Abstract
The leukocyte integrin Mac-1 (alphaMbeta2, CD11b/CD18) regulates important cell functions in inflammation, including adhesion, phagocytosis, and oxidative burst. Deficiency of Mac-1 reduces vessel wall inflammation and neointimal thickening after murine carotid artery injury. Although Mac-1 has been implicated in modulating AP-1 and NF-kappaB activity, the signal transduction pathways involved are undefined. cDNA array analysis of Mac-1-clustered compared with -nonclustered monocytic THP-1 cells showed increased expression of the signal transducer TRAF6 (TNF receptor-associated factor 6), leading us to consider the possibility that Mac-1 used a Toll/IL-1 receptor family-like signaling pathway. Mac-1-dependent activation of NF-kappaB was potentiated by wild-type, and attenuated by dominant negative, TRAF6- and TGF-beta-activated kinase (TAK1) constructs. IRAK1 (IL-1 receptor associated kinase), a kinase immediately upstream of TRAF6, coimmunoprecipitated with Mac-1. Taken together, these observations indicate that Mac-1 recruits a Toll/IL-1 receptor family-like cascade to modulate NF-kappaB activity. This represents a new pathway for integrin-dependent modulation of gene expression.
Publication types
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Research Support, U.S. Gov't, P.H.S.
MeSH terms
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Adaptor Proteins, Signal Transducing
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Antigens, Differentiation / genetics
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Antigens, Differentiation / metabolism
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Cell Adhesion / immunology
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Cell Line
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Gene Expression Regulation / immunology
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Genes, Reporter
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Humans
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Interleukin-1 Receptor-Associated Kinases
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MAP Kinase Kinase Kinases / metabolism
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Macrophage-1 Antigen / genetics
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Macrophage-1 Antigen / metabolism*
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Membrane Glycoproteins*
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Membrane Proteins / metabolism*
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Monocytes / cytology
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Monocytes / immunology
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Monocytes / metabolism
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Myeloid Differentiation Factor 88
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NF-kappa B / genetics
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NF-kappa B / metabolism*
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Oligonucleotide Array Sequence Analysis
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Protein Kinases / metabolism
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Proteins / metabolism
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Receptor Aggregation / immunology
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Receptors, Cell Surface*
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Receptors, Immunologic / metabolism*
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Receptors, Interleukin-1 / metabolism*
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Signal Transduction / immunology
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TNF Receptor-Associated Factor 6
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Toll-Like Receptors
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Transfection
Substances
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Adaptor Proteins, Signal Transducing
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Antigens, Differentiation
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MYD88 protein, human
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Macrophage-1 Antigen
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Membrane Glycoproteins
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Membrane Proteins
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Myeloid Differentiation Factor 88
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NF-kappa B
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Proteins
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Receptors, Cell Surface
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Receptors, Immunologic
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Receptors, Interleukin-1
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TNF Receptor-Associated Factor 6
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Toll-Like Receptors
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Protein Kinases
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IRAK1 protein, human
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Interleukin-1 Receptor-Associated Kinases
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MAP Kinase Kinase Kinases
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MAP kinase kinase kinase 7