Non-Raft AC2 Defines a cAMP Signaling Compartment That Selectively Regulates IL-6 Expression in Airway Smooth Muscle Cells

Authors

Amy S. Bogard, University of Tennessee
Anna V. Birg, University of Tennessee
Rennolds S. Ostrom, Chapman UniversityFollow

Document Type

Article

Publication Date

2014

Abstract

Adenylyl cyclase (AC) isoforms differ in their tissue distribution, cellular localization, regulation, and protein interactions. Most cell types express multiple AC isoforms. We hypothesized that cAMP produced by different AC isoforms regulates unique cellular responses in human bronchial smooth muscle cells (BSMC). Overexpression of AC2, AC3, or AC6 had distinct effects on forskolin (Fsk)-induced expression of a number of known cAMP-responsive genes. These data show that different AC isoforms can differentially regulate gene expression. Most notable, overexpression and activation of AC2 enhanced interleukin 6 (IL-6) expression, but overexpression of AC3 or AC6 had no effect. IL-6 production by BSMC was induced by Fsk and select G protein-coupled receptor (GPCR) agonists, though IL-6 levels did not directly correlate with global cAMP levels. Treatment with PKA selective 6-Bnz-cAMP or Epac selective 8-CPT-2Me-cAMP cAMP analogs revealed a predominant role for PKA in cAMP-mediated induction of IL-6. IL-6 promoter mutations demonstrated that AP-1 and CRE transcription sites were required for Fsk to stimulate IL-6 expression. Our present study defines an AC2 cAMP signaling compartment that specifically regulates IL-6 expression in BSMC via Epac and PKA and demonstrates that other AC isoforms are excluded from this pool.

Comments

This article was originally published in Naunyn-Schmiedeberg's Archives of Pharmacology, volume 387, issue 4, in 2014. DOI: 10.1007/s00210-013-0950-4

An abstract of the same title was published in FASEB Journal, volume 27, issue 1 (supplement), in 2013. DOI: 10.1007/s00210-013-0950-4

Recommended Citation

Amy S. Bogard, Anna V. Birg and Rennolds S Ostrom. Non-raft AC2 defines a cAMP signaling compartment that selectively regulates IL-6 expression in airway smooth muscle cells. Naunyn-Schmiedebergs Arch Pharmacol, 387(4):329-39, 2014.

Copyright

Springer