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Tumor Necrosis Factor  -Induced Eosinophil Accumulation in Rat Skin Is Dependent on 4 Integrin/Vascular Cell Adhesion Molecule-1 Adhesion Pathways
Maria-Jesus Sanz,
Adele Hartnell,
Patricia Chisholm,
Cindy Williams,
Dawn Davies,
Vivian B. Weg,
Marc Feldmann,
Mark A. Bolanowski,
Roy R. Lobb, and
Sussan Nourshargh
From the National Heart and Lung Institute, Imperial College School of Medicine, London, UK; the Kennedy Institute of Rheumatology, London, UK; the Unit of Cellular and Molecular Biology, Searle Research and Development, Monsanto Co, St Louis, MO; and Biogen Inc, Cambridge, MA.
Tumor necrosis factor  (TNF) 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 in inducing eosinophil accumulation in rat skin and have shown the inhibitory effects of anti-4 integrin and anti-vascular cell adhesion molecule-1 (VCAM-1) antibodies on this response. The intradermal injection of recombinant human TNF 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 TNF with the soluble TNF receptor (p55)-IgG fusion protein (TNFR-IgG) totally inhibited the 111In-eosinophil accumulation induced by the cytokine. The TNF-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-4 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 TNF (the responses detected at 10-11 mol/site were inhibited by 78% and 50%, respectively). These results show that TNF is an effective inducer of eosinophil accumulation in vivo, with this response being dependent on an interaction between 4 integrins and VCAM-1.
Blood, Vol. 90 No. 10 (November 15), 1997:
pp. 4144-4152
© 1997 by The American Society of Hematology.
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