Differential Regulation of Cholangiocyte Growth by Activation of Different Histamine Receptor Subtypes

Abstract

Histamine exerts its functions by binding to four histamine G-coupled receptor proteins (H1R, H2R, H3R and H4R). Cross-talk between Ca2+ and cAMP regulates cholangiocyte growth. We tested the HYPOTHESIS that the activation of H3/H4R decreases cholangiocyte proliferation, whereas activation of H1/H2R increases biliary growth. The expression of H1-H4R was evaluated in cholangiocytes from normal and bile duct ligated (BDL) rats. BDL (immediately after BDL) rats were treated daily with RAMH (a H3/H4R agonist, 10 mg/Kg BW) for one week. Normal rats were treated with the selective histamine agonists: H1R, HTMT dimaleate (375 μg/day) or H2R, amthamine dihydrobromide (375 μg/day) for 1 week. Following in vitro treatment of: BDL cholangiocytes with RAMH (10 μM); and normal cholangiocytes with H1/H2R agonists we evaluated cholangiocyte proliferation and transduction pathways. Results: Cholangiocytes express H1-H4R. RAMH inhibition of BDL cholangiocyte growth was associated with decreased cAMP levels and PKA/ERK1/2/Elk-1 phosphorylation. H1/H2-induced increase in cholangiocyte growth was associated with Ca2+-(H1R) or cAMP-(H2R) dependent phosphorylation of Src/ERK1/2. Conclusion: We propose that a balance between the stimulatory (by activation of H1/H2R) and inhibitory (by activation of H3/H4R) effects of histamine regulates cholangiocyte growth in liver diseases.