Chemokine-cytokine cross-talk -: The ELR+ CXC chemokine LIX (CXCL5) amplifies a proinflammatory cytokine response via a phosphatidylinositol 3-kinase-NF-κB pathway

被引:86
作者
Chandrasekar, B
Melby, PC
Sarau, HM
Raveendran, M
Perla, RP
Marelli-Berg, FM
Dulin, NO
Singh, IS
机构
[1] Univ Texas, Hlth Sci Ctr, Dept Med, San Antonio, TX 78229 USA
[2] GlaxoSmithKline Beecham, Ctr Excellence Drug Discovery, King Of Prussia, PA 19406 USA
[3] Univ London Imperial Coll Sci Technol & Med, Sch Med, Dept Immunol, London W12 0NN, England
[4] Univ Illinois, Dept Pharmacol, Coll Med, Chicago, IL 60612 USA
[5] Univ Maryland, Sch Med, Dept Med, Baltimore, MD 21201 USA
关键词
D O I
10.1074/jbc.M207006200
中图分类号
Q5 [生物化学]; Q7 [分子生物学];
学科分类号
071010 ; 081704 ;
摘要
It is well established that cytokines can induce the production of chemokines, but the role of chemokines in the regulation of cytokine expression has not been fully investigated. Exposure of rat cardiac-derived endothelial cells (CDEC) to lipopolysaccharide-induced CXC chemokine (LIX), and to a lesser extent to KC and MIP-2, activated NF-kappaB and induced kappaB-driven promoter activity. LIX did not activate Oct-1. LIX-induced interleukin-1beta and tumor necrosis factor-alpha promoter activity, and up-regulated mRNA expression. Increased transcription and mRNA stability both contributed to cytokine expression. LIX-mediated cytokine gene transcription was inhibited by interleukin-10. Transient overexpression of kinase-deficient NF-kappaB-inducing kinase (NIK) and IkappaB kinase (IKK), and dominant negative IkappaB significantly inhibited LIX-mediated NF-kappaB activation in rat CDEC. Inhibition of Gi protein-coupled signal transduction, poly(ADP-ribose) polymerase, phosphatidylinositol 3-kinase, and the 26 S proteasome significantly inhibited LIX-mediated NF-kappaB activation and cytokine gene transcription. Blocking CXCR2 attenuated LIX-mediated kappaB activation and kappaB-driven promoter activity in rat CDEC that express both CXCR1 and -2, and abrogated its activation in mouse CDEC that express only CXCR2. These results indicate that LIX activates NF-kappaB and induces kappaB-responsive proinflammatory cytokines via either CXCR1 or CXCR2, and involved phosphatidylinositol 3-kinase, NIK, IKK, and IkappaB. Thus, in addition to attracting and activating neutrophils, the ELR+ CXC chemokines amplify the inflammatory cascade, stimulating local production of cytokines that have negative inotropic and proapoptotic effects.
引用
收藏
页码:4675 / 4686
页数:12
相关论文
共 67 条