GSE104908
A novel non-canonical signaling pathway mediates TGF-ß1-induced glucocorticoid insensitivity in epithelial cells
Limited therapeutic responses to glucocorticoids in chronic inflammatory disease are partly attributable to interleukins and transforming growth factor-ß1 (TGF-ß1). Global inhibition of TGF-ß1 carries known risks, including autoimmune disease.  Here we elucidate the signaling pathway subserving modulation of glucocorticoid activity by TGF-ß1. The proteomic response of airway epithelial cells to TGF-ß1 revealed 24 candidate proteins of which 3 were prioritized by exclusion of changes induced by: TGF-ß2, which lacks the modulatory activity of TGF-ß1 and TGF-ß3; and those of TGF-ß1 that were prevented by small molecule inhibitors of non-canonical TGF-ß1 signaling, that did not prevent glucocorticoid modulation. Pharmacological and genetic approaches establish that TGF-ß1-induced glucocorticoid insensitivity is mediated by a novel signaling cascade involving LIM domain kinase 2 mediated phosphorylation of phospho-cofilin1 that activates phospholipase D to generate the effector(s) (lyso)phophatidic acid. This study identifies several promising drug targets that potentially enable safe modulation of TGF-ß1 in chronic inflammatory diseases. Overall design: Biological triplicates of BEAS-2B cell lines treated with Dexamethasone, TGFbeta1 and a combination of Dexamethasone +TGFbeta1 were compared among themselves and with an untreated control