Tumor necrosis factor alpha-induced eosinophil accumulation in rat skin is dependent on alpha(4) integrin vascular cell adhesion molecule-1 adhesion pathways

Tumor necrosis factor alpha (TNF alpha) is a cytokine implicated in the pathogenesis of numerous chronic and acute inflammatory conditions. In the present study, we have characterized the ability of TNF alpha in inducing eosinophil accumulation in rat skin and have shown the inhibitory effects of anti-alpha(4) integrin and anti-vascular cell adhesion molecule-1 (VCAM-1) antibodies on this response. The intradermal injection of recombinant human TNF alpha induced a slowly developing, dose-dependent accumulation of In-111-eosinophils in rat shin that was maximal at the dose of 10(-11) mol/site. Coadministration of TNF alpha with the soluble TNF alpha receptor (p55)-IgG fusion protein (TNFR-IgG) totally inhibited the In-111-eosinophil accumulation induced by the cytokine. The TNF alpha-induced In-111-eosinophil accumulation was not affected after pretreatment of rats with the platelet-activating factor (PAF) receptor antagonist UK-74,505 or the antihuman interleukin-8 monoclonal antibody (MoAb) DM/C7. In contrast, the intravenous administration of an anti-alpha(4) integrin MoAb. HP2/1 (3.5 mg/kg), or an anti-VCAM-1 MoAb, 5F10 (2 mg/kg), greatly inhibited the In-111-eosinophil accumulation induced by TNF alpha (the responses detected at 10(-11) mol/site were inhibited by 78% and 50%, respectively). These results show that TNF alpha is an effective inducer of eosinophil accumulation in vivo. with this response being dependent on an interaction between alpha(4) integrins and VCAM-1. (C) 1997 by The American Society of Hematology.