Adenosine inhibits cytosolic calcium signals and chemotaxis in hepatic stellate cells.
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.
Hashmi
Ardeshir Z
AZ
Section of Digestive Diseases, Yale Univ., 333 Cedar St., 1080 LMP, PO Box 208019, New Haven, CT 06520-8019, USA.
Hakim
Wyel
W
Kruglov
Emma A
EA
Watanabe
Azuma
A
Watkins
William
W
Dranoff
Jonathan A
JA
Mehal
Wajahat Z
WZ
D000241:Adenosine / Q000494:pharmacology*; D000255:Adenosine Triphosphate / Q000494:pharmacology; D000818:Animals; D020013:Calcium Signaling / Q000187:drug effects / Q000502:physiology*; D002460:Cell Line; D002633:Chemotaxis / Q000187:drug effects / Q000502:physiology*; D024042:Collagen Type I / Q000235:genetics; D003600:Cytosol / Q000187:drug effects / Q000502:physiology; D005786:Gene Expression Regulation / Q000187:drug effects; D006801:Humans; D008099:Liver / Q000166:cytology / Q000187:drug effects / Q000502:physiology*; D051379:Mice; D008810:Mice, Inbred C57BL; D010982:Platelet-Derived Growth Factor / Q000494:pharmacology; D020133:Reverse Transcriptase Polymerase Chain Reaction; D016212:Transforming Growth Factor beta / Q000235:genetics
D024042:Collagen Type I; D010982:Platelet-Derived Growth Factor; D016212:Transforming Growth Factor beta; D000255:Adenosine Triphosphate; D000241:Adenosine