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Inhibition by pentoxifylline of TNF-alpha-stimulated fractalkine production in vascular smooth muscle cells: evidence for mediation by NF-kappa B down-regulation.
Br J Pharmacol. 2003 Mar; 138(5):950-8.BJ

Abstract

(1) Fractalkine is a CX(3)C chemokine for mononuclear leukocytes that is expressed mainly by vascular cells, and regulated by pro-inflammatory cytokines. This study investigated signal transduction mechanisms by which tumor necrosis factor (TNF)-alpha stimulated fractalkine expression in cultured rat vascular smooth muscle cells (VSMCs), and the modulatory effect of a haemorrheologic agent, pentoxifylline, on its production. (2) TNF-alpha (1-50 ng ml(-1)) stimulated fractalkine mRNA and protein expression in concentration- and time-dependent manners. Pretreatment with calphostin C (0.4 micro M, a selective inhibitor of protein kinase C (PKC), and PD98059 (40 micro M), a specific inhibitor of p42/44 mitogen-activated protein kinase (MAPK) kinase, attenuated TNF-alpha-stimulated fractalkine mRNA and protein expression. In contrast, H-89 (2 micro M), a selective inhibitor of cAMP-dependent protein kinase, wortmannin (0.5 micro M), a selective inhibitor of phosphatidylinositol 3-kinase, and SB203580 (40 micro M), a specific inhibitor of p38 MAPK, had no discernible effect. (3) The ubiquitin/proteosome inhibitors, MG132 (10 micro M) and pyrrolidine dithiocarbamate (200 micro M), suppressed activation of NF-kappaB as well as stimulation of fractalkine mRNA and protein expression by TNF-alpha. (4) TNF-alpha-activated phosphorylation of PKC was blocked by calphostin C, whereas TNF-alpha-augmented phospho-p42/44 MAPK and phospho-c-Jun levels were reduced by PD98059. Neither calphostin C nor PD98059 affected TNF-alpha-induced degradation of I-kappaBalpha or p65 nuclear translocation. (5) Pretreatment with pentoxifylline (0.1-1 mg ml(-1)) decreased TNF-alpha-stimulated fractalkine mRNA and protein expression, which was preceded by a reduction in TNF-alpha-activated phosphorylation of PKC, p42/44 MAPK and c-Jun as well as degradation of I-kappaBalpha and p65/NF-kappaB nuclear translocation. (6) These data indicate that activation of PKC, p42/44 MAPK kinase, and NF-kappaB are involved in TNF-alpha-stimulated fractalkine production in VSMCs. Down-regulation of the PKC, p42/44 MAPK, and p65/NF-kappaB signals by PTX may be therapeutically relevant and provide an explanation for the anti-fractalkine effect of this drug.

Authors+Show Affiliations

Department of Internal Medicine, National Taiwan University Hospital and College of Medicine National Taiwan University, Taipei, Taiwan.No affiliation info availableNo affiliation info availableNo affiliation info availableNo affiliation info availableNo affiliation info available

Pub Type(s)

