Functional regulation of beta 1 integrins on human eosinophils by divalent cations and cytokines.
Divalent cations and various soluble stimuli can alter cell adherence by affecting the avidity of adhesion molecules. We hypothesized that beta 1 integrin function of human eosinophils may be altered by divalent cations and eosinophil-activating cytokines such as interleukin-5 (IL-5). Expression of the beta 1 integrin activation epitope recognized by monoclonal antibody (mAb) 15/7 was evaluated by flow cytometry using purified eosinophils from allergic subjects, normal subjects, and late-phase bronchoalveolar lavage (BAL) fluids. Rapid and reversible 15/7 binding on eosinophils from each source was induced in Mn2+ (0.01-1 mM) but not in buffers containing other divalent cations and occurred without affecting the total level of beta 1 integrin expression (quantified using mAb 33B6). Augmentation of eosinophil adhesion to immobilized vascular cell adhesion molecule (VCAM-1) in Mn2+ followed a similar concentration dependence as mAb 15/7 binding. Net binding to VCAM-1 in Mn2+ was completely inhibited with a mixture of alpha 4 and beta 1 integrin mAb while beta 2 integrin mAb had no effect. Exposure of eosinophils from allergic subjects to as little as 1 pg/ml IL-5 completely inhibited mAb 15/7 binding induced by Mn2+. In contrast, increased binding of mAb 15/7 in Mn2+ was not blocked by IL-5 in eosinophils from normal subjects. For eosinophils from allergic subjects, IL-5 also inhibited Mn(2+)-induced adhesion to VCAM-1. Thus, beta 1 integrins on eosinophils from allergic and nonallergic subjects are modulated differently by Mn2+ and IL-5. Altered beta 1 integrin avidity may be one mechanism involved in preferential eosinophil recruitment in vivo.
Werfel
S J
SJ
Department of Medicine, Johns Hopkins University School of Medicine, Johns Hopkins Asthma and Allergy Center, Baltimore, Maryland 21224-6801, USA.
Yednock
T A
TA
Matsumoto
K
K
Sterbinsky
S A
SA
Schleimer
R P
RP
Bochner
B S
BS
D000911:Antibodies, Monoclonal / Q000494:pharmacology; D001249:Asthma / Q000097:blood; D001992:Bronchoalveolar Lavage Fluid / Q000166:cytology; D002413:Cations, Divalent; D002448:Cell Adhesion / Q000187:drug effects*; D016207:Cytokines / Q000494:pharmacology*; D004804:Eosinophils / Q000502:physiology*; D005434:Flow Cytometry; D006801:Humans; D006967:Hypersensitivity / Q000097:blood; D019012:Integrin beta1 / Q000276:immunology / Q000502:physiology*; D015848:Interleukin-5 / Q000494:pharmacology; D008345:Manganese / Q000494:pharmacology*; D012220:Rhinitis / Q000097:blood; D019010:Vascular Cell Adhesion Molecule-1 / Q000378:metabolism
D000911:Antibodies, Monoclonal; D002413:Cations, Divalent; D016207:Cytokines; D019012:Integrin beta1; D015848:Interleukin-5; D019010:Vascular Cell Adhesion Molecule-1; D008345:Manganese