Aggregation of beta2 integrins activates human neutrophils through the IkappaB/NF-kappaB pathway.
Neutrophils are now considered central to the pathogenesis of most forms of acute lung injury. Neutrophils do not cause damage while suspended in the bloodstream; however, a release of cytotoxic agents occurs when neutrophils are adherent to endothelium, epithelium, or extracellular matrix proteins in the interstitium. Such neutrophil adherence is mediated predominantly through beta(2) integrins (CD11/CD18) on its surface. This study was undertaken to investigate whether the IkappaB/nuclear factor (NF)-kappaB cascade is involved in this beta(2) integrin-mediated activation of human neutrophils. beta(2) Integrin Mac-1 (CD11b/CD18) aggregation was induced by antibody cross-linking of the integrins on the cell surface. beta(2) Integrin aggregation induced interleukin-1beta and tumor necrosis factor-alpha production, which suggests the activation of neutrophils by beta(2) integrin. IkappaBalpha was markedly degraded at 1 h, and NF-kappaB-DNA-binding activity markedly increased 2 h after beta(2) integrin aggregation, which activated IkappaB kinase activity at 1 h. beta(2) Integrin-induced cytokine production was suppressed by MG132 or SN50 pretreatment, which blocked the activation of NF-kappaB. These findings suggest that the activation of human neutrophils by beta(2) integrin aggregation is mediated through the activation of the IkappaB/NF-kappaB pathway.
Division Pulmonar and Critical Care Medicine, Department of Internal Medicine, Seoul National University College of Medicine, Seoul 110-744, Korea.
Cheol Hyeon
CH
Kim
Kyoung-Hee
KH
Lee
Choon-Taek
CT
Lee
Young Whan
YW
Kim
Sung Koo
SK
Han
Young-Soo
YS
Shim
Chul-Gyu
CG
Yoo
D018821:CD18 Antigens / Q000378:metabolism* / Q000502:physiology; D016207:Cytokines / Q000096:biosynthesis; D006801:Humans; D051550:I-kappa B Kinase; D020672:I-kappa B Proteins / Q000378:metabolism*; D016177:Macrophage-1 Antigen / Q000378:metabolism; D000072000:NF-KappaB Inhibitor alpha; D016328:NF-kappa B / Q000378:metabolism*; D018375:Neutrophil Activation; D011485:Protein Binding; D017346:Protein Serine-Threonine Kinases / Q000378:metabolism; D015398:Signal Transduction
D018821:CD18 Antigens; D016207:Cytokines; D020672:I-kappa B Proteins; D016177:Macrophage-1 Antigen; D016328:NF-kappa B; C000606204:NFKBIA protein, human; D000072000:NF-KappaB Inhibitor alpha; D017346:Protein Serine-Threonine Kinases; C496559:CHUK protein, human; D051550:I-kappa B Kinase; C496560:IKBKB protein, human; C496565:IKBKE protein, human