Growing evidence supports the idea that adhesion via β₂ integrins not only allows cellular targeting, but also induces intracellular signaling, which in turn activates functional responses of adherent cells. This study investigates whether β₂ integrin‐mediated adhesion of human polymorphonuclear neutrophils (PMN) has a functional impact on cytokine production. Aggregation of the β₂ integrin Mac‐1 (CD11b/CD18) by antibody cross‐linking was found to induce substantial de novo synthesis of IL‐8 mRNA as measured by semiquantitative RT‐PCR and Northern blotting technique, respectively. Induction of IL‐8 mRNA was also observed upon adhesion of PMN to immobilized fibrinogen, a functional equivalent of its clotting product fibrin that serves as a native ligand of Mac‐1. Results were confirmed using PMN derived from CD18‐deficient mice, which were unable to produce MIP‐2 mRNA, a homologue of human IL‐8, in the presence of immobilized fibrinogen. In contrast, a substantial increase of MIP‐2 mRNA was observed when wild‐type PMN were incubated on immobilized fibrinogen. In human PMN, ELISA technique showed that the gene activation that required tyrosine kinase activity resulted in a substantial production and secretion of biologically active IL‐8 and IL‐1β. In contrast, no TNF‐α or IL‐6 production was found, revealing that β₂ integrins mediate differential expression of proinflammatory cytokines. The biological relevance of the present findings was confirmed in an in vivo model of acute inflammation. Altogether, the present findings provide evidence for a functional link between clotting and inflammatory responses that may contribute to the recruitment and/or activation of PMN and other cells at sites of lesion.—Walzog, B., Weinmann, P., Jeblonski, F., Scharffetter‐Kochanek, K., Bommert, K., Gaehtgens, P. A role for β₂ integrins (CD11/CD18) in the regulation of cytokine gene expression of polymorphonuclear neutrophils during the inflammatory response. FASEB J. 13, 1855–1865 (1999)