Chemokine-cytokine cross-talk. The ELR+ CXC chemokine LIX (CXCL5) amplifies a proinflammatory cytokine response via a phosphatidylinositol 3-kinase-NF-kappa B pathway.
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 G(i) 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.
Chandrasekar
Bysani
B
Department of Medicine, University of Texas Health Science Center, San Antonio, Texas 78229-3900, USA. chandraseka@uthscsa.edu
Melby
Peter C
PC
Sarau
Henry M
HM
Raveendran
Muthuswamy
M
Perla
Rao P
RP
Marelli-Berg
Federica M
FM
Dulin
Nickolai O
NO
Singh
Ishwar S
IS
D000818:Animals; D002478:Cells, Cultured; D054360:Chemokine CXCL1; D054426:Chemokine CXCL2; D054365:Chemokine CXCL5; D018925:Chemokines / Q000378:metabolism / Q000494:pharmacology; D019743:Chemokines, CXC / Q000378:metabolism* / Q000494:pharmacology; D002630:Chemotactic Factors / Q000378:metabolism / Q000494:pharmacology; D004727:Endothelium / Q000378:metabolism*; D036341:Intercellular Signaling Peptides and Proteins / Q000378:metabolism / Q000494:pharmacology; D051379:Mice; D016328:NF-kappa B / Q000378:metabolism*; D019869:Phosphatidylinositol 3-Kinases / Q000378:metabolism*; D051381:Rats; D020239:Receptor Cross-Talk; D023062:Receptors, Interleukin-8A / Q000378:metabolism; D023063:Receptors, Interleukin-8B / Q000378:metabolism; D015398:Signal Transduction / Q000187:drug effects
D054360:Chemokine CXCL1; D054426:Chemokine CXCL2; D054365:Chemokine CXCL5; D018925:Chemokines; D019743:Chemokines, CXC; D002630:Chemotactic Factors; C475895:Cxcl1 protein, mouse; C513297:Cxcl1 protein, rat; C404915:Cxcl2 protein, mouse; C513296:Cxcl2 protein, rat; C094739:Cxcl5 protein, mouse; D036341:Intercellular Signaling Peptides and Proteins; D016328:NF-kappa B; D023062:Receptors, Interleukin-8A; D023063:Receptors, Interleukin-8B; D019869:Phosphatidylinositol 3-Kinases