Interleukin-17 stimulates C-reactive protein expression in hepatocytes and smooth muscle cells via p38 MAPK and ERK1/2-dependent NF-kappaB and C/EBPbeta activation.
Elevated systemic levels of the acute phase C-reactive protein (CRP) are predictors of future cardiovascular events. There is evidence that CRP may also play a direct role in atherogenesis. Here we determined whether the proinflammatory interleukin (IL)-17 stimulates CRP expression in hepatocytes (Hep3B cell line and primary hepatocytes) and coronary artery smooth muscle cells (CASMC). Our results demonstrate that IL-17 potently induces CRP expression in Hep3B cells independent of IL-1beta and IL-6. IL-17 induced CRP promoter-driven reporter gene activity that could be attenuated by dominant negative IkappaBalpha or C/EBPbeta knockdown and stimulated both NF-kappaB and C/EBP DNA binding and reporter gene activities. Targeting NF-kappaB and C/EBPbeta activation by pharmacological inhibitors, small interfering RNA interference and adenoviral transduction of dominant negative expression vectors blocked IL-17-mediated CRP induction. Overexpression of wild type p50, p65, and C/EBPbeta stimulated CRP transcription. IL-17 stimulated p38 MAPK and ERK1/2 activation, and SB203580 and PD98059 blunted IL-17-mediated NF-kappaB and C/EBP activation and CRP transcription. These results, confirmed in primary human hepatocytes and CASMC, demonstrate for the first time that IL-17 is a potent inducer of CRP expression via p38 MAPK and ERK1/2-dependent NF-kappaB and C/EBPbeta activation and suggest that IL-17 may mediate chronic inflammation, atherosclerosis, and thrombosis.
Patel
Devang N
DN
Department of Medicine, University of Texas Health Science Center, San Antonio, Texas 78229-3900, and the.
King
Carter A
CA
Department of Medicine, University of Texas Health Science Center, San Antonio, Texas 78229-3900, and the.
Bailey
Steven R
SR
Department of Medicine, University of Texas Health Science Center, San Antonio, Texas 78229-3900, and the.
Holt
Jeffrey W
JW
Department of Medicine, University of Texas Health Science Center, San Antonio, Texas 78229-3900, and the.
Venkatachalam
Kaliyamurthi
K
Department of Medicine, University of Texas Health Science Center, San Antonio, Texas 78229-3900, and the.
Agrawal
Alok
A
Department of Pharmacology, East Tennessee State University, Johnson City, Tennessee 37614.
Valente
Anthony J
AJ
Department of Medicine, University of Texas Health Science Center, San Antonio, Texas 78229-3900, and the.
Chandrasekar
Bysani
B
Department of Medicine, University of Texas Health Science Center, San Antonio, Texas 78229-3900, and the; Department of Veterans Affairs, South Texas Veterans Health Care System, San Antonio, Texas 78229-4404, the. Electronic address: chandraseka@uthscsa.edu.
D002097:C-Reactive Protein / Q000235:genetics*; D022782:CCAAT-Enhancer-Binding Protein-beta / Q000502:physiology*; D045744:Cell Line, Tumor; D048049:Extracellular Signal-Regulated MAP Kinases / Q000502:physiology*; D022781:Hepatocytes / Q000378:metabolism*; D006801:Humans; D020672:I-kappa B Proteins / Q000502:physiology; D020381:Interleukin-17 / Q000494:pharmacology*; D053583:Interleukin-1beta / Q000502:physiology; D015850:Interleukin-6 / Q000502:physiology; D009131:Muscle, Smooth, Vascular / Q000166:cytology / Q000378:metabolism*; D032389:Myocytes, Smooth Muscle / Q000378:metabolism*; D000072000:NF-KappaB Inhibitor alpha; D016328:NF-kappa B / Q000502:physiology*; D017346:Protein Serine-Threonine Kinases / Q000502:physiology; D012333:RNA, Messenger / Q000032:analysis; D048029:TNF Receptor-Associated Factor 6 / Q000502:physiology; D048051:p38 Mitogen-Activated Protein Kinases / Q000502:physiology*; D000097782:NF-kappaB-Inducing Kinase
D002097:C-Reactive Protein; D022782:CCAAT-Enhancer-Binding Protein-beta; D048049:Extracellular Signal-Regulated MAP Kinases; D020672:I-kappa B Proteins; D020381:Interleukin-17; D053583:Interleukin-1beta; D015850:Interleukin-6; D000072000:NF-KappaB Inhibitor alpha; D016328:NF-kappa B; D017346:Protein Serine-Threonine Kinases; D012333:RNA, Messenger; D048029:TNF Receptor-Associated Factor 6; D048051:p38 Mitogen-Activated Protein Kinases; D000097782:NF-kappaB-Inducing Kinase; C000606204:NFKBIA protein, human