TNF-alpha potentiates C5a-stimulated eosinophil adhesion to human bronchial epithelial cells: a role for alpha 5 beta 1 integrin.
Cooperative action of inflammatory mediators and adhesion molecules orchestrates eosinophil recruitment during allergic inflammation in the airways. This study investigated the mechanisms involved in increasing eosinophil adhesion to human bronchial epithelial cells (HBEC) following priming and activation of eosinophils with TNF-alpha and complement protein C5a, respectively. Under primed conditions, eosinophil adhesion increased 3-fold from basal (16%), and the effect was significantly greater (p < 0.05) than the increase following stimulation with C5a alone (2-fold). Eosinophil contact with HBEC was essential for priming. In contrast to C5a, adhesion of eotaxin-stimulated eosinophils to HBEC was not primed with TNF-alpha nor IL-5, a known eosinophil-priming agent