Involvement of Protein Kinase Cδ/Extracellular Signal-regulated Kinase/Poly(ADP-ribose) Polymerase-1 (PARP-1) Signaling Pathway in Histamine-induced Up-regulation of Histamine H1 Receptor Gene Expression in HeLa Cells

The histamine H-1 receptor (H1R) gene is up-regulated in patients with allergic rhinitis. However, the mechanism and reason underlying this up-regulation are still unknown. Recently, we reported that the H1R expression level is strongly correlated with the severity of allergic symptoms. Therefore, understanding the mechanism of this up-regulation will help to develop new anti-allergic drugs targeted for H1R gene expression. Here we studied the molecular mechanism of H1R up-regulation in HeLa cells that express H1R endogenously in response to histamine and phorbol 12-myristate 13-acetate (PMA). In HeLa cells, histamine stimulation caused up-regulation of H1R gene expression. Rottlerin, a PKC delta-selective inhibitor, inhibited up-regulation of H1R gene expression, but Go6976, an inhibitor of Ca2+-dependent PKCs, did not. Histamine or PMA stimulation resulted in PKC delta phosphorylation at Tyr(311) and Thr(505). Activation of PKC delta by H2O2 resulted in H1R mRNA up-regulation. Overexpression of PKC delta enhanced up-regulation of H1R gene expression, and knockdown of the PKC delta gene suppressed this up-regulation. Histamine or PMA caused translocation PKC delta from the cytosol to the Golgi. U0126, an MEK inhibitor, and DPQ, a poly(ADP-ribose) polymerase-1 inhibitor, suppressed PMA-induced up-regulation of H1R gene expression. These results were confirmed by a luciferase assay using the H1R promoter. Phosphorylation of ERK and Raf-1 in response to PMA was also observed. However, real-time PCR analysis showed no inhibition of H1R mRNA up-regulation by a Raf-1 inhibitor. These results suggest the involvement of the PKC delta/ERK/poly(ADP-ribose) polymerase-1 signaling pathway in histamine-or PMA-induced up-regulation of H1R gene expression in HeLa cells.