Monocyte chemoattractant protein-1 induces proliferation and interleukin-6 production in human smooth muscle cells by differential activation of nuclear factor-kappaB and activator protein-1.
Inflammatory response and chemotaxis of vascular wall cells play an important pathogenic role in the development of atherosclerosis. Monocyte chemoattractant protein-1 (MCP-1) is a potent chemoattractant for monocytes. Besides the induction of monocyte recruitment, it has been suggested that MCP-1 may directly activate smooth muscle cells. We investigated whether MCP-1 affects the proliferation and cytokine production of human vascular smooth muscle cells (VSMCs) and determined the underlying signal transduction pathways. Stimulation of VSMCs with MCP-1 induced proliferation and resulted in a concentration- and time-dependent release of the proinflammatory cytokine interleukin-6 (IL-6). Pretreatment with pertussis toxin, GF109203X, and pyrrolidine dithiocarbamate inhibited MCP-1-dependent IL-6 release, suggesting the involvement of G(i) proteins, protein kinase C, and nuclear factor-kappaB (NF-kappaB). MCP-1 also induced extracellular signal-regulated kinase, which, along with IL-6 release, was inhibited by pertussis toxin. PD98059 prevented MCP-1-induced extracellular signal-regulated kinase activation and cell proliferation. MCP-1 stimulated the binding activity of NF-kappaB and of activator protein-1 (AP-1). As demonstrated by cis element double-stranded (decoy) oligodeoxynucleotides, NF-kappaB was involved in IL-6 release by MCP-1, whereas proliferation was dependent on AP-1. The results clearly demonstrate that MCP-1 induces differential activation of NF-kappaB and AP-1 in VSMCs. Thus, our data propose a new mechanism for the proatherogenic effect of MCP-1.
Viedt
Christiane
C
Innere Medizin III, Universität Heidelberg, Germany.
Vogel
Judith
J
Athanasiou
Thomas
T
Shen
Weili
W
Orth
Stephan R
SR
Kübler
Wolfgang
W
Kreuzer
Jörg
J
D002455:Cell Division / Q000502:physiology; D018932:Chemokine CCL2 / Q000502:physiology*; D001026:Coronary Artery Bypass; D004789:Enzyme Activation / Q000502:physiology; D006133:Growth Substances / Q000502:physiology*; D006801:Humans; D007249:Inflammation / Q000378:metabolism; D015850:Interleukin-6 / Q000096:biosynthesis* / Q000378:metabolism; D019950:Mitogen-Activated Protein Kinase 1 / Q000378:metabolism; D048052:Mitogen-Activated Protein Kinase 3; D020928:Mitogen-Activated Protein Kinases / Q000378:metabolism; D009131:Muscle, Smooth, Vascular / Q000166:cytology* / Q000378:metabolism*; D016328:NF-kappa B / Q000502:physiology*; D012333:RNA, Messenger / Q000096:biosynthesis; D054390:Receptors, CCR2; D019707:Receptors, Chemokine / Q000096:biosynthesis; D011994:Recombinant Proteins / Q000378:metabolism; D012501:Saphenous Vein / Q000166:cytology; D018808:Transcription Factor AP-1 / Q000502:physiology*
C515334:CCR2 protein, human; D018932:Chemokine CCL2; D006133:Growth Substances; D015850:Interleukin-6; D016328:NF-kappa B; D012333:RNA, Messenger; D054390:Receptors, CCR2; D019707:Receptors, Chemokine; D011994:Recombinant Proteins; D018808:Transcription Factor AP-1; D019950:Mitogen-Activated Protein Kinase 1; D048052:Mitogen-Activated Protein Kinase 3; D020928:Mitogen-Activated Protein Kinases