Chemokine-cytokine cross-talk: The ELR+ CXC chemokine LIX (CXCl5) amplifies a proinflammatory cytokine response via a phosphatidylinositol 3-kinase-NF-κB pathway

Bysani Chandrasekar, Peter C. Melby, Henry M. Sarau, Muthuswamy Raveendran, Rao P. Perla, Federica M. Marelli-Berg, Nickolai O. Dulin, Ishwar S. Singh

Research output: Contribution to journalArticlepeer-review

79 Scopus citations


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-κB and induced κB-driven promoter activity. LIX did not activate Oct-1. LIX-induced interleukin-1β and tumor necrosis factor-α 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-κB-inducing kinase (NIK) and IκKB kinase (IKK), and dominant negative IKB significantly inhibited LIX-mediated NF-κB 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-κB activation and cytokine gene transcription. Blocking CXCR2 attenuated LIX-mediated κB activation and κB-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-κKB and induces κB-responsive proinflammatory cytokines via either CXCR1 or CXCR2, and involved phosphatidylinositol 3-kinase, NIK, IKK, and IκB. 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.

Original languageEnglish (US)
Pages (from-to)4675-4686
Number of pages12
JournalJournal of Biological Chemistry
Issue number7
StatePublished - Feb 14 2003
Externally publishedYes

ASJC Scopus subject areas

  • Biochemistry
  • Molecular Biology
  • Cell Biology


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