HUMAN EOTAXIN INDUCES ALPHA-INTEGRIN-DEPENDENT AND BETA(2)-INTEGRIN-DEPENDENT EOSINOPHIL ACCUMULATION IN RAT SKIN IN-VIVO - DELAYED GENERATION OF EOTAXIN IN RESPONSE TO IL-4

The CC chemokine eotaxin, originally purified from bronchoalveolar lav age fluid of sensitized guinea pigs following allergen challenge, is a potent eosinophil-selective chemoattractant. In the present study, we have used In-111-eosinophils and human eotaxin to characterize the pr ofile of chemokine-induced eosinophil accumulation in vivo in rat skin . Intradermally injected eotaxin caused a dose-dependent accumulation of In-111-eosinophils. Time course studies indicated that the response was rapid, since all the accumulation occurred within the first 1 to 2 h of eotaxin injection, The i,v, administration of anti-intercellula r adhesion molecule-1, anti-vascular cell adhesion molecule-1, or anti -alpha 4 integrin mAbs significantly inhibited the eosinophil accumula tion induced by 100 pmol of human eotaxin by 73, 43, and 67%, respecti vely, Further, when In-111-eosinophils were pretreated in vitro with a nti-alpha(4) integrin or anti-beta(2) integrin mAbs, or with a combina tion of both mAbs, eotaxin-induced responses in vivo were reduced by 5 2, 49, and 68%, respectively, Eosinophil accumulation induced by intra dermal IL-4, but not that induced by TNF-alpha or leukotriene B-4, app eared to be mediated in part by endogenously generated eotaxin. Anti-e otaxin Abs significantly inhibited (54%) the later phases (24-28 h) bu t not the early phase (0-4 h) of the response to IL-4, This was consis tent with eotaxin mRNA expression peaking at 18 h after IL-4 injection , Our findings show that human eotaxin is a potent inducer of eosinoph il accumulation in vivo, this response being dependent on alpha(4) int egrin/vascular cell adhesion molecule-1 and beta(2) integrin/intercell ular adhesion molecule-1 adhesion pathways, Further,the eosinophil acc umulation in response to IL-4 is partly mediated by endogenously gener ated eotaxin.