Intercellular adhesion molecule 1 and beta2 integrins in C1q-stimulated superoxide production by human neutrophils: an example of a general regulatory mechanism governing acute inflammation.
OBJECTIVE
To investigate the role of intercellular adhesion molecule 1 (ICAM-1) and beta2 integrins in the production of superoxide (O2-) by C1q-stimulated human polymorphonuclear leukocytes (PMN).


METHODS
PMN were pretreated with F(ab')2 fragments of monoclonal antibodies (mAb) that blocked or did not block beta2 integrin-mediated adhesion. The cells were added to wells coated with C1q, and the production of O2- was monitored kinetically as a color change due to reduction of cytochrome c. In some experiments, C1q was co-immobilized with purified ICAM-1.


RESULTS
Blocking mAb to the shared beta2 integrin subunit, CD18, completely inhibited the O2- response triggered by immobilized C1q, while blocking mAb to the alpha subunits of the beta2 integrins each partially blocked the O2- response. PMN treated with C1q were found to activate the beta2 integrins lymphocyte function-associated antigen 1 and CR3 for binding to ICAM-1. Co-immobilization of ICAM-1 with C1q cooperatively triggered O2- production by PMN.


CONCLUSIONS
beta2 integrin binding to an ICAM provided an essential costimulatory signal for O2-production triggered by C1q in PMN. Our findings suggest a model for PMN activation in which 2 stimuli are required for O2- production: a first signal that also activates PMN beta2 integrins, followed by a second, beta2 integrin-mediated signal, which occurs physiologically upon PMN binding to ICAM-1. The requirement for this dual signal for PMN generation of O2- would serve as a regulatory mechanism to limit the production of O2- to a tissue environment where C1q, or some other stimulus, is colocalized with stromal cells bearing up-regulated ICAM-1. This mechanism may explain why all tissues can express ICAM-1 and may explain in part why inhibitors of tumor necrosis factor alpha, a major physiologic stimulus of ICAM-1 up-regulation, are potent antiinflammatory agents.
Tyagi
S
S
Beth Israel Deaconess Medical Center, Harvard Medical School, Boston, Massachusetts, USA.
Nicholson-Weller
A
A
Barbashov
S F
SF
Tas
S W
SW
Klickstein
L B
LB
D019138:Antibodies, Blocking / Q000502:physiology; D018821:CD18 Antigens / Q000276:immunology / Q000502:physiology*; D015922:Complement C1q / Q000037:antagonists & inhibitors / Q000494:pharmacology*; D006801:Humans; D007249:Inflammation / Q000503:physiopathology; D018799:Intercellular Adhesion Molecule-1 / Q000378:metabolism / Q000502:physiology*; D019169:Jurkat Cells; D016169:Lymphocyte Function-Associated Antigen-1 / Q000378:metabolism / Q000502:physiology; D016177:Macrophage-1 Antigen / Q000378:metabolism / Q000502:physiology; D009504:Neutrophils / Q000378:metabolism*; D017463:Receptors, Complement 3b / Q000276:immunology; D013481:Superoxides / Q000378:metabolism*
D019138:Antibodies, Blocking; D018821:CD18 Antigens; D016169:Lymphocyte Function-Associated Antigen-1; D016177:Macrophage-1 Antigen; D017463:Receptors, Complement 3b; D013481:Superoxides; D018799:Intercellular Adhesion Molecule-1; D015922:Complement C1q