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 Melby

Research output: Contribution to journalArticle

120 Citations (Scopus)

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
Externally publishedYes

Fingerprint

Chemokine CX3CL1
Cell proliferation
Smooth Muscle Myocytes
Muscle
Cell Proliferation
Phosphotransferases
Tumor Necrosis Factor-alpha
1-Phosphatidylinositol 4-Kinase
Pertussis Toxin
Cell adhesion
Phosphatidylinositols
Cell Adhesion
CX3C Chemokines
Rats
Monocytes
Chemical activation
Tumor Necrosis Factor Receptor-Associated Peptides and Proteins
V28 receptor
Signal transduction
Macrophages

Keywords

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

ASJC Scopus subject areas

  • Biochemistry

Cite this

Fractalkine (CX3CL1) stimulated by nuclear factor κB (NF-κB)-dependent inflammatory signals induces aortic smooth muscle cell proliferation through an autocrine pathway. / Chandrasekar, Bysani; Mummidi, Srinivas; Perla, Rao P.; Bysani, Sailaja; Dulin, Nickolai O.; Liu, Feng; Melby, Peter.

In: Biochemical Journal, Vol. 373, No. 2, 15.07.2003, p. 547-558.

Research output: Contribution to journalArticle

Chandrasekar, Bysani ; Mummidi, Srinivas ; Perla, Rao P. ; Bysani, Sailaja ; Dulin, Nickolai O. ; Liu, Feng ; Melby, Peter. / Fractalkine (CX3CL1) stimulated by nuclear factor κB (NF-κB)-dependent inflammatory signals induces aortic smooth muscle cell proliferation through an autocrine pathway. In: Biochemical Journal. 2003 ; Vol. 373, No. 2. pp. 547-558.
@article{806d5199dcdb45ac8421b6d1a4970858,
title = "Fractalkine (CX3CL1) stimulated by nuclear factor κB (NF-κB)-dependent inflammatory signals induces aortic smooth muscle cell proliferation through an autocrine pathway",
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.",
keywords = "Atherosclerosis, Autoregulation, Cell adhesion, CX3C receptor 1 (CX3CR1), Fractalkine (CX3CL1), Mitosis, Nuclear factor κB (NF-κB)",
author = "Bysani Chandrasekar and Srinivas Mummidi and Perla, {Rao P.} and Sailaja Bysani and Dulin, {Nickolai O.} and Feng Liu and Peter Melby",
year = "2003",
month = "7",
day = "15",
doi = "10.1042/BJ20030207",
language = "English (US)",
volume = "373",
pages = "547--558",
journal = "Biochemical Journal",
issn = "0264-6021",
publisher = "Portland Press Ltd.",
number = "2",

}

TY - JOUR

T1 - Fractalkine (CX3CL1) stimulated by nuclear factor κB (NF-κB)-dependent inflammatory signals induces aortic smooth muscle cell proliferation through an autocrine pathway

AU - Chandrasekar, Bysani

AU - Mummidi, Srinivas

AU - Perla, Rao P.

AU - Bysani, Sailaja

AU - Dulin, Nickolai O.

AU - Liu, Feng

AU - Melby, Peter

PY - 2003/7/15

Y1 - 2003/7/15

N2 - 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.

AB - 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.

KW - Atherosclerosis

KW - Autoregulation

KW - Cell adhesion

KW - CX3C receptor 1 (CX3CR1)

KW - Fractalkine (CX3CL1)

KW - Mitosis

KW - Nuclear factor κB (NF-κB)

UR - http://www.scopus.com/inward/record.url?scp=0041845203&partnerID=8YFLogxK

UR - http://www.scopus.com/inward/citedby.url?scp=0041845203&partnerID=8YFLogxK

U2 - 10.1042/BJ20030207

DO - 10.1042/BJ20030207

M3 - Article

C2 - 12729461

AN - SCOPUS:0041845203

VL - 373

SP - 547

EP - 558

JO - Biochemical Journal

JF - Biochemical Journal

SN - 0264-6021

IS - 2

ER -