Crosstalk between mitogen-activated protein kinase inhibitors and transforming growth factor-β signaling results in variable activation of human dermal fibroblasts.

Abstract

Fibroblast activation is a key step in the establishment of skin fibrosis induced by acute injury, and it is characterized by the differentiation of plastic resident tissue fibroblasts into contractile, extracellular matrix-secreting myofibroblasts. As fibroblast activation must be regulated in vivo, fibroblasts receive signals from the surrounding environment that initiate their fibrotic program. Thus, the present study investigated the effects of mitogen-activated protein kinase (MAPK) signaling pathways on fibroblast activation. It was demonstrated in primary human dermal fibroblasts that small molecule-mediated inhibition of extracellular signal-regulated kinase (ERK) and c-Jun N-terminal kinase (JNK) potentiated fibroblast activation, and that small molecule-mediated inhibition of p38 antagonized fibroblast activation. ERK and JNK inhibition cooperatively enhanced fibroblast activation mediated by treatment with exogenous transforming growth factor (TGF)-β1, and p38 inhibition antagonized ERK inhibitor-mediated or JNK inhibitor-mediated fibroblast activation. Transcript analysis demonstrated that ERK and JNK inhibitor-mediated fibroblast activation was accompanied by distinct changes in the expression of TGF-β-associated ligands and receptors, and that p38 inhibitor-mediated antagonism of fibroblast activation was accompanied by a distinct expression paradigm of TGF-β-associated genes, including upregulation of beta-glycan. ERK inhibitor-mediated and JNK inhibitor-mediated fibroblast activation was partially antagonized by small molecule-mediated inhibition of TGF-β receptor (R)1, indicating that these mechanisms of fibroblast activation are partially dependent on TGF-β/TGF-βR signaling. These data collectively demonstrate and provide partial explanations of the varied effects and pathway dependencies of MAPK inhibitor-mediated effects on fibroblast activation.