Interleukin-17A stimulates cardiac fibroblast proliferation and migration via negative regulation of the dual-specificity phosphatase MKP-1/DUSP-1.
The dual-specificity mitogen-activated protein kinase (MAPK) phosphatase-1 (MKP-1) inactivates MAP kinases by dephosphorylation. Here we show that the proinflammatory cytokine interleukin (IL)-17A induces adult mouse primary cardiac fibroblast (CF) proliferation and migration via IL-17 receptor A//IL-17 receptor C-dependent MKP-1 suppression, and activation of p38 MAPK and ERK1/2. IL-17A mediated p38 MAPK and ERK1/2 activation is inhibited by MKP-1 overexpression, but prolonged by MKP-1 knockdown. IL-17A induced miR-101 expression via PI3K/Akt, and miR-101 inhibitor reversed MKP-1 down regulation. Importantly, MKP-1 knockdown, pharmacological inhibition of p38 MAPK and ERK1/2, or overexpression of dominant negative MEK1, each markedly attenuated IL-17A-mediated CF proliferation and migration. Similarly, IL-17F and IL-17A/F heterodimer that also signal via IL-17RA/IL-17RC, stimulated CF proliferation and migration. These results indicate that IL-17A stimulates CF proliferation and migration via Akt/miR-101/MKP-1-dependent p38 MAPK and ERK1/2 activation. These studies support a potential role for IL-17 in cardiac fibrosis and adverse myocardial remodeling.
Department of Medicine, University of Texas Health Science Center, San Antonio, TX 78229, United States.
Anthony J
AJ
Valente
Heart and Vascular Institute, Tulane University School of Medicine, New Orleans, LA 70112, United States.
Tadashi
T
Yoshida
Department of Physiology, Louisiana State University Health Sciences Center, New Orleans, LA 70112, United States.
Jason D
JD
Gardner
Department of Microbiology and Immunology, Tulane University School of Medicine, New Orleans, LA 70112, United States.
Naveen
N
Somanna
Heart and Vascular Institute, Tulane University School of Medicine, New Orleans, LA 70112, United States; Research Service, Southeast Louisiana Veterans Health Care System, New Orleans, LA 70161, United States.
Patrice
P
Delafontaine
Heart and Vascular Institute, Tulane University School of Medicine, New Orleans, LA 70112, United States; Research Service, Southeast Louisiana Veterans Health Care System, New Orleans, LA 70161, United States. Electronic address: bchandra@tulane.edu.
Bysani
B
Chandrasekar
D000818:Animals; D002465:Cell Movement / Q000187:drug effects / Q000235:genetics*; D049109:Cell Proliferation / Q000187:drug effects; D054638:Dual Specificity Phosphatase 1 / Q000037:antagonists & inhibitors / Q000172:deficiency / Q000235:genetics*; D004791:Enzyme Inhibitors / Q000494:pharmacology; D048049:Extracellular Signal-Regulated MAP Kinases / Q000037:antagonists & inhibitors / Q000235:genetics / Q000378:metabolism; D005347:Fibroblasts / Q000166:cytology / Q000187:drug effects / Q000378:metabolism*; D005355:Fibrosis / Q000235:genetics / Q000378:metabolism* / Q000473:pathology; D015870:Gene Expression; D005822:Genetic Vectors / Q000235:genetics / Q000378:metabolism; D020381:Interleukin-17 / Q000235:genetics / Q000378:metabolism*; D051379:Mice; D035683:MicroRNAs / Q000235:genetics / Q000378:metabolism*; D009206:Myocardium / Q000378:metabolism* / Q000473:pathology; D019869:Phosphatidylinositol 3-Kinases / Q000235:genetics / Q000378:metabolism; D051057:Proto-Oncogene Proteins c-akt / Q000235:genetics / Q000378:metabolism; D053722:Receptors, Interleukin-17 / Q000235:genetics / Q000378:metabolism; D015398:Signal Transduction / Q000187:drug effects; D014158:Transcription, Genetic; D014162:Transfection; D020257:Ventricular Remodeling; D048051:p38 Mitogen-Activated Protein Kinases / Q000037:antagonists & inhibitors / Q000235:genetics / Q000378:metabolism
D004791:Enzyme Inhibitors; D020381:Interleukin-17; D035683:MicroRNAs; D053722:Receptors, Interleukin-17; D019869:Phosphatidylinositol 3-Kinases; D051057:Proto-Oncogene Proteins c-akt; D048049:Extracellular Signal-Regulated MAP Kinases; D048051:p38 Mitogen-Activated Protein Kinases; D054638:Dual Specificity Phosphatase 1; C517020:Dusp1 protein, mouse