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Am J Physiol Gastrointest Liver Physiol (October 19, 2006). doi:10.1152/ajpgi.00208.2006
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Submitted on May 12, 2006
Accepted on October 6, 2006

Adenosine inhibits cytosolic calcium signals and chemotaxis in hepatic stellate cells

Ardeshir Hashmi1, Wyel Hakim1, Emma Kruglov1, Azuma Watanabe1, William Watkins2, Jonathan A. Dranoff3, and Wajahat Zafar Mehal1*

1 Digestive Diseases, Yale, New Haven, Connecticut, United States
2 Medicinal Chemistry, Gilead Sciences, California, United States
3 Section of Digestive Diseases, Yale University School of Medicine, New Haven, Connecticut, United States

* To whom correspondence should be addressed. E-mail: wajahat.mehal{at}yale.edu.

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 biology and liver fibrosis is poorly understood. We tested the effect of adenosine on cytosolic Ca++ concentration, chemotaxis and upregulation of activation markers in hepatic stellate cells (HSC). We show that adenosine did not increase the cytosolic Ca++ concentration in HSC, and in addition inhibited increases in cytosolic Ca++ concentration in response to ATP and PDGF. Using a transwell system we show that adenosine strongly inhibits PDGF induced HSC chemotaxis in a dose dependent manner. This inhibition is mediated via the A2a receptor, is reversible, reproduced by forskolin and blocked by the adenylate cyclase inhibitor 2,5 DDA. Adenosine also upregulated the production of TGF-{beta} and collagen 1 m-RNA. In conclusion, adenosine reversibly inhibits Ca++ fluxes and chemotaxis of HSC, and upregulates TGF-{beta} and collagen 1 and mRNA. We propose that adenosine provides i) a STOP signal to HSC when they reach sites of tissue injury with high adenosine concentrations ii) stimulates trans-differentiation of HSC by upregulating collagen and TGF-{beta} production.




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