PMID- 12729461
OWN - NLM
STAT- MEDLINE
DCOM- 20030815
LR  - 20220316
IS  - 0264-6021 (Print)
IS  - 1470-8728 (Electronic)
IS  - 0264-6021 (Linking)
VI  - 373
IP  - Pt 2
DP  - 2003 Jul 15
TI  - Fractalkine (CX3CL1) stimulated by nuclear factor kappaB (NF-kappaB)-dependent 
      inflammatory signals induces aortic smooth muscle cell proliferation through an 
      autocrine pathway.
PG  - 547-58
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-alpha (TNF-alpha) and interferon-gamma (IFN-gamma)], 
      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-alpha activated nuclear factor kappaB (NF-kappaB) and induced fractalkine and 
      CX3CR1 expression in a time-dependent manner in rat aortic SMCs. Transient 
      transfections with dominant-negative (dn) inhibitory kappaB (IkappaB)-alpha, 
      dnIkappaB-beta, dnIkappaB kinase (IKK)-gamma, kinase-dead (kd) NF-kappaB-inducing 
      kinase (NIK) and kdIKK-beta, or pretreatment with wortmannin, Akt inhibitor, 
      pyrrolidinecarbodithioc acid ammonium salt ('PDTC') or MG-132, significantly 
      attenuated TNF-alpha-induced fractalkine and CX3CR1 expression. Furthermore, 
      expression of dn TNF-alpha-receptor-associated factor 2 (TRAF2), but not dnTRAF6, 
      inhibited TNF-alpha signal transduction. Pretreatment with pertussis toxin or 
      neutralizing anti-CX3CR1 antibodies attenuated TNF-alpha-induced fractalkine 
      expression, indicating that fractalkine autoregulation plays a role in 
      TNF-alpha-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-kappaB activation, and induced SMC cell-cell adhesion and cellular 
      proliferation. Taken together, our results demonstrate that TNF-alpha induces the 
      expression of fractalkine and CX3CR1 in rat aortic SMCs and that this induction 
      is mediated by NF-kappaB activation. We also show that fractalkine induces its 
      own expression, which is mediated by the PI 3-kinase/PDK1/Akt/NIK/IKK/NF-kappaB 
      signalling pathway. More importantly, fractalkine increased cell-cell adhesion 
      and aortic SMC proliferation, indicating a role in initiation and progression of 
      atherosclerotic vascular disease.
FAU - Chandrasekar, Bysani
AU  - Chandrasekar B
AD  - Department of Medicine, University of Texas Health Science Center, San Antonio, 
      TX 78229, USA. chandraseka@uthscsa.edu
FAU - Mummidi, Srinivas
AU  - Mummidi S
FAU - Perla, Rao P
AU  - Perla RP
FAU - Bysani, Sailaja
AU  - Bysani S
FAU - Dulin, Nickolai O
AU  - Dulin NO
FAU - Liu, Feng
AU  - Liu F
FAU - Melby, Peter C
AU  - Melby PC
LA  - eng
GR  - HL68020/HL/NHLBI NIH HHS/United States
PT  - Journal Article
PT  - Research Support, Non-U.S. Gov't
PT  - Research Support, U.S. Gov't, P.H.S.
PL  - England
TA  - Biochem J
JT  - The Biochemical journal
JID - 2984726R
RN  - 0 (Androstadienes)
RN  - 0 (Antineoplastic Agents)
RN  - 0 (CX3C Chemokine Receptor 1)
RN  - 0 (Chemokine CX3CL1)
RN  - 0 (Chemokines, CX3C)
RN  - 0 (Cx3cl1 protein, rat)
RN  - 0 (Enzyme Inhibitors)
RN  - 0 (I-kappa B Proteins)
RN  - 0 (Membrane Proteins)
RN  - 0 (NF-kappa B)
RN  - 0 (Phosphoinositide-3 Kinase Inhibitors)
RN  - 0 (Proteins)
RN  - 0 (Proto-Oncogene Proteins)
RN  - 0 (RNA, Messenger)
RN  - 0 (Receptors, Cytokine)
RN  - 0 (Receptors, HIV)
RN  - 0 (TNF Receptor-Associated Factor 2)
RN  - 0 (TNF Receptor-Associated Factor 6)
RN  - 0 (Thiocarbamates)
RN  - 0 (Tumor Necrosis Factor-alpha)
RN  - 135467-92-4 (prolinedithiocarbamate)
RN  - 9DLQ4CIU6V (Proline)
RN  - EC 1.13.12.- (Luciferases)
RN  - EC 2.7.11.1 (Akt1 protein, rat)
RN  - EC 2.7.11.1 (Protein Serine-Threonine Kinases)
RN  - EC 2.7.11.1 (Proto-Oncogene Proteins c-akt)
RN  - EC 3.6.1.- (GTP-Binding Proteins)
RN  - XVA4O219QW (Wortmannin)
SB  - IM
MH  - Androstadienes/pharmacology
MH  - Animals
MH  - Antineoplastic Agents/pharmacology
MH  - Aorta/cytology
MH  - Autocrine Communication
MH  - CX3C Chemokine Receptor 1
MH  - Cell Division/drug effects
MH  - Cells, Cultured
MH  - Chemokine CX3CL1
MH  - Chemokines, CX3C/*metabolism
MH  - Electrophoretic Mobility Shift Assay
MH  - Enzyme Inhibitors/pharmacology
MH  - GTP-Binding Proteins/metabolism
MH  - I-kappa B Proteins/metabolism
MH  - Luciferases/metabolism
MH  - Membrane Proteins/*metabolism
MH  - Muscle, Smooth, Vascular/*cytology/drug effects
MH  - NF-kappa B/*metabolism
MH  - Phosphatidylinositol 3-Kinases/metabolism
MH  - Phosphoinositide-3 Kinase Inhibitors
MH  - Proline/*analogs & derivatives/pharmacology
MH  - *Protein Serine-Threonine Kinases
MH  - Proteins/metabolism
MH  - Proto-Oncogene Proteins/antagonists & inhibitors
MH  - Proto-Oncogene Proteins c-akt
MH  - RNA, Messenger/metabolism
MH  - Rats
MH  - Receptors, Cytokine/metabolism
MH  - Receptors, HIV/metabolism
MH  - TNF Receptor-Associated Factor 2
MH  - TNF Receptor-Associated Factor 6
MH  - Thiocarbamates/pharmacology
MH  - Transfection
MH  - Tumor Necrosis Factor-alpha/*pharmacology
MH  - Wortmannin
PMC - PMC1223517
EDAT- 2003/05/06 05:00
MHDA- 2003/08/16 05:00
PMCR- 2004/01/15
CRDT- 2003/05/06 05:00
PHST- 2003/05/02 00:00 [accepted]
PHST- 2003/04/24 00:00 [revised]
PHST- 2003/02/03 00:00 [received]
PHST- 2003/05/06 05:00 [pubmed]
PHST- 2003/08/16 05:00 [medline]
PHST- 2003/05/06 05:00 [entrez]
PHST- 2004/01/15 00:00 [pmc-release]
AID - BJ20030207 [pii]
AID - 10.1042/BJ20030207 [doi]
PST - ppublish
SO  - Biochem J. 2003 Jul 15;373(Pt 2):547-58. doi: 10.1042/BJ20030207.