Histidine decarboxylase regulates biliary homeostasis via autocrine histamine signaling

Abstract

Cholangiocyte homeostasis is regulated by both autocrine/paracrine signaling. In bile duct ligated (BDL) rats large cholangiocyte proliferate, whereas CCl4 induces large cholangiocyte apoptosis. Histidine decarboxylase (HDC) regulates histamine synthesis. We have shown that: (i) cholangiocytes express HDC and secrete histamine; (ii) histamine stimulates biliary growth; and (ii) HDC inhibition decreases biliary growth. No information exists that HDC/histamine regulates cholangiocyte homeostasis. In vivo, normal and 1 wk BDL rats were treated with saline or histamine (0.5 mg/kg) and given CCl4 by gavage (0.5 ml/100 gm). Liver blocks and large cholangiocytes were obtained. HDC, PCNA, TUNEL and CK‐19 biliary expression was measured by immunohistochemistry in liver sections and by qPCR and immunoblots in large cholangiocytes. In vitro, control (MSE‐neg) or stable transfected HDC knockdown large cholangiocytes (MSE‐HDC) were treated with CCl4 (5 mM) in the absence/presence of histamine (10 μM) before evaluating apoptosis and proliferation. After BDL, there was enhanced cholangiocyte proliferation, ductal mass and biliary HDC expression. CCl4 treatment (i) enhanced biliary apoptosis; and (ii) decreased HDC and serum/biliary histamine levels and biliary proliferation and ductal mass, changes that were prevented by histamine. In MSE‐HDC cells there was reduced biliary growth and enhanced apoptosis compared to Mz‐neg. In MSE‐HDC cells treated with CCl4, apoptosis increased compared to MSE‐neg cells treated with CCl4. In Mz‐HDC, CCl4‐induced apoptosis and loss of proliferation was prevented by histamine. HDC is a key regulator of cholangiocyte homeostasis and histamine may be a protective factor after toxic injury. Treatment of cholangiopathies characterized by proliferation or loss may be regulated by the modulation of histamine levels.