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Integrins and Cytokines Activate Nuclear Transcription Factor-κB in Human Neutrophils*

R. Kettritz,Mira Choi,S. Rolle,M. Wellner,F. Luft

Published 2004 in Journal of Biological Chemistry

ABSTRACT

Neutrophil adhesion to extracellular matrix is necessary for an effective inflammatory response. Adhesion may accelerate neutrophil activation by affecting intracellular signaling pathways. The nuclear transcription factor κB (NF-κB) controls several cellular functions, including inflammation, proliferation, and cell survival. We explored the role of adhesion in NF-κB activation in human neutrophils. Cells were stimulated with tumor necrosis factor-α (TNF-α), granulocyte macrophage-colony-stimulating factor (GM-CSF), interleukin-8 (IL-8), and formyl-methionyl-leucyl-phenylalanine (fMLP). All four initiated neutrophil adherence to and spreading on fibronectin. GM-CSF and IL-8 did not activate NF-κB in suspended neutrophils but rapidly activated NF-κB under adherent conditions on matrix, as shown by IκB kinase activity assay, IκBα degradation, electromobility shift assay, and quantitative reverse transcriptase-PCR. In contrast, TNF–α activated NF-κB both in suspended cells and adherent cells. fMLP did not activate NF-κB in either suspended or adherent cells. Specific β2 integrin blockade prevented NF-κB activation by GM-CSF and IL-8 on fibronectin. Co-stimulating CD18 and CD11b with activating antibodies resulted in NF-κB activation by GM-CSF and IL-8 in suspended cells. We inhibited actin polymerization with cytochalasin and blocked the non-receptor kinase Syk with piceatannol. Both maneuvers prevented the co-stimulatory NF-κB-activating signal by β2 integrins. Thus, in addition to β2 integrin ligand binding, NF-κB activation depended on the formation of the receptor-associated intracellular focal adhesion complex. We conclude that β2 integrins may provide co-stimulatory signals allowing some soluble mediators to activate the NF-κB pathway even when they are not capable of doing so in suspension. This effect may become important when human neutrophils leave the circulating blood and migrate through extracellular matrix during inflammation.

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