title: Interleukin-17 modulates myoblast cell migration by inhibiting urokinase type plasminogen activator expression through p38 mitogen-activated protein kinase.
abstract: Interleukin-17 belongs to a family of pro-inflammatory cytokines with pleiotropic effects, which can be associated with several inflammatory diseases of the muscle tissue. Although elevated levels of interleukin-17 have been described in inflammatory myopathies, its role in muscle homeostasis remains to be elucidated. The requirement of the urokinase type plasminogen activator in skeletal myogenesis was recently demonstrated in vivo and in vitro, suggesting its involvement in the regulation of extracellular matrix remodeling, cell migration and myoblast fusion. Our previous results have demonstrated that interleukin-17 inhibits myogenic differentiation of C2C12 myoblasts in vitro concomitantly with the inhibition of cell migration. However, the involvement of urokinase type plasminogen activator in interleukin-17-inhibited myogenesis and migration remained to be analyzed. Therefore, the effect of interleukin-17 on the production of urokinase type plasminogen activator by C2C12 myoblasts was determined in the present study. Our results demonstrated that interleukin-17 strongly inhibits urokinase type plasminogen activator expression during myogenic differentiation. This reduction of urokinase type plasminogen activator production corresponded with the inhibition of cell migration by interleukin-17. Activation of p38 signaling pathway elicited by interleukin-17 mediated the inhibition of both urokinase type plasminogen activator expression and cell migration. Additionally, IL-17 inhibited C2C12 cells migration by causing the cells to reorganize their cytoskeleton and lose polarity. Therefore, our results suggest a novel mechanism by which interleukin-17 regulates myogenic differentiation through the inhibition of urokinase type plasminogen activator expression and cell migration. Accordingly, interleukin-17 may represent a potential clinical target worth investigating for the treatment of inflammatory muscle diseases.
authors.affiliation: Laboratory for Experimental Hematology and Stem Cells, Institute for Medical Research, University of Belgrade, Dr Subotića 4, 11129 Belgrade, Serbia.
authors.forename: Jelena
authors.initials: J
authors.lastname: Kocić
authors.forename: Juan F
authors.initials: JF
authors.lastname: Santibañez
authors.forename: Aleksandra
authors.initials: A
authors.lastname: Krstić
authors.forename: Slavko
authors.initials: S
authors.lastname: Mojsilović
authors.forename: Vesna
authors.initials: V
authors.lastname: Ilić
authors.forename: Diana
authors.initials: D
authors.lastname: Bugarski
mesh_terms: D008841:Actin Cytoskeleton / Q000378:metabolism; D000818:Animals; D002454:Cell Differentiation; D002460:Cell Line; D002465:Cell Movement; D049109:Cell Proliferation; D015536:Down-Regulation; D004789:Enzyme Activation; D048049:Extracellular Signal-Regulated MAP Kinases / Q000378:metabolism; D007093:Imidazoles / Q000494:pharmacology; D020381:Interleukin-17 / Q000502:physiology*; D020935:MAP Kinase Signaling System; D051379:Mice; D032446:Myoblasts / Q000502:physiology*; D011725:Pyridines / Q000494:pharmacology; D015533:Transcriptional Activation; D014568:Urokinase-Type Plasminogen Activator / Q000235:genetics* / Q000378:metabolism; D048051:p38 Mitogen-Activated Protein Kinases / Q000037:antagonists & inhibitors / Q000378:metabolism*
chemical_list: D007093:Imidazoles; D020381:Interleukin-17; D011725:Pyridines; D048049:Extracellular Signal-Regulated MAP Kinases; D048051:p38 Mitogen-Activated Protein Kinases; D014568:Urokinase-Type Plasminogen Activator; C093642:SB 203580