STAT3 controls COL1A2 enhancer activation cooperatively with JunB, regulates type I collagen synthesis posttranscriptionally, and is essential for lung myofibroblast differentiation.

Fibroblast differentiation is a key cellular process that underlies the process of fibrosis, a deadly complication of fibrotic diseases like scleroderma (SSc). This transition coincides with the overproduction of collagen type I (COL1) and other extracellular matrix proteins. High-level expression of the collagen type 1α2 subunit (COL1A2), requires the engagement of a far-upstream enhancer, whose activation is strongly dependent on the AP1 factor JunB. We now report that STAT3 also binds the COL1A2 enhancer and is essential for RNA polymerase recruitment, without affecting JunB binding. STAT3 is required for the increased COL1A2 expression observed in myofibroblasts. We also report that TGFβ partially activates STAT3 and show that inhibiting STAT3 potently blocks TGFβ signaling, matrix remodeling, and TGFβ-induced myofibroblast differentiation. Activation of STAT3 with IL6 transsignaling alone, however, only increased COL1A2 protein expression, leaving COL1A2 mRNA levels unchanged. Our results suggest that activated STAT3 is not the limiting factor for collagen enhancer activation in human lung fibroblasts. Yet, a certain threshold level of STAT3 activity is essential to support activation of the COL1A2 enhancer and TGFβ signaling in fibroblasts. We propose that STAT3 operates at the posttranscriptional as well as the transcriptional level.