Recombinant human eotaxin induces oxygen radical production, Ca(2+)-mobilization, actin reorganization, and CD11b upregulation in human eosinophils via a pertussis toxin-sensitive heterotrimeric guanine nucleotide-binding protein.
The novel human CC-chemokine Eotaxin is a potent and selective chemotaxin for eosinophils. Here, the biological activities and the activation profile of Eotaxin were further characterized and compared with those of other eosinophil chemotaxins such as complement fragment C5a (C5a), platelet-activating factor (PAF), and RANTES in human eosinophils. Eotaxin stimulated the production of reactive oxygen metabolites as shown by lucigenin-dependent chemiluminescence and superoxide dismutase-inhibitable cytochrome C reduction. Furthermore, Eotaxin induced upregulation of the integrin CD11b. In addition, fluorescence measurements with Fura-2-labeled eosinophils in the presence of EGTA indicated Ca(2+)-mobilization from intracellular stores by Eotaxin. Flow cytometric studies showed rapid and translent actin polymerization on stimulation with Eotaxin. At optimal concentrations, the changes induced by Eotaxin were comparable with those obtained by C5a, PAF, and RANTES. Call responses elicited by Eotaxin were inhibited by pertussis toxin, indicating coupling of its putative receptor to heterotrimeric guanine nucleotide-binding proteins. These results indicate that Eotaxin is a strong activator of eosinophils with biological activity comparable with those of the eosinophil chemotaxins C5a, PAF, and RANTES. These findings point to a role of Eotaxin in the pathogenesis of eosinophilic inflammation as a chemotaxin as well as an activator of proinflammatory effector functions.
Tenscher
K
K
Department of Dermatology, University of Freiburg, Germany.
Metzner
B
B
Schöpf
E
E
Norgauer
J
J
Czech
W
W
D000199:Actins / Q000378:metabolism*; D002118:Calcium / Q000378:metabolism*; D054413:Chemokine CCL11; D018946:Chemokine CCL5 / Q000494:pharmacology; D019742:Chemokines, CC; D002631:Chemotactic Factors, Eosinophil / Q000494:pharmacology*; D015936:Complement C5a / Q000494:pharmacology; D016207:Cytokines / Q000037:antagonists & inhibitors / Q000494:pharmacology*; D004804:Eosinophils / Q000187:drug effects* / Q000378:metabolism; D005609:Free Radicals / Q000378:metabolism; D019206:GTP-Binding Protein alpha Subunits, Gi-Go / Q000737:chemistry / Q000502:physiology*; D005786:Gene Expression Regulation / Q000187:drug effects*; D006801:Humans; D016177:Macrophage-1 Antigen / Q000096:biosynthesis* / Q000235:genetics; D037342:Pertussis Toxin; D010972:Platelet Activating Factor / Q000494:pharmacology; D011994:Recombinant Proteins / Q000037:antagonists & inhibitors / Q000494:pharmacology; D016897:Respiratory Burst / Q000187:drug effects*; D010566:Virulence Factors, Bordetella / Q000494:pharmacology
D000199:Actins; C515456:CCL11 protein, human; D054413:Chemokine CCL11; D018946:Chemokine CCL5; D019742:Chemokines, CC; D002631:Chemotactic Factors, Eosinophil; D016207:Cytokines; D005609:Free Radicals; D016177:Macrophage-1 Antigen; D010972:Platelet Activating Factor; D011994:Recombinant Proteins; D010566:Virulence Factors, Bordetella; D015936:Complement C5a; D037342:Pertussis Toxin; D019206:GTP-Binding Protein alpha Subunits, Gi-Go; D002118:Calcium