Adenosine inhibits cytosolic calcium signals and chemotaxis in hepatic stellate cells
Adenosine inhibits cytosolic calcium signals and chemotaxis in hepatic stellate cells
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DOI：
10.1152/ajpgi.00208.2006
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发表时间：
2007-01-01
影响因子：
4.5
通讯作者：
Mehal, Wajahat Z.
中科院分区：
文献类型：
--
作者：
Hashmi, Ardeshir Z.;Hakim, Wyel;Mehal, Wajahat Z.
腺苷在细胞缺氧和凋亡过程中产生，导致损伤部位组织水平升高。腺苷也被认为可以调节许多细胞对损伤的反应，但其在肝星状细胞（HSC）生物学和肝纤维化中的作用却知之甚少。我们测试了腺苷对造血干细胞细胞质内Ca2+浓度、趋化性和激活标记上调的影响。我们发现腺苷不会诱导LX-2细胞胞质Ca2+浓度的增加，此外，在ATP和PDGF的作用下，腺苷抑制了胞质Ca2+浓度的增加。使用Transwell系统，我们发现腺苷以剂量依赖的方式强烈抑制pdgf诱导的HSC趋化性。这种抑制是通过A（2a）受体介导的，是可逆的，由forskolin复制，并被腺苷酸环化酶抑制剂2,5-二脱氧腺苷阻断。腺苷也上调tgf - β和胶原I mRNA的产生。总之，腺苷可逆地抑制Ca2+通量和造血干细胞的趋化性，上调tgf - β和胶原I mRNA。我们认为腺苷提供了1)当hsc到达高腺苷浓度的组织损伤部位时一个“停止”信号，2)通过上调胶原和tgf - β的产生来刺激hsc的转分化。
Adenosine is produced during cellular hypoxia and apoptosis, resulting in elevated tissue levels at sites of injury. Adenosine is also known to regulate a number of cellular responses to injury, but its role in hepatic stellate cell (HSC) biology and liver fibrosis is poorly understood. We tested the effect of adenosine on the cytosolic Ca2+ concentration, chemotaxis, and upregulation of activation markers in HSCs. We showed that adenosine did not induce an increase in the cytosolic Ca2+ concentration in LX-2 cells and, in addition, inhibited increases in the cytosolic Ca2+ concentration in response to ATP and PDGF. Using a Transwell system, we showed that adenosine strongly inhibited PDGF-induced HSC chemotaxis in a dose-dependent manner. This inhibition was mediated via the A(2a) receptor, was reversible, was reproduced by forskolin, and was blocked by the adenylate cyclase inhibitor 2,5-dideoxyadenosine. Adenosine also upregulated the production of TGF-beta and collagen I mRNA. In conclusion, adenosine reversibly inhibits Ca2+ fluxes and chemotaxis of HSCs and upregulates TGF-beta and collagen I mRNA. We propose that adenosine provides 1) a "stop" signal to HSCs when they reach sites of tissue injury with high adenosine concentrations and 2) stimulates transdifferentiation of HSCs by upregulating collagen and TGF-beta production.