Transforming growth factor (TGF)-β1 increases endothelial monolayer permeability and myosin light chain phosphorylation (MLC-P) beginning 1–2 h posttreatment, suggesting that changes in gene expression may be required for these responses. The role of extracellular signal-regulated kinase (ERK) 1/2 and p38 mitogen-activated protein kinase (p38 MAPK) was investigated because both kinases have been implicated in regulating gene expression after TGF-β1. ERK1/2 phosphorylation increased threefold above the control level, and the increase was temporally associated with the increase in MLC-P. Inhibition of ERK1/2 phosphorylation with the MAPK kinase inhibitor U-0126 did not prevent the increase in either monolayer permeability or MLC-P. p38 MAPK phosphorylation increased fourfold above the control level, but unlike ERK1/2, this increase peaked 30 min and 1 h post-TGF-β1 treatment. Inhibition of p38 MAPK activity with SB-203580 prevented the increases in both monolayer permeability and MLC-P. Treatment of the monolayers with cycloheximide in conjunction with TGF-β1-inhibited MLC-P, showing a requirement for protein synthesis. These studies demonstrate that p38 MAPK activation and subsequent protein synthesis are part of the signal transduction pathway leading to the TGF-β1-induced increases in monolayer permeability and MLC-P.

Goldberg, P. L., MacNaughton, D. E., Clements, R. T., Minnear, F. L., & Vincent, P. A. (2002). p38 MAPK activation by TGF-β1 increases MLC phosphorylation and endothelial monolayer permeability. American Journal of Physiology-Lung Cellular and Molecular Physiology, 282(1), L146–L154.