CAMP levels inhibit TGF‐β‐induced expression of extracellular matrix (ECM) components by interfering with the SMAD pathway. A potential effector mechanism of hormones signaling via cAMP?

Abstract

Through their ability to modulate the expression of extracellular matrix (ECM) components and ECM‐degrading enzymes, cytokines and growth factors orchestrate the balance between ECM destruction and neosynthesis and therefore play an important role in the control of tissue homeostasis and repair. Disruption of the fragile equilibrium between anabolic and catabolic cytokines in favor of TGF‐β may lead to excessive collagen deposition, the hallmark of fibrotic conditions. TGF‐β elicits its effects on target genes through Smad proteins, which transduce signals from TGF‐β receptors into the nucleus where they bind directly to specific promoter sequences. Using an artificial Smad3/4 dependent reporter construct, we show that synthetic cAMP, prevents TGF‐β‐induced Smad‐specific gene transactivation in human dermal fibroblasts. Activation of adenylate cyclase by forskolin mimics the shown Smad opposing effect. Northern blot studies reveal that cAMP inhibits TGF‐β/SMAD‐dependent α(2) type I collagen and type 1 plasminogen activator inhibitor gene expression. In addition, TGF‐β‐induced C‐terminal propeptide of type I procollagen secretion into cell supernatants is significantly inhibited by cAMP. Together these results demonstrate the suppression of TGF‐β‐induced expression of ECM components by increased intracellular cAMP levels. Our data support the notion that various hormones and neuropeptides, which signal via the cAMP pathway, may function as antagonists of fibrosis.