Session Title: Cytokines, Mediators, and Gene Regulation
Session Type: Abstract Submissions (ACR)
We have previously demonstrated that the nucleoside adenosine mediates collagen production and induce dermal fibrosis in in vitro and in vivo models. IL–13 expression is upregulated in tissues characterized by high levels of adenosine (adenosine deaminase-deficient mice). However, the receptor(s) and mechanism involved in this upregulation are unknown. Here, we further characterize the contributions of endogenous adenosine and adenosine A2A and A2Breceptors in skin fibrosis via IL-33 and IL-13 signaling.
Human dermal fibroblasts were treated with A2A receptor agonist (CGS-21680), A2A antagonist (ZM241385); A2B (BAY606583), and A2Bantagonist (MRS1706). Fold changes in the expression of IL-13 and associated receptors were analysed after 2 hours. Message for IL-33, IL-13 and three IL-13 receptor proteins – IL-13Rα1, IL-13Rα2 and IL-4R, were assessed using quantitative real-time PCR and compared to untreated controls.
Stimulation of the A2A receptor with CGS-21680 induces expression of IL-13 and three IL-13 receptors: IL-13Rα1, IL-13Rα2, and IL-4R. A 2.8x increase in expression was found for IL-13Rα1 (p<0.05), 3.4x increase for IL-13Rα2 (p<0.05), and 3.9x increase for IL-4 (p<0.05) was seen. IL-33 expression was increased by 8.6x (p<0.05). These elevations were all blocked by the A2A receptor antagonist. Stimulation of the A2Breceptor alone does not cause significant changes in the expression of the receptors studied.
Despite efforts at investigating the mechanisms underlying fibrogenesis in the skin of patients with scleroderma, no effective antifibrotic therapy exists. The nucleoside adenosine induces expression of pro-fibrotic cytokine IL-13 and particularly its cognate receptors IL-13Rα1, IL-13R α2, and IL-4. Furthermore, Upregulation of IL-33 may in part contribute to the induction of IL-13 expression by A2A receptors. These findings suggest that blockade of the A2A receptor may be useful as a novel therapeutic modality to prevent dermal fibrosis in scleroderma.
R. C. Radusky,
J. L. Feig,
B. N. Cronstein,
NIH, URL Pharma, OSI,
Bristol-Myers Squibb, Novartis, URL, Regeneron, Gismo Therapeutics,
Arthritis Foundation, SLE Foundation,
Patents on use of adenosine receptor antagonists to treat or prevent fibrosis. Multiple other patents.,
A. G. Franks Jr.,
E. S. Chan,
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ACR Meeting Abstracts - https://acrabstracts.org/abstract/the-pro-fibrotic-cytokines-il-33-and-il-13-modulates-dermal-fibrosis-via-the-a2a-adenosine-receptor/