Signalling Pathways of Tumor Necrosis Factor-alpha-Stimulated Fractalkine Expression in Rat Mesangial Cells: Down-regulation by cAMP

腫瘤懷死因子誘發大鼠膈細胞表現fractalkine的訊息傳遞途逕：可被cAMP向下調控

陳永銘 ； 林水龍 ； 姜文智 ； 蔡敦仁 ； 謝博生

《Acta Nephrologica》 14卷4期 (2000/10) Pp. 250-250

並列摘要

Fractalkine is a CX3C chemokine for mononuclear cells that has been implicated in the recruitment and accumulation of monocytes seen in glomerular diseases. This study examine the role of tumor necrosis factor (TNF)-alpha-mediated cellular signal transduction pathways on mesangial cell (MC) fractalkine expression. Incubation of MCs with TNF-alpha stimulated both cell-bound and cleaved soluble fractalkine mRNA and protein expression in dose-and time-dependent manner. The incubation of MCs with calphostin C (an inhibtor of protein kinase C(PKC)) or PD98059 (an inhibitor of p42/44 mitogen-activated protein kinase (MAPK)kinase) attenuated MC fractalkine mRNA and protein expression stimulated by TNF-alpha.
When calphostin C and PD98059 were coincubated with MCs, TNF-alpha-stimulated fractalkine mRNA and protein expression was synergistically inhibited. In contrast, J-89 (an inhibitor of cAMP-dependent protein kinase), wortmannin (an inhibitor of phosphatidylinositol 3-kinase) and SB203580 (an inhibitor of p38 MAPK) did not have discernible effects on TNF-alpha-stimulated fractalkine expression. The incubation of MCs with various nuclear factor (NF)-kappa B inhibitors(quercetin, MG132, and TPCK) abolished TNF-alpha-induced degradation of inhibitory protein of NF-kappa B (I-Kappa B) alpha and nuclear translocation of p65/NF-kappa B, and subsequent fractalkine mRNA and protein expression, without inhibition of phosphor-p42/44 MAPK or c-Jun levels. In contrast, curcumin, an activating protein (AO)-1 inhibitor, as will as calphostin C and PD98059, attenuated TNF-alpha-stimulated phosphor-c-Jun levels and fractalkine expression, without discernible effects on TNF-alpha-induced degradation of I-kappa B alpha or p65/NF-kappa B nuclear translocation. Additional experiments examining the role of cAMP on MC fractalkine expression showed that the coincubation of MCs with TNF-alpha and either db-cAMP, forskolin, or pentoxifylline attenuated TNF-alpha-stimulated fractalkine mRNA and protein expression, preceded by attenuation of TNF-alpha-activated phosphorylation of p42/44 MARK and c-Jun, but not nuclear translocation of p65/NF-kappa B. Taken together, these data indicate that TNF-alpha activation of OKC,p42/44 MAPK, AP-1,and NF-kappa B are involved in TNF-alpha-stimulated MC fractalkine expression Uncoupling of p42/44 MAPK or c-Jun/AP-1signals may contribute to cAMP inhibition of MC fractalkine expression activated by TNF-alpha.