Journal Article
Research Support, Non-U.S. Gov't

Language

eng

PubMed ID

12642397

Citation

Chen, Yung-Ming, et al. "Inhibition By Pentoxifylline of TNF-alpha-stimulated Fractalkine Production in Vascular Smooth Muscle Cells: Evidence for Mediation By NF-kappa B Down-regulation." British Journal of Pharmacology, vol. 138, no. 5, 2003, pp. 950-8.
Chen YM, Tu CJ, Hung KY, et al. Inhibition by pentoxifylline of TNF-alpha-stimulated fractalkine production in vascular smooth muscle cells: evidence for mediation by NF-kappa B down-regulation. Br J Pharmacol. 2003;138(5):950-8.
Chen, Y. M., Tu, C. J., Hung, K. Y., Wu, K. D., Tsai, T. J., & Hsieh, B. S. (2003). Inhibition by pentoxifylline of TNF-alpha-stimulated fractalkine production in vascular smooth muscle cells: evidence for mediation by NF-kappa B down-regulation. British Journal of Pharmacology, 138(5), 950-8.
Chen YM, et al. Inhibition By Pentoxifylline of TNF-alpha-stimulated Fractalkine Production in Vascular Smooth Muscle Cells: Evidence for Mediation By NF-kappa B Down-regulation. Br J Pharmacol. 2003;138(5):950-8. PubMed PMID: 12642397.
* Article titles in AMA citation format should be in sentence-case
TY - JOUR T1 - Inhibition by pentoxifylline of TNF-alpha-stimulated fractalkine production in vascular smooth muscle cells: evidence for mediation by NF-kappa B down-regulation. AU - Chen,Yung-Ming, AU - Tu,Chao-Jung, AU - Hung,Kung-Yu, AU - Wu,Kwan-Dun, AU - Tsai,Tun-Jun, AU - Hsieh,Bor-Shen, PY - 2003/3/19/pubmed PY - 2003/10/16/medline PY - 2003/3/19/entrez SP - 950 EP - 8 JF - British journal of pharmacology JO - Br J Pharmacol VL - 138 IS - 5 N2 - (1) Fractalkine is a CX(3)C chemokine for mononuclear leukocytes that is expressed mainly by vascular cells, and regulated by pro-inflammatory cytokines. This study investigated signal transduction mechanisms by which tumor necrosis factor (TNF)-alpha stimulated fractalkine expression in cultured rat vascular smooth muscle cells (VSMCs), and the modulatory effect of a haemorrheologic agent, pentoxifylline, on its production. (2) TNF-alpha (1-50 ng ml(-1)) stimulated fractalkine mRNA and protein expression in concentration- and time-dependent manners. Pretreatment with calphostin C (0.4 micro M, a selective inhibitor of protein kinase C (PKC), and PD98059 (40 micro M), a specific inhibitor of p42/44 mitogen-activated protein kinase (MAPK) kinase, attenuated TNF-alpha-stimulated fractalkine mRNA and protein expression. In contrast, H-89 (2 micro M), a selective inhibitor of cAMP-dependent protein kinase, wortmannin (0.5 micro M), a selective inhibitor of phosphatidylinositol 3-kinase, and SB203580 (40 micro M), a specific inhibitor of p38 MAPK, had no discernible effect. (3) The ubiquitin/proteosome inhibitors, MG132 (10 micro M) and pyrrolidine dithiocarbamate (200 micro M), suppressed activation of NF-kappaB as well as stimulation of fractalkine mRNA and protein expression by TNF-alpha. (4) TNF-alpha-activated phosphorylation of PKC was blocked by calphostin C, whereas TNF-alpha-augmented phospho-p42/44 MAPK and phospho-c-Jun levels were reduced by PD98059. Neither calphostin C nor PD98059 affected TNF-alpha-induced degradation of I-kappaBalpha or p65 nuclear translocation. (5) Pretreatment with pentoxifylline (0.1-1 mg ml(-1)) decreased TNF-alpha-stimulated fractalkine mRNA and protein expression, which was preceded by a reduction in TNF-alpha-activated phosphorylation of PKC, p42/44 MAPK and c-Jun as well as degradation of I-kappaBalpha and p65/NF-kappaB nuclear translocation. (6) These data indicate that activation of PKC, p42/44 MAPK kinase, and NF-kappaB are involved in TNF-alpha-stimulated fractalkine production in VSMCs. Down-regulation of the PKC, p42/44 MAPK, and p65/NF-kappaB signals by PTX may be therapeutically relevant and provide an explanation for the anti-fractalkine effect of this drug. SN - 0007-1188 UR - https://www.unboundmedicine.com/medline/citation/12642397/Inhibition_by_pentoxifylline_of_TNF_alpha_stimulated_fractalkine_production_in_vascular_smooth_muscle_cells:_evidence_for_mediation_by_NF_kappa_B_down_regulation_ L2 - https://doi.org/10.1038/sj.bjp.0705088 DB - PRIME DP - Unbound Medicine ER -