Leukocyte integrin Mac-1 recruits toll/interleukin-1 receptor superfamily signaling intermediates to modulate NF-kappaB activity.
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.
Mesh Terms:
Adaptor Proteins, Signal Transducing, Antigens, Differentiation, Cell Adhesion, Cell Line, Gene Expression Regulation, Genes, Reporter, Humans, Interleukin-1 Receptor-Associated Kinases, MAP Kinase Kinase Kinases, Macrophage-1 Antigen, Membrane Glycoproteins, Membrane Proteins, Monocytes, Myeloid Differentiation Factor 88, NF-kappa B, Oligonucleotide Array Sequence Analysis, Protein Kinases, Proteins, Receptor Aggregation, Receptors, Cell Surface, Receptors, Immunologic, Receptors, Interleukin-1, Signal Transduction, TNF Receptor-Associated Factor 6, Toll-Like Receptors, Transfection
Adaptor Proteins, Signal Transducing, Antigens, Differentiation, Cell Adhesion, Cell Line, Gene Expression Regulation, Genes, Reporter, Humans, Interleukin-1 Receptor-Associated Kinases, MAP Kinase Kinase Kinases, Macrophage-1 Antigen, Membrane Glycoproteins, Membrane Proteins, Monocytes, Myeloid Differentiation Factor 88, NF-kappa B, Oligonucleotide Array Sequence Analysis, Protein Kinases, Proteins, Receptor Aggregation, Receptors, Cell Surface, Receptors, Immunologic, Receptors, Interleukin-1, Signal Transduction, TNF Receptor-Associated Factor 6, Toll-Like Receptors, Transfection
Circ. Res.
Date: Nov. 09, 2001
PubMed ID: 11701612
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