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Non‐raft AC2 defines a cAMP signaling compartment that selectively regulates IL‐6 expression in airway smooth muscle cells
Author(s) -
Bogard Amy S.,
Ostrom Rennolds S
Publication year - 2013
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/fasebj.27.1_supplement.656.6
Subject(s) - adenylyl cyclase , microbiology and biotechnology , gene isoform , phosphodiesterase , receptor , signal transduction , messenger rna , phosphodiesterase 3 , biology , chemistry , protein kinase a , phosphorylation , gene , enzyme , biochemistry
The ubiquitous second messenger cAMP is produced in response to several stimuli and must initiate a variety of situation‐specific responses. The nine isoforms of the cAMP generating adenylyl cyclase (AC) enzyme differ in their tissue distribution, regulation, protein interactions, and localization in the plasma membrane. We hypothesized that these differences allow AC isoforms to differentially regulate cellular responses, including gene expression, in human bronchial smooth muscle cells (BSMC). A PCR array with 84 genes regulated by cAMP revealed that some were controlled in an AC isoform‐specific manner. Expression of pro‐inflammatory cytokine interleukin 6 (IL‐6) was selectively regulated by AC2. IL‐6 mRNA, protein and promoter activation was measured by quantitative RT‐PCR, ELISA and luciferase assay. Direct activation of AC's with Fsk, inhibition of phosphodiesterases with IBMX, or stimulation of a subset of the cell's Gs‐coupled receptors led to IL‐6 expression that was enhanced by overexpression and activation of AC2 but not AC6. Not all Gs‐coupled receptors expressed in BSMC were linked to IL‐6 expression, but AC2 specificity remained regardless of the receptor activated. BSMC from an asthmatic donor had increased basal IL‐6 expression but impaired induction by Fsk. AC2, but not AC6, produces cAMP in a compartment capable of inducing IL‐6 expression. Supported by NIH (HL079166).