Interleukin-17 stimulates C-reactive protein expression in hepatocytes and smooth muscle cells via p38 MAPK and ERK1/2-dependent NF-κB and C/EBP β activation
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Patel, Devang N.
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机构:Univ Texas, Hlth Sci Ctr, Dept Med, San Antonio, TX 78229 USA
Patel, Devang N.
King, Carter A.
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机构:Univ Texas, Hlth Sci Ctr, Dept Med, San Antonio, TX 78229 USA
King, Carter A.
Bailey, Steven R.
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机构:Univ Texas, Hlth Sci Ctr, Dept Med, San Antonio, TX 78229 USA
Bailey, Steven R.
Holt, Jeffrey W.
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机构:Univ Texas, Hlth Sci Ctr, Dept Med, San Antonio, TX 78229 USA
Holt, Jeffrey W.
Venkatachalam, Kaliyamurthi
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机构:Univ Texas, Hlth Sci Ctr, Dept Med, San Antonio, TX 78229 USA
Venkatachalam, Kaliyamurthi
Agrawal, Alok
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机构:Univ Texas, Hlth Sci Ctr, Dept Med, San Antonio, TX 78229 USA
Agrawal, Alok
Valente, Anthony J.
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机构:Univ Texas, Hlth Sci Ctr, Dept Med, San Antonio, TX 78229 USA
Valente, Anthony J.
Chandrasekar, Bysani
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机构:Univ Texas, Hlth Sci Ctr, Dept Med, San Antonio, TX 78229 USA
Chandrasekar, Bysani
机构:
[1] Univ Texas, Hlth Sci Ctr, Dept Med, San Antonio, TX 78229 USA
[2] E Tennessee State Univ, Dept Pharmacol, Johnson City, TN 37614 USA
[3] S Texas Vet Hlth Care Syst, Dept Vet Affairs, San Antonio, TX 78229 USA
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-1 beta and IL-6. IL-17 induced CRP promoter-driven reporter gene activity that could be attenuated by dominant negative I kappa B alpha or C/EBP beta knockdown and stimulated both NF-kappa B and C/EBP DNA binding and reporter gene activities. Targeting NF-kappa B and C/EBP beta 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/EBP beta stimulated CRP transcription. IL-17 stimulated p38 MAPK and ERK1/2 activation, and SB203580 and PD98059 blunted IL-17-mediated NF-kappa B 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-kappa B and C/EBP beta activation and suggest that IL-17 may mediate chronic inflammation, atherosclerosis, and thrombosis.