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Department of Physiology, Freie Universität, D-14195 Berlin, Germany;
* Department of Dermatology, Universität zu Köln; and
Max Delbrück Center for Molecular Medicine, D-13122 Berlin-Buch, Germany
1Correspondence: Freie Universität Berlin, Department of Physiology, Arnimallee 22, D-14195 Berlin, Germany. E-mail walzog{at}zedat.fu-berlin.de
Growing evidence supports the idea that adhesion via
ß2 integrins not only allows cellular targeting, but also
induces intracellular signaling, which in turn activates functional
responses of adherent cells. This study investigates whether
ß2 integrin-mediated adhesion of human polymorphonuclear
neutrophils (PMN) has a functional impact on cytokine production.
Aggregation of the ß2 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-1ß. In contrast, no TNF-
or IL-6
production was found, revealing that ß2 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 ß2 integrins (CD11/CD18) in the
regulation of cytokine gene expression of polymorphonuclear neutrophils
during the inflammatory response.
Key Words: inflammation • adhesion • host defense • interleukin 8 • interleukin 1
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