title: Human eotaxin induces alpha 4 and beta 2 integrin-dependent eosinophil accumulation in rat skin in vivo: delayed generation of eotaxin in response to IL-4.
abstract: The CC chemokine eotaxin, originally purified from bronchoalveolar lavage fluid of sensitized guinea pigs following allergen challenge, is a potent eosinophil-selective chemoattractant. In the present study, we have used (111)In-eosinophils and human eotaxin to characterize the profile of chemokine-induced eosinophil accumulation in vivo in rat skin. Intradermally injected eotaxin caused a dose-dependent accumulation of (111)In-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-intercellular adhesion molecule-1, anti-vascular cell adhesion molecule-1, or anti-alpha4 integrin mAbs significantly inhibited the eosinophil accumulation induced by 100 pmol of human eotaxin by 73, 43, and 67%, respectively. Further, when (111)In-eosinophils were pretreated in vitro with anti-alpha4 integrin or anti-beta2 integrin mAbs, or with a combination of both mAbs, eotaxin-induced responses in vivo were reduced by 52, 49, and 68%, respectively. Eosinophil accumulation induced by intradermal IL-4, but not that induced by TNF-alpha or leukotriene B4, appeared to be mediated in part by endogenously generated eotaxin. Anti-eotaxin Abs significantly inhibited (54%) the later phases (24-28 h) but not the early phase (0-4 h) of the response to IL-4. This was consistent with eotaxin mRNA expression peaking at 18 h after IL-4 injection. Our findings show that human eotaxin is a potent inducer of eosinophil accumulation in vivo, this response being dependent on alpha4 integrin/vascular cell adhesion molecule-1 and beta2 integrin/intercellular adhesion molecule-1 adhesion pathways. Further, the eosinophil accumulation in response to IL-4 is partly mediated by endogenously generated eotaxin.
authors.affiliation: Leukocyte Biology Centre, Biomedical Sciences Division, Imperial College School of Medicine, London, United Kingdom.
authors.forename: M J
authors.initials: MJ
authors.lastname: Sanz
authors.forename: P D
authors.initials: PD
authors.lastname: Ponath
authors.forename: C R
authors.initials: CR
authors.lastname: Mackay
authors.forename: W
authors.initials: W
authors.lastname: Newman
authors.forename: M
authors.initials: M
authors.lastname: Miyasaka
authors.forename: T
authors.initials: T
authors.lastname: Tamatani
authors.forename: B F
authors.initials: BF
authors.lastname: Flanagan
authors.forename: R R
authors.initials: RR
authors.lastname: Lobb
authors.forename: T J
authors.initials: TJ
authors.lastname: Williams
authors.forename: S
authors.initials: S
authors.lastname: Nourshargh
authors.forename: P J
authors.initials: PJ
authors.lastname: Jose
mesh_terms: D000818:Animals; D000911:Antibodies, Monoclonal / Q000494:pharmacology; D015703:Antigens, CD / Q000276:immunology / Q000502:physiology*; D018821:CD18 Antigens / Q000276:immunology / Q000502:physiology*; D002118:Calcium / Q000378:metabolism; D002465:Cell Movement / Q000187:drug effects / Q000276:immunology; D054413:Chemokine CCL11; D019742:Chemokines, CC; D002631:Chemotactic Factors, Eosinophil / Q000494:pharmacology; D016207:Cytokines / Q000008:administration & dosage / Q000096:biosynthesis / Q000494:pharmacology*; D004487:Edema / Q000209:etiology / Q000276:immunology / Q000473:pathology; D004804:Eosinophils / Q000187:drug effects / Q000276:immunology* / Q000473:pathology; D006801:Humans; D007205:Indium Radioisotopes; D007271:Injections, Intradermal; D007275:Injections, Intravenous; D039441:Integrin alpha4; D016023:Integrins / Q000276:immunology / Q000502:physiology*; D015847:Interleukin-4 / Q000494:pharmacology*; D007424:Intracellular Fluid / Q000378:metabolism; D008297:Male; D051381:Rats; D017207:Rats, Sprague-Dawley; D012867:Skin / Q000276:immunology* / Q000473:pathology; D013997:Time Factors
chemical_list: D000911:Antibodies, Monoclonal; D015703:Antigens, CD; C515456:CCL11 protein, human; D018821:CD18 Antigens; C515458:Ccl11 protein, rat; D054413:Chemokine CCL11; D019742:Chemokines, CC; D002631:Chemotactic Factors, Eosinophil; D016207:Cytokines; D007205:Indium Radioisotopes; D016023:Integrins; D039441:Integrin alpha4; D015847:Interleukin-4; D002118:Calcium