TGFβ1-Smad canonical and -Erk noncanonical pathways participate in interleukin-17-induced epithelial–mesenchymal transition in Sjögren’s syndrome

• Published in: Laboratory investigation Vol. 100; no. 6; pp. 824 - 836
• Main Authors: Sisto, Margherita, Lorusso, Loredana, Ingravallo, Giuseppe, Ribatti, Domenico, Lisi, Sabrina
• Format: Journal Article
• Language: English
• Published: New York Nature Publishing Group US 01.06.2020; Nature Publishing Group
• Subjects: 13/21; 13/31; 14/63; 38/77; 692/308/575; 692/420/256/2515; 82/80; Activation; Activation analysis; Aged; Cells, Cultured; Cytokines; Enzyme inhibitors; Epithelial cells; Epithelial-Mesenchymal Transition - physiology; Extracellular signal-regulated kinase; Fibrosis; Humans; Inflammatory diseases; Interleukin 17; Interleukin-17 - metabolism; Interleukins; Kinases; Laboratory Medicine; Lip - cytology; MAP Kinase Signaling System - physiology; Medicine; Medicine & Public Health; Mesenchyme; Middle Aged; Pathology; Salivary gland; Salivary glands; Signal transduction; Sjogren's syndrome; Sjogren's Syndrome - metabolism; Sjogren's Syndrome - pathology; Smad protein; Smad Proteins - metabolism; Smad2 protein; Transforming Growth Factor beta1 - metabolism; Transforming growth factor-b1
• ISSN: 0023-6837; 1530-0307; 1530-0307
• DOI: 10.1038/s41374-020-0373-z

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 Sjögren’s syndrome (pSS). This study focused on the activation of the canonical TGF-β1/Smad2/3 and noncanonical TGF-β1/Erk1/2 pathways in IL-17-dependent TGFβ1-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 TGFβ 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 TGFβ1/Smad2/3 signal transduction had no effect on activation of the noncanonical TGFβ1/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 Sjögren’s syndrome. This study demonstrates the IL-17-dependent activation of EMT in human SG epithelial cells that occurs through both the canonical TGF-β1/Smad2/3 and noncanonical TGF-β1/Erk1/2 pathways.