Aggregation of β2 integrins activates human neutrophils through the IκB/NF-κB 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 interlenkin-1beta and tumor necrosis factor-alpha production, which suggests the activation of neutrophils by beta(2) integrin. IKBalpha 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 IKB/NF-kappaB pathway.