The human histamine H-2 receptor regulates c-jun and c-fos in a differential manner

Previously, we demonstrated that activation of the human H-2 receptor (hH(2 )R) leads to an increase in c-fos transcription and cell proliferation. The purpose of these studies was to examine whether hH(2)R regulates c-jun exp ression and, if so, explore the mechanisms by which it does so. Histamine i nduced an increase in c-jun mRNA in human embryonic kidney cells stably tra nsfected with the hH2R (maximal effect: 554.6 +/- 86.8% of control). The pr otein kinase C (PKC) inhibitors staurosporine (10(-6) M) and GF-109203X (10 (-6) M) significantly inhibited histamine-stimulated c-fos mRNA while not a ltering c-jun expression. The protein kinase A (PKA) pathway inhibitors Rp- cAMP and protein kinase inhibitor did not affect the action of histamine on c-jun or c-fos mRNA. Histamine (10(-4) M) stimulated extracellularly regul ated kinase 2 tyrosine phosphorylation. The specific inhibitor of the mitog en-activated protein (MAP) kinase pathway, PD-98059 (5 x 10(-5) M), signifi cantly inhibited histamine-induced c-fos and c-jun mRNA. Of interest, the p 70 S6 kinase inhibitor rapamycin (10(-6) M) but not wortmannin decreased hi stamine-stimulated c-jun mRNA by 58.5 +/- 12% (mean +/- SE, n = 4) while no t significantly altering c-fos message. Histamine (10(-4) M) also led to an similar to 4.5-fold increase in Jun NH2-terminal kinase activity in a PKC- , PKA-, and MAP kinase-independent but rapamycin-sensitive manner. Our find ings suggest that histamine stimulates both c-fos and c-jun mRNA in a diffe rential manner. PKC is involved in histamine-mediated c-fos activation, whe reas p70 S6 kinase is important for linkage of this receptor to c-jun.