Journal
AMERICAN JOURNAL OF PHYSIOLOGY-CELL PHYSIOLOGY
Volume 290, Issue 6, Pages C1583-C1591Publisher
AMER PHYSIOLOGICAL SOC
DOI: 10.1152/ajpcell.00390.2005
Keywords
nitric oxide synthase
Categories
Funding
- NCI NIH HHS [CA-89366] Funding Source: Medline
- NHLBI NIH HHS [R01-HL-49426, T-32-HL-07194, R01-HL-40992] Funding Source: Medline
- NATIONAL CANCER INSTITUTE [R01CA089366] Funding Source: NIH RePORTER
- NATIONAL HEART, LUNG, AND BLOOD INSTITUTE [R01HL040992, T32HL007194, R01HL049426] Funding Source: NIH RePORTER
Ask authors/readers for more resources
Although the inflammatory cytokine interleukin-1 beta (IL-beta) is an important regulator of gene expression in vascular smooth muscle (VSM), the signal transduction pathways leading to transcriptional activation upon IL-1 beta stimulation are poorly understood. Recent studies have implicated IL-1 beta-mediated ERK1/2 activation in the upregulation of type II nitric oxide synthase (iNOS) in VSM. We report that these events are mediated in a phospholipase C (PLC)- and protein kinase C (PKC)- dependent manner utilizing a signaling mechanism independent of p21(ras) (Ras) and Raf1 activation. Stimulation of rat aortic VSM cells with IL-1 beta activated PLC-gamma and pharmacological inhibition of PLC attenuated IL-1 beta-induced ERK1/2 activation and subsequent iNOS expression. Stimulation with IL-1 beta activated PKC-alpha and -delta, which was blocked using the PLC inhibitor U-73122. Pharmacological studies using isoform-specific PKC inhibitors and adenoviral overexpression of constitutively active PKC-delta indicated that ERK1/2 activation was PKC-alpha independent and PKC-delta dependent. Similarly, adenoviral overexpression of constitutively activated PKC-delta enhanced iNOS expression. IL-1 beta stimulation did not induce either Ras or Raf1 activity. The absence of a functional role for Ras and Raf1 related to ERK1/2 activation and iNOS expression was further confirmed by adenoviral overexpression of dominant-negative Ras and treatment with the Raf1 inhibitor GW5074. Taken together, we have outlined a novel transduction pathway implicating PKC-delta as a critical component of the IL-1-dependent activation of ERK in VSM cells.
Authors
I am an author on this paper
Click your name to claim this paper and add it to your profile.
Reviews
Recommended
No Data Available