PLX255490

GSE104908: A novel non-canonical signaling pathway mediates TGF-1-induced glucocorticoid insensitivity in epithelial cells

• Organsim human
• Type RNASEQ
• Target gene
• Project ARCHS4

Limited therapeutic responses to glucocorticoids in chronic inflammatory disease are partly attributable to interleukins and transforming growth factor-1 (TGF-1). Global inhibition of TGF-1 carries known risks, including autoimmune disease. Here we elucidate the signaling pathway subserving modulation of glucocorticoid activity by TGF-1. The proteomic response of airway epithelial cells to TGF-1 revealed 24 candidate proteins of which 3 were prioritized by exclusion of changes induced by: TGF-2, which lacks the modulatory activity of TGF-1 and TGF-3; and those of TGF-1 that were prevented by small molecule inhibitors of non-canonical TGF-1 signaling, that did not prevent glucocorticoid modulation. Pharmacological and genetic approaches establish that TGF-1-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-1 in chronic inflammatory diseases. SOURCE: Guillermo López-Campos Queen's University of Belfast