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.

Abstract

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.

• Authors: Devang N Patel, Carter A King, Steven R Bailey, Jeffrey W Holt, Kaliyamurthi Venkatachalam, Alok Agrawal, Anthony J Valente, Bysani Chandrasekar
• Journal: The Journal of biological chemistry (J Biol Chem) Vol. 282 Issue 37 Pg. 27229-27238 (Sep 14 2007) ISSN: 0021-9258 [Print] United States
• PMID: 17652082 (Publication Type: Journal Article, Research Support, N.I.H., Extramural, Research Support, U.S. Gov't, Non-P.H.S.)

Chemical References

• CCAAT-Enhancer-Binding Protein-beta
• I-kappa B Proteins
• Interleukin-17
• Interleukin-1beta
• Interleukin-6
• NF-kappa B
• NFKBIA protein, human
• RNA, Messenger
• TNF Receptor-Associated Factor 6
• NF-KappaB Inhibitor alpha
• C-Reactive Protein
• Protein Serine-Threonine Kinases
• Extracellular Signal-Regulated MAP Kinases
• p38 Mitogen-Activated Protein Kinases
• NF-kappa B kinase

Topics

• C-Reactive Protein (genetics)
• CCAAT-Enhancer-Binding Protein-beta (physiology)
• Cell Line, Tumor
• Extracellular Signal-Regulated MAP Kinases (physiology)
• Hepatocytes (metabolism)
• Humans
• I-kappa B Proteins (physiology)
• Interleukin-17 (pharmacology)
• Interleukin-1beta (physiology)
• Interleukin-6 (physiology)
• Muscle, Smooth, Vascular (cytology, metabolism)
• Myocytes, Smooth Muscle (metabolism)
• NF-KappaB Inhibitor alpha
• NF-kappa B (physiology)
• Protein Serine-Threonine Kinases (physiology)
• RNA, Messenger (analysis)
• TNF Receptor-Associated Factor 6 (physiology)
• p38 Mitogen-Activated Protein Kinases (physiology)