Small mouse cholangiocytes proliferate in response to H1 histamine receptor stimulation by activation of the IP3/CaMK I/CREB pathway
Small mouse cholangiocytes proliferate in response to H1 histamine receptor stimulation by activation of the IP3/CaMK I/CREB pathway
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DOI：
10.1152/ajpcell.00369.2007
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发表时间：
2008-08-01
影响因子：
5.5
通讯作者：
Alpini, Gianfranco
中科院分区：
文献类型：
--
作者：
Francis, Heather;Glaser, Shannon;Alpini, Gianfranco
胆管病的特征在于不同大小的胆管细胞的异质性增殖。大胆管细胞通过cAMP依赖性机制增殖。小胆管细胞的功能可能依赖于三磷酸肌醇（IP 3）/Ca 2+依赖性信号通路的激活;然而，缺乏支持这一推测的数据。存在四种组胺受体（HRH 1、HRH 2、HRH 3和HRH 4）。在几个牢房：1）HRH 1的活化增加细胞内Ca 2+浓度水平;和2）增加的[Ca 2 +]（i）水平与钙调蛋白依赖性蛋白激酶（CaMK）的钙调蛋白依赖性刺激和cAMP-反应元件结合蛋白（CREB）的活化相结合。HRH 1激动剂通过激活IP 3/Ca 2+依赖性CaMK/CREB调节小胆管细胞增殖。我们评估了胆管细胞中HRH 1的表达。在测量增殖之前，用组胺三氟甲基甲苯胺（HTMT二马来酸盐; HRH 1激动剂）刺激小和大胆管细胞24-48小时，有/没有特非那定、BAPTA/AM或W7。在小型和大型胆管细胞中评价了CaMK I、II和IV的表达。我们测量了用HTMT二马来酸盐处理的小胆管细胞中的IP 3、Ca 2+和cAMP水平、CaMK I的磷酸化和CREB的活化（在W7存在/不存在的情况下）。在测量增殖和CREB活性之前，在用HTMT二马来酸盐刺激的小胆管细胞中进行CaMK I敲低。小型和大型胆管细胞表达HRH 1，CaMK I和CaMK II。小的（但不是大的）胆管细胞对HTMT二马来酸盐的反应是增殖，并被特非那定（HRH 1拮抗剂）、BAPTA/AM和W7阻断。在小胆管细胞中，HTMT二马来酸盐增加IP 3/Ca 2+水平，CaMK I磷酸化和CREB活性。CaMK I的基因敲低消除了HTMT二马来酸盐对小胆管细胞增殖和CREB激活的影响。IP 3/Ca 2 +/CaMK I/CREB通路在调节小胆管细胞功能中起重要作用。
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.