TGF beta 1-Smad canonical and -Erk noncanonical pathways participate in interleukin-17-induced epithelial-mesenchymal transition in Sjogren's syndrome

Interleukin-17 (IL-17) is a pleiotropic cytokine that plays a primary role in triggering epithelial-mesenchymal transition (EMT) in many chronic inflammatory diseases. EMT plays a critical role in the progression of salivary gland (SG) fibrosis in primary Sjogren's syndrome (pSS). This study focused on the activation of the canonical TGF-beta 1/Smad2/3 and noncanonical TGF-beta 1/Erk1/2 pathways in IL-17-dependent TGF beta 1-induced EMT in human SG epithelial cells (SGEC) derived from healthy subjects. The expression of phosphorylated Smad2/3 and Erk1/2 during IL-17 treatment-stimulated EMT was evaluated in healthy SGEC. Cotreatment with IL-17 and specific TGF beta receptor type I kinase inhibitor SB431542, or Erk 1/2 inhibitor U0126, abrogates the corresponding morphological changes and EMT phenotypic markers expression in healthy SGEC. Interestingly, inhibition of canonical TGF beta 1/Smad2/3 signal transduction had no effect on activation of the noncanonical TGF beta 1/Erk1/2/EMT pathway, suggesting that the two pathways act independently in activating IL-17-dependent EMT in SGEC. Epithelial-mesenchymal transition (EMT) plays a critical role in the progression of salivary gland (SG) fibrosis in primary Sjogren's syndrome. This study demonstrates the IL-17-dependent activation of EMT in human SG epithelial cells that occurs through both the canonical TGF-beta 1/Smad2/3 and noncanonical TGF-beta 1/Erk1/2 pathways.