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Inhibition by pentoxifylline of TNF‐α‐stimulated fractalkine production in vascular smooth muscle cells: evidence for mediation by NF‐ κ B down‐regulation
Author(s) -
Chen YungMing,
Tu ChaoJung,
Hung KungYu,
Wu KwanDun,
Tsai TunJun,
Hsieh BorShen
Publication year - 2003
Publication title -
british journal of pharmacology
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 2.432
H-Index - 211
eISSN - 1476-5381
pISSN - 0007-1188
DOI - 10.1038/sj.bjp.0705088
Subject(s) - calphostin c , calphostin , protein kinase c , pyrrolidine dithiocarbamate , mg132 , pentoxifylline , wortmannin , protein kinase a , lactacystin , vascular smooth muscle , anisomycin , tumor necrosis factor alpha , mapk/erk pathway , cycloheximide , chemokine , p38 mitogen activated protein kinases , endocrinology , biology , protein kinase inhibitor , medicine , kinase , signal transduction , microbiology and biotechnology , proteasome inhibitor , nf κb , pharmacology , phosphatidylinositol , inflammation , proteasome , protein biosynthesis , smooth muscle
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)‐α stimulated fractalkine expression in cultured rat vascular smooth muscle cells (VSMCs), and the modulatory effect of a haemorrheologic agent, pentoxifylline, on its production. TNF‐ α (1–50 ng ml −1 ) stimulated fractalkine mRNA and protein expression in concentration‐ and time‐dependent manners. Pretreatment with calphostin C (0.4 μ M , a selective inhibitor of protein kinase C (PKC), and PD98059 (40 μ M ), a specific inhibitor of p42/44 mitogen‐activated protein kinase (MAPK) kinase, attenuated TNF‐α‐stimulated fractalkine mRNA and protein expression. In contrast, H‐89 (2 μ M ), a selective inhibitor of cAMP‐dependent protein kinase, wortmannin (0.5 μ M ), a selective inhibitor of phosphatidylinositol 3‐kinase, and SB203580 (40 μ M ), a specific inhibitor of p38 MAPK, had no discernible effect. The ubiquitin/proteosome inhibitors, MG132 (10 μ M ) and pyrrolidine dithiocarbamate (200 μ M ), suppressed activation of NF‐κB as well as stimulation of fractalkine mRNA and protein expression by TNF‐α. TNF‐α‐activated phosphorylation of PKC was blocked by calphostin C, whereas TNF‐α‐augmented phospho‐p42/44 MAPK and phospho‐c‐Jun levels were reduced by PD98059. Neither calphostin C nor PD98059 affected TNF‐α‐induced degradation of I‐κBα or p65 nuclear translocation. Pretreatment with pentoxifylline (0.1–1 mg ml −1 ) decreased TNF‐α‐stimulated fractalkine mRNA and protein expression, which was preceded by a reduction in TNF‐α‐activated phosphorylation of PKC, p42/44 MAPK and c‐Jun as well as degradation of I‐κBα and p65/NF‐κB nuclear translocation. These data indicate that activation of PKC, p42/44 MAPK kinase, and NF‐κB are involved in TNF‐α‐stimulated fractalkine production in VSMCs. Down‐regulation of the PKC, p42/44 MAPK, and p65/NF‐κB signals by PTX may be therapeutically relevant and provide an explanation for the anti‐fractalkine effect of this drug.British Journal of Pharmacology (2003) 138 , 950–958. doi: 10.1038/sj.bjp.0705088