Integrin regulation of leukocyte inflammatory functions. CD11b/CD18 enhancement of the tumor necrosis factor-alpha responses of monocytes.
Engagement of the integrin CD11b/CD18 (alpha M beta 2, Mac-1, CR3) on cells of monocyte (Mo) lineage has recently been demonstrated to enhance synthesis and surface expression of the integral plasmalemma receptor tissue factor. The role of cognate interactions between integrin and its ligands in the regulation of cellular responses important to inflammation can be extended to the effect on the enhancement of TNF-alpha mRNA accumulation and protein secretion by Mo once stimulated by an initial signal such as LPS. At a concentration optimal for inducing TNF-alpha responses, LPS was observed to rapidly increase by two- to threefold the surface expression on Mo of CD11b but not CD11a or CD11c. In the absence of initial signal, engagement of CD11/CD18 integrins per se failed to elicit a TNF-alpha response. In the presence of the initial transcriptional agonist LPS, both TNF-alpha mRNA expression and protein secretion were enhanced several-fold by cells adherent to a CD11b/CD18 ligand, to endothelial cells as well as engagement of CD11b/CD18 integrin by specific antibodies. This enhancement appears to be CD11b/CD18 specific and not from mere attachment or spreading. The enhancement effect after HUVEC binding was inhibited 75% by anti-CD11b mAb M1/70. These studies lead to the hypothesis that engagement of the CD11b/CD18 integrin results in the transduction of cellular signals that quantitatively enhance the expression of inflammatory mediators of Mo-mediated responses.
Fan
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Department of Immunology, Scripps Research Institute, La Jolla, CA 92037.
Edgington
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D000911:Antibodies, Monoclonal / Q000494:pharmacology; D015703:Antigens, CD / Q000032:analysis / Q000502:physiology*; D018845:CD11 Antigens; D018821:CD18 Antigens; D002448:Cell Adhesion; D004730:Endothelium, Vascular / Q000166:cytology; D006801:Humans; D016023:Integrins / Q000502:physiology*; D008070:Lipopolysaccharides / Q000494:pharmacology; D016177:Macrophage-1 Antigen / Q000502:physiology*; D008565:Membrane Proteins / Q000096:biosynthesis; D009000:Monocytes / Q000276:immunology / Q000378:metabolism*; D012333:RNA, Messenger / Q000378:metabolism; D014409:Tumor Necrosis Factor-alpha / Q000096:biosynthesis* / Q000235:genetics
D000911:Antibodies, Monoclonal; D015703:Antigens, CD; D018845:CD11 Antigens; D018821:CD18 Antigens; D016023:Integrins; D008070:Lipopolysaccharides; D016177:Macrophage-1 Antigen; D008565:Membrane Proteins; D012333:RNA, Messenger; D014409:Tumor Necrosis Factor-alpha