Fractalkine (CX3CL1) stimulated by nuclear factor κB (NF-κB)-dependent inflammatory signals induces aortic smooth muscle cell proliferation through an autocrine pathway

Bysani Chandrasekar, Srinivas Mummidi, Rao P. Perla, Sailaja Bysani, Nickolai O. Dulin, Feng Liu, Peter C. Melby

Research output: Contribution to journalArticle

120 Scopus citations

Abstract

Fractalkine (also known as CX3CL1), a CX3C chemokine, activates and attracts monocytes/macrophages to the site of injury/inflammation. It binds to CX3C receptor 1 (CX3CR1), a pertussis toxin-sensitive G-protein-coupled receptor. In smooth muscle cells (SMCs), fractalkine is induced by proinflammatory cytokines [tumour necrosis factor-α (TNF-α) and interferon-γ (IFN-γ)], which may mediate monocyte adhesion to SMCs. However, the mechanisms underlying its induction are unknown. In addition, it is unlear whether SMCs express CX3CR1. TNF-α activated nuclear factor κB (NF-κB) and induced fractalkine and CX3CR1 expression in a time-dependent manner in rat aortic SMCs. Transient transfections with dominant-negative (dn) inhibitory κB (IκB)-α, dnIκB-β, dnIκB kinase (IKK)-γ, kinase-dead (kd) NF-κB-inducing kinase (NIK) and kdIKK-β, or pretreatment with wortmannin, Akt inhibitor, pyrrolidinecarbodithioc acid ammonium salt ('PDTC') or MG-132, significantly attenuated TNF-α-induced fractalkine and CX3CR1 expression. Furthermore, expression of dn TNF-α-receptor-associated factor 2 (TRAF2), but not dnTRAF6, inhibited TNF-α signal transduction. Pretreatment with pertussis toxin or neutralizing anti-CX3CR1 antibodies attenuated TNF-α-induced fractalkine expression, indicating that fractalkine autoregulation plays a role in TNF-α-induced sustained fractalkine expression. Fractalkine induced its own expression, via pertussis toxin-sensitive G-proteins, phosphoinositide 3-kinase (PI 3-kinase), phosphoinositide-dependent kinase 1 (PDK1), Akt, NIK, IKK and NF-κB activation, and induced SMC cell-cell adhesion and cellular proliferation. Taken together, our results demonstrate that TNF-α induces the expression of fractalkine and CX3CR1 in rat aortic SMCs and that this induction is mediated by NF-κB activation. We also show that fractalkine induces its own expression, which is mediated by the PI 3-kinase/PDK1/Akt/NIK/IKK/NF-κB signalling pathway. More importantly, fractalkine increased cell-cell adhesion and aortic SMC proliferation, indicating a role in initiation and progression of atherosclerotic vascular disease.

Original languageEnglish (US)
Pages (from-to)547-558
Number of pages12
JournalBiochemical Journal
Volume373
Issue number2
DOIs
StatePublished - Jul 15 2003

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Keywords

  • Atherosclerosis
  • Autoregulation
  • CX3C receptor 1 (CX3CR1)
  • Cell adhesion
  • Fractalkine (CX3CL1)
  • Mitosis
  • Nuclear factor κB (NF-κB)

ASJC Scopus subject areas

  • Biochemistry
  • Molecular Biology
  • Cell Biology

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