Dissecting the Dualistic Effects of Transforming Growth Factor (TGF)-β on Fibroproliferation and Extracellular Matrix Production in PrimaryHuman Lung Fibroblasts – The Role of p38δ MAP Kinase

Abstract

Rationale: Inflammation, increased fibroblast proliferation, and increased deposition of extracellular matrix (ECM) are hallmarks of early lung fibrosis and asthma. Transforming growth factor-� (TGF-� ) has been suggested as a key regulator of lung tissue homeostasis with several and often opposite effects on fibroblast proliferation and ECM production. In human and animal model systems, it has been shown that TGF-� induced several signaling cascades including Smads, p38 mitogen-activated protein (MAP) kinases, and extracellular signal-regulated kinases 1/2 (ERK). Information on how TGF- regulates and controls normal primary lung fibroproliferation and ECM production is not present. Objectives: We sought to dissect the effects of TGF-� on fibroproliferation and ECM production of primary adult human lung fibroblasts and elucidate the involved signaling pathways. Results: Depending on the presence of fetal bovine serum (FBS; 10%), TGF- exerted opposite effects on fibroproliferation. In the absence of FBS, low TGF- concentrations (0.01 and 0.001 ng/ml) significantly induced fibroproliferation. In the presence of FBS, TGF-� (1 ng/ml, 10 ng/ml) significantly reduced fibroproliferation. TGF- dose-dependently increased ECM deposition, which was independent of the presence of FBS. The anti-proliferative effect of TGF-� was associated with increased prostaglandin E2 (PGE2) production, that was induced via p38 and ERK 1/2 MAP kinases. Indomethacin (2.5 μM) and a small interfering RNA specific for p38 MAP kinase completely reversed the TGF-� -dependent inhibition of fibroblast proliferation. Conclusions: Both pro- and anti-proliferative cascades can be activated by TGF-� . In a mitogenic or inflammatory environment TGF-� induces PGE2 synthesis via activation of p38� MAP kinase, which then exerts a strong anti- proliferative effect. This dualistic nature of TGF- may exist in order to maintain lung tissue integrity.