levels of these kinases and by AP-1 binding, but only in 1,25 D(3)-treated cells. This shows that an up-regulation of the JNK stress pathway during 1,25 D(3)-induced monocytic differentiation occurs selectively in this lineage of differentiation and is not necessary for the expression of the differentiated phenotype. Copyright 2001 Wiley-Liss, Inc.