Tumor necrosis factor alpha-induced eosinophil accumulation in rat skin is dependent on alpha4 integrin/vascular cell adhesion molecule-1 adhesion pathways.
Tumor necrosis factor alpha (TNFalpha) is a cytokine implicated in the pathogenesis of numerous chronic and acute inflammatory conditions. In the present study, we have characterized the ability of TNFalpha in inducing eosinophil accumulation in rat skin and have shown the inhibitory effects of anti-alpha4 integrin and anti-vascular cell adhesion molecule-1 (VCAM-1) antibodies on this response. The intradermal injection of recombinant human TNFalpha 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 TNFalpha with the soluble TNFalpha receptor (p55)-IgG fusion protein (TNFR-IgG) totally inhibited the 111In-eosinophil accumulation induced by the cytokine. The TNFalpha-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-alpha4 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 TNFalpha (the responses detected at 10(-11) mol/site were inhibited by 78% and 50%, respectively). These results show that TNFalpha is an effective inducer of eosinophil accumulation in vivo, with this response being dependent on an interaction between alpha4 integrins and VCAM-1.
Sanz
M J
MJ
National Heart and Lung Institute, Imperial College School of Medicine, London, UK.
Hartnell
A
A
Chisholm
P
P
Williams
C
C
Davies
D
D
Weg
V B
VB
Feldmann
M
M
Bolanowski
M A
MA
Lobb
R R
RR
Nourshargh
S
S
D000818:Animals; D015703:Antigens, CD / Q000276:immunology*; D004804:Eosinophils / Q000187:drug effects / Q000276:immunology* / Q000473:pathology; D006801:Humans; D039441:Integrin alpha4; D051381:Rats; D017207:Rats, Sprague-Dawley; D016201:Receptors, Lymphocyte Homing / Q000276:immunology; D015398:Signal Transduction / Q000276:immunology*; D012867:Skin / Q000187:drug effects / Q000276:immunology* / Q000473:pathology; D014409:Tumor Necrosis Factor-alpha / Q000494:pharmacology*; D019010:Vascular Cell Adhesion Molecule-1 / Q000276:immunology*
D015703:Antigens, CD; D016201:Receptors, Lymphocyte Homing; D014409:Tumor Necrosis Factor-alpha; D019010:Vascular Cell Adhesion Molecule-1; D039441:Integrin alpha4