The function of neutrophils in the inflammatory response is modulated by contact with ECM proteins. We have now investigated the effect of collagen type I on secretion of the cytokine IL-8 by human neutrophils in vitro. Collagen type I inhibited the secretion of IL-8 from neutrophils maintained under basal conditions or stimulated with fMLF. This effect was accompanied by down-regulation of IL-8 mRNA, and it appeared to be specific to collagen type I among ECM proteins, in that it was not observed with fibronectin or laminin. The inhibitory effect of collagen type I on IL-8 secretion was dependent on collagen concentration and cell density. It was also abolished in the presence of antibodies to integrin alpha2beta1 but was not affected by antibodies to integrin alpha5beta1 or beta4. Our results thus suggest that collagen type I inhibits the secretion of IL-8 by human neutrophils in a selective manner and that this effect is mediated by the interaction of collagen with integrin alpha2beta1.