Molecular mechanisms underlying IL-4-induced leukocyte recruitment in vivo: a critical role for the alpha 4 integrin.
IL-4 is known to induce recruitment of eosinophils and mononuclear leukocytes. In vitro this occurs in part by selective expression of VCAM-1, the ligand for the alpha 4 integrin. The objective of this study was to determine the molecular mechanisms that underlie IL-4-induced leukocyte recruitment in vivo. Mice received an intrascrotal injection of IL-4 (100 ng). Twenty-four hours later, leukocyte rolling, adhesion, and emigration in cremasteric postcapillary venules were examined via intravital microscopy, and expression of VCAM-1 and P- and E-selectin was quantitated using a radiolabeled mAb technique. IL-4 increased VCAM-1 expression, but P-selectin and E-selectin remained at constitutive levels. IL-4 induced significant increases in leukocyte adhesion and emigration, with 50% of the emigrated cells being eosinophils and the remainder being mononuclear leukocytes. Leukocyte rolling in IL-4-treated mice was >95% inhibitable using an anti-P-selectin Ab. However, IL-4-induced leukocyte recruitment was unaltered in mice treated chronically with P-selectin Ab or mice deficient in either P-selectin or P- and E-selectin, suggesting that the residual rolling supported all of the IL-4-induced recruitment. In IL-4-treated mice following P-selectin blockade, tethering and rolling were not dependent on L-selectin, but were abolished by alpha 4 integrin blockade. These findings show that the alpha 4 integrin can initiate leukocyte-endothelial cell interactions in the absence of selectins under shear conditions in vivo, and that the absence of selectins does not affect recruitment of eosinophils and mononuclear cells to IL-4-treated tissue.
Hickey
M J
MJ
Immunology Research Group, University of Calgary, Alberta, Canada.
Granger
D N
DN
Kubes
P
P
D000818:Animals; D015703:Antigens, CD / Q000502:physiology*; D002448:Cell Adhesion / Q000276:immunology; D002465:Cell Movement / Q000276:immunology*; D019040:E-Selectin / Q000096:biosynthesis; D004804:Eosinophils / Q000276:immunology / Q000502:physiology* / Q000648:ultrastructure; D007271:Injections, Intradermal; D039441:Integrin alpha4; D016023:Integrins / Q000502:physiology*; D015847:Interleukin-4 / Q000008:administration & dosage*; D007963:Leukocytes, Mononuclear / Q000276:immunology / Q000502:physiology* / Q000648:ultrastructure; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D008833:Microcirculation / Q000166:cytology / Q000276:immunology / Q000502:physiology; D018715:Microscopy, Video / Q000379:methods; D019007:P-Selectin / Q000096:biosynthesis / Q000502:physiology; D019010:Vascular Cell Adhesion Molecule-1 / Q000096:biosynthesis
D015703:Antigens, CD; D019040:E-Selectin; D016023:Integrins; D019007:P-Selectin; D019010:Vascular Cell Adhesion Molecule-1; D039441:Integrin alpha4; D015847:Interleukin-4