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Adenosine 2A receptor promotes collagen production by human fibroblasts via pathways involving cyclic AMP and AKT but independent of Smad2/3
Author(s) -
PerezAso Miguel,
Fernandez Patricia,
Mediero Aránzazu,
Chan Edwin S.,
Cronstein Bruce N.
Publication year - 2014
Publication title -
the faseb journal
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.709
H-Index - 277
eISSN - 1530-6860
pISSN - 0892-6638
DOI - 10.1096/fj.13-241646
Subject(s) - forskolin , chemistry , protein kinase b , adenosine , adenylyl cyclase , endocrinology , medicine , microbiology and biotechnology , pi3k/akt/mtor pathway , downregulation and upregulation , fibroblast , signal transduction , receptor , biology , biochemistry , in vitro , gene
Activation of adenosine A2A receptor (A 2A R) promotes fibrosis and collagen synthesis. However, the underlying mechanism is still unclear, not least because cAMP, its principal effector, has been found to inhibit TGFβ1‐induced collagen synthesis. Here, we show that in primary normal human dermal fibroblasts, A 2A R stimulation with CGS21680 elicits a modest cAMP increase (150±12% of control; EC 50 54.8 nM), which stimulates collagen1 (Col1) and collagen3 (Col3), but maximal cAMP resulting from direct activation of adenylyl cyclase by forskolin (15,689±7038% of control; EC 50 360.7 nM) inhibits Col1 and increases Col3. Similar to Col1 expression, fibroblast proliferation increased following physiological cAMP increases by CGS21680 but was inhibited by cAMP increases beyond the physiological range by forskolin. The A 2A R‐mediated increase of Col1 and Col3 was mediated by AKT, while Col3, but not Col1, expression was dependent on p38 and repressed by ERK. TGFβ1 induced phosphorylation of Smad2/3 and increased Col3 expression, which was prevented by Smad3 depletion. In contrast, CGS21680 did not activate Smad2/3, and Smad2/3 knockdown did not prevent CGS21680‐induced Col1 or Col3 increases. Our results indicate that cAMP is a concentration‐dependent switch for collagen production via noncanonical, AKT‐dependent, Smad2/3‐independent signaling. These observations explain the paradoxical effects of cAMP on collagen expression.—Perez‐Aso, M., Fernandez, P., Mediero, A., Chan, E. S., and Cronstein, B. N. Adenosine 2A receptor promotes collagen production by human fibroblasts via pathways involving cyclic AMP and AKT but independent of Smad2/3. FASEB J. 28, 802–812 (2014). www.fasebj.org