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GROWTH, DIFFERENTIATION, AND APOPTOSIS

Small mouse cholangiocytes proliferate in response to H1 histamine receptor stimulation by activation of the IP₃/CaMK I/CREB pathway

¹Central Texas Veterans Health Care System, ²Department of Medicine and ³Systems Biology and Translational Medicine, ⁴Division of Research and Education, ⁵Division of Molecular Cardiology, Scott & White and Texas A&M Health Science Center, College of Medicine, Temple, Texas; ⁶Department of Human Anatomy, University of Rome, "La Sapienza," Rome; ⁷Division of Gastroenterology, Tohoku University Hospital, Aobaku, Sendai, Japan; ⁸Department of Experimental Medicine, State University of l'Aquila, l'Aquila; and ⁹Department of Gastroenterology, Università Politecnica delle Marche, Ancona, Italy

Submitted 16 August 2007 ; accepted in final form 21 May 2008

Cholangiopathies are characterized by the heterogeneous proliferation of different-sized cholangiocytes. Large cholangiocytes proliferate by a cAMP-dependent mechanism. The function of small cholangiocytes may depend on the activation of inositol trisphosphate (IP₃)/Ca²⁺-dependent signaling pathways; however, data supporting this speculation are lacking. Four histamine receptors exist (HRH1, HRH2, HRH3, and HRH4). In several cells: 1) activation of HRH1 increases intracellular Ca²⁺ concentration levels; and 2) increased [Ca²⁺]_i levels are coupled with calmodulin-dependent stimulation of calmodulin-dependent protein kinase (CaMK) and activation of cAMP-response element binding protein (CREB). HRH1 agonists modulate small cholangiocyte proliferation by activation of IP₃/Ca²⁺-dependent CaMK/CREB. We evaluated HRH1 expression in cholangiocytes. Small and large cholangiocytes were stimulated with histamine trifluoromethyl toluidide (HTMT dimaleate; HRH1 agonist) for 24–48 h with/without terfenadine, BAPTA/AM, or W7 before measuring proliferation. Expression of CaMK I, II, and IV was evaluated in small and large cholangiocytes. We measured IP₃, Ca²⁺ and cAMP levels, phosphorylation of CaMK I, and activation of CREB (in the absence/presence of W7) in small cholangiocytes treated with HTMT dimaleate. CaMK I knockdown was performed in small cholangiocytes stimulated with HTMT dimaleate before measurement of proliferation and CREB activity. Small and large cholangiocytes express HRH1, CaMK I, and CaMK II. Small (but not large) cholangiocytes proliferate in response to HTMT dimaleate and are blocked by terfenadine (HRH1 antagonist), BAPTA/AM, and W7. In small cholangiocytes, HTMT dimaleate increased IP₃/Ca²⁺ levels, CaMK I phosphorylation, and CREB activity. Gene knockdown of CaMK I ablated the effects of HTMT dimaleate on small cholangiocyte proliferation and CREB activation. The IP₃/Ca²⁺/CaMK I/CREB pathway is important in the regulation of small cholangiocyte function.

heterogeneity; calcium; intrahepatic biliary epithelium; mitosis; transcription factors

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