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

Abstract

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- Histamine is a major chemical mediator of allergic reactions, and its action is mainly mediated by the histamine H 1 receptor (H1R), 2 which is one of the four histamine receptor isoforms. H1R, which is a G protein-coupled receptor, is coupled to the G q protein. The stimulation of H1R activates inositol phospholipid hydrolysis and intracellular Ca 2ϩ mobilization. Typically, the activation of G protein-coupled receptors by their agonists induces down-regulation of the receptors. However, to date, a few reports have demonstrated up-regulation of G proteincoupled receptors by their agonists (1-4). Previously, we found that histamine stimulation up-regulated H1R at both the mRNA and protein level via activation of H1R in HeLa cells that express H1R endogenously (5). Up-regulation of H1R has been observed in patients with allergic rhinitis (6, 7). The strength of H1R signaling depends on the H1R expression level (8). Our recent studies have demonstrated that the level of H1R gene expression is strongly correlated with the severity of allergic symptoms in model rats and patients with pollinosis (9, 10), and compounds that suppress H1R gene up-regulation alleviate allergic symptoms (11-16). These findings suggest that the H1R gene is an allergy-sensitive gene, i.e. its expression level affects the severity of symptoms. Hence, understanding the molecular mechanism of H1R up-regulation may be useful for developing new anti-allergic drugs that target H1R gene expression. However, the mechanism of H1R up-regulation in response to histamine is unknown.Previously, we demonstrated that PKC-dependent signaling is involved in up-regulation of H1R gene expression in HeLa cells (5). PKC consists of at least 11 isoforms, and based on their structures and cofactor requirements, the PKC isoforms are divided into three subgroups; that is, conventional PKC (␣, ␤, and ␥), novel PKC (␦, ⑀, , and ), and atypical PKC ( and /) (17). It has been reported that PKC ␣, ␤, ␦, ⑀, and isoforms are expressed in HeLa cells (18 -20).Coupling of H1R signaling with PKC␣ has been reported in H1R-overexpressing CHO cells (21) and native human epidermal keratinocytes (22). In these cells, however, no up-regulation of H1R gene expression was observed. In addition, NF-B (23), the cAMP response element-binding protein (CREB) (24)), the nuclear factor of activated T-cell (25), and the serumresponsive element (26)

Protein kinase C-δ signaling regulates glucagon secretion from pancreatic islets

“…Rottlerin has been used to confirm the possible role of PKCδ isoform in several signaling pathways. Moreover, the results obtained with rottlerin were compatible with those obtained utilizing more selective approaches to inhibit PKCδ in a previous report (17). It was recently reported rottlerin also inhibited PKCθ (23).…”

“…We showed that treatment with PMA significantly increased glucagon secretion from isolated islets and quercetin treatment suppressed the PMA-induced increase in glucagon secretion in α-cells. We reported that quercetin suppressed PMA-induced Tyr 311 phosphorylation of PKCδ in HeLa cells (17). In the present study, we showed that quercetin also suppressed PMA-induced Tyr 311 phosphorylation of PKCδ in isolated islets.…”

“…We have demonstrated that PKCδ signaling is involved in PMAinduced upregulation of histamine H1 receptor (H1R) gene expression in HeLa cells and compounds, including quercetin and (-)-maackiain, suppressed H1R gene expression through the inhibition of PKCδ signaling (17)(18)(19). Thus, suppression of PKCδ signaling by these compounds could improve diabetic symptoms and help to further elucidate the mechanisms underlying these actions to better understand the role of PKCδ signaling in diabetes onset and progression.…”

Inverse Agonistic Activity of Antihistamines and Suppression of Histamine H1 Receptor Gene Expression

“…Next, we investigated the effect of these antihistamines on H1R gene expression in HeLa cells. We previously found that the protein kinase Cδ (PKCδ) / extracellularregulated kinase / poly (ADP-ribose) polymerase-1 signaling pathway is involved in H1R gene expression in HeLa cells and that pretreatment with rottlerin, a selective PKCδ inhibitor, completely blocks this pathway (15). Pretreatment with 5 μM rottlerin significantly decreased basal H1R gene expression to 60% of the control level, indicating that there is constitutive H1R activation in HeLa cells (Fig.…”

Combination of Leukotoriene Receptor Antagonist With Antihistamine Has an Additive Suppressive Effect on the Up-regulation of H1-Receptor mRNA in the Nasal Mucosa of Toluene 2,4-Diisocyanate-Sensitized Rat

“…The mechanism of LT-mediated up-regulation of H1R is unknown, although histamine up-regulates the expression of H1R mRNA in HeLa cells through protein kinase C (PKC)-mediated H1R gene transcription (10). However it was reported that treatment of OVAsensitized mice with PKC inhibitors (GF109203X and rottlerin) before provocation diminished not only the CysLT production but also the effects of LT such as eosinophil infiltration and AHR (11), suggesting the involvement of PKC in the LT signaling pathway.…”