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 leukocyt es. In vitro this occurs in part by selective expression of VCAM-1, the lig and 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-f our hours later, leukocyte rolling, adhesion, and emigration in cremasteric postcapillary venules were examined via intravital microscopy, and express ion of VCAM-1 and P- and E-selectin was quantitated using a radiolabeled mA b technique. IL-4 increased VCAM-1 expression, but P-selectin and E-selecti n remained at constitutive levels. IL-4 induced significant increases in le ukocyte adhesion and emigration, with 50% of the emigrated cells being eosi nophils and the remainder being mononuclear leukocytes, Leukocyte rolling i n IL-4-treated mice was >95% inhibitable using an anti-P-selectin Ab. Howev er, IL-4-induced leukocyte recruitment was unaltered in mice treated chroni cally 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-i nduced recruitment. In IL-4-treated mice following P-selectin blockade, tet hering 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 sele ctins under shear conditions in vivo, and that the absence of selectins doe s not affect recruitment of eosinophils and mononuclear cells to IL-4-treat ed tissue.