Tumor Necrosis Factor α-Induced Eosinophil Accumulation in Rat Skin Is Dependent on α4 Integrin/Vascular Cell Adhesion Molecule-1 Adhesion Pathways

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Abstract
Tumor necrosis factor α (TNFα) is a cytokine implicated in the pathogenesis of numerous chronic and acute inflammatory conditions. In the present study, we have characterized the ability of TNFα in inducing eosinophil accumulation in rat skin and have shown the inhibitory effects of anti-α4 integrin and anti–vascular cell adhesion molecule-1 (VCAM-1) antibodies on this response. The intradermal injection of recombinant human TNFα induced a slowly developing, dose-dependent accumulation of 111In-eosinophils in rat skin that was maximal at the dose of 10−11 mol/site. Coadministration of TNFα with the soluble TNFα receptor (p55)-IgG fusion protein (TNFR-IgG) totally inhibited the 111In-eosinophil accumulation induced by the cytokine. The TNFα-induced 111In-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-α4 integrin MoAb, HP2/1 (3.5 mg/kg), or an anti–VCAM-1 MoAb, 5F10 (2 mg/kg), greatly inhibited the 111In-eosinophil accumulation induced by TNFα (the responses detected at 10−11 mol/site were inhibited by 78% and 50%, respectively). These results show that TNFα is an effective inducer of eosinophil accumulation in vivo, with this response being dependent on an interaction between α4 integrins and VCAM-1.