Journal
CIRCULATION RESEARCH
Volume 89, Issue 10, Pages 859-865Publisher
LIPPINCOTT WILLIAMS & WILKINS
DOI: 10.1161/hh2201.099166
Keywords
leukocytes; integrins; signal transduction; gene expression
Funding
- NHLBI NIH HHS [R01 HL57506] Funding Source: Medline
- NIDDK NIH HHS [R01 DK55656] Funding Source: Medline
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The leukocyte integrin Mac-1 (alphaM beta2, 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.
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