Histamine and specific histamine receptors increase normal cholangiocyte growth via differential mechanisms

Abstract

Normal cholangiocytes proliferate after injury. Histamine (HA) interacts with four receptors (H1–H4). We have shown that histamine receptors (HRs) induce differential effects in cholangiocytes. We evaluated: (i) HR expression, (ii) chronic effects of HA or specific HRs in normal rats (NR) and (iii) signaling mechanisms. HR expression was evaluated in cholangiocytes and cholangiocyte cultures (NRC). In vivo, NR were treated with HA or selected HR agonists: H1, HTMT dimaleate; H2, amthamine dihydrobromide; RAMH; H4, clobenpropit or NaCl. Cholangiocyte growth was evaluated by: (i) immunohistochemistry in liver sections and (ii) PCNA expression. NRIC were treated with HA or selected HR agonists. We measured growth, IP3 and cAMP levels and phosphorylation of PKA and ERK1/2. HRs are found in NR and NRC. Administration of HA or H1 and H2 (but not H3 or H4) to NR increased cholangiocyte growth compared to NR + NaCl. In vitro, HA and H1HR increased growth (via Ca2+signaling), IP3 and ERK1/2 phosphorylation. HA and H2HR stimulation increased growth (via PKA signaling), cAMP and phosphorylation of PKA and ERK 1/2. H3 and H4 had no effect. HA induces normal cholangiocyte growth. Activation of specific HRs modulates growth via independent mechanisms. Stimulatory (H1/H2) and inhibitory (H3/H4) effects by HRs may be important in the regulation of cholangiocyte growth/loss related to cholangiopathies.