Expression of a soluble and functional form of the human beta 2 integrin CD11b/CD18.
Polymorphonuclear cells and monocytes (phagocytes) are a critical component of host defense against infections. However, these cells also play a significant role in host tissue damage in many noninfectious diseases, such as ischemia-reperfusion injury syndromes and rejection of transplanted organs. The leukocyte adhesion molecule family CD11/CD18 (beta 2 integrins) is critical to the function of polymorphonuclear cells and monocytes in inflammation and injury. Inherited deficiency of CD11/CD18 impairs phagocyte chemotaxis, adhesion and transmigration across endothelium, and clearance of invading microorganisms through phagocytosis and cell-mediated killing. Furthermore, murine monoclonal antibodies directed against the CD11b/CD18 (CR3) heterodimer have been shown to reduce, by 50%-80%, phagocyte-mediated ischemia-reperfusion injury in several organ systems, such as the myocardium, liver, and gastrointestinal tract and to inhibit development of insulin-dependent diabetes mellitus in nonobese diabetic (NOD) mice. Expression of CD11b/CD18 in a soluble and functional form might therefore be potentially useful as an anti-inflammatory agent. We have now expressed a recombinant soluble heterodimeric form of this human beta 2 integrin, normally expressed as two noncovalently associated membrane-bound subunits. The secreted receptor exhibited direct and specific binding to its ligand, iC3b, the major complement C3 opsonin, and inhibited binding of polymorphonuclear cells to recombinant interleukin 1-activated endothelium.
Dana
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Renal Unit, Massachusetts General Hospital, Boston, MA.
Fathallah
D M
DM
Arnaout
M A
MA
D000595:Amino Acid Sequence; D015703:Antigens, CD / Q000235:genetics* / Q000378:metabolism; D001483:Base Sequence; D018821:CD18 Antigens; D003001:Cloning, Molecular; D003179:Complement C3b / Q000378:metabolism; D004730:Endothelium, Vascular / Q000166:cytology; D006801:Humans; D066298:In Vitro Techniques; D007249:Inflammation / Q000473:pathology; D016023:Integrins / Q000235:genetics* / Q000378:metabolism; D046911:Macromolecular Substances; D016177:Macrophage-1 Antigen / Q000235:genetics* / Q000378:metabolism; D008969:Molecular Sequence Data; D009504:Neutrophils / Q000378:metabolism; D011233:Precipitin Tests; D016028:Receptors, Leukocyte-Adhesion / Q000235:genetics* / Q000378:metabolism; D011994:Recombinant Proteins / Q000378:metabolism; D012995:Solubility; D014162:Transfection
D015703:Antigens, CD; D018821:CD18 Antigens; D016023:Integrins; D046911:Macromolecular Substances; D016177:Macrophage-1 Antigen; D016028:Receptors, Leukocyte-Adhesion; D011994:Recombinant Proteins; D003179:Complement C3b