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PKC-delta mediates activation of ERK1/2 and induction of iNOS by IL-1beta in vascular smooth muscle cells.
Am J Physiol Cell Physiol 2006; 290(6):C1583-91AJ

Abstract

Although the inflammatory cytokine interleukin-1beta (IL-beta) is an important regulator of gene expression in vascular smooth muscle (VSM), the signal transduction pathways leading to transcriptional activation upon IL-1beta stimulation are poorly understood. Recent studies have implicated IL-1beta-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)-delta-dependent manner utilizing a signaling mechanism independent of p21(ras) (Ras) and Raf1 activation. Stimulation of rat aortic VSM cells with IL-1beta activated PLC-gamma and pharmacological inhibition of PLC attenuated IL-1beta-induced ERK1/2 activation and subsequent iNOS expression. Stimulation with IL-1beta 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-1beta 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+Show Affiliations

Center for Cardiovascular Sciences, MC-8, Albany Medical College, Albany, NY 12208, USA. ginnanr@mail.amc.eduNo affiliation info availableNo affiliation info availableNo affiliation info available

Pub Type(s)

Journal Article
Research Support, N.I.H., Extramural

Language

eng

PubMed ID

16436473

Citation

Ginnan, Roman, et al. "PKC-delta Mediates Activation of ERK1/2 and Induction of iNOS By IL-1beta in Vascular Smooth Muscle Cells." American Journal of Physiology. Cell Physiology, vol. 290, no. 6, 2006, pp. C1583-91.
Ginnan R, Guikema BJ, Singer HA, et al. PKC-delta mediates activation of ERK1/2 and induction of iNOS by IL-1beta in vascular smooth muscle cells. Am J Physiol, Cell Physiol. 2006;290(6):C1583-91.
Ginnan, R., Guikema, B. J., Singer, H. A., & Jourd'heuil, D. (2006). PKC-delta mediates activation of ERK1/2 and induction of iNOS by IL-1beta in vascular smooth muscle cells. American Journal of Physiology. Cell Physiology, 290(6), pp. C1583-91.
Ginnan R, et al. PKC-delta Mediates Activation of ERK1/2 and Induction of iNOS By IL-1beta in Vascular Smooth Muscle Cells. Am J Physiol, Cell Physiol. 2006;290(6):C1583-91. PubMed PMID: 16436473.
* Article titles in AMA citation format should be in sentence-case
TY - JOUR T1 - PKC-delta mediates activation of ERK1/2 and induction of iNOS by IL-1beta in vascular smooth muscle cells. AU - Ginnan,Roman, AU - Guikema,Benjamin J, AU - Singer,Harold A, AU - Jourd'heuil,David, Y1 - 2006/01/25/ PY - 2006/1/27/pubmed PY - 2006/7/15/medline PY - 2006/1/27/entrez SP - C1583 EP - 91 JF - American journal of physiology. Cell physiology JO - Am. J. Physiol., Cell Physiol. VL - 290 IS - 6 N2 - Although the inflammatory cytokine interleukin-1beta (IL-beta) is an important regulator of gene expression in vascular smooth muscle (VSM), the signal transduction pathways leading to transcriptional activation upon IL-1beta stimulation are poorly understood. Recent studies have implicated IL-1beta-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)-delta-dependent manner utilizing a signaling mechanism independent of p21(ras) (Ras) and Raf1 activation. Stimulation of rat aortic VSM cells with IL-1beta activated PLC-gamma and pharmacological inhibition of PLC attenuated IL-1beta-induced ERK1/2 activation and subsequent iNOS expression. Stimulation with IL-1beta 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-1beta 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. SN - 0363-6143 UR - https://www.unboundmedicine.com/medline/citation/16436473/PKC_delta_mediates_activation_of_ERK1/2_and_induction_of_iNOS_by_IL_1beta_in_vascular_smooth_muscle_cells_ L2 - http://www.physiology.org/doi/full/10.1152/ajpcell.00390.2005?url_ver=Z39.88-2003&rfr_id=ori:rid:crossref.org&rfr_dat=cr_pub=pubmed DB - PRIME DP - Unbound Medicine ER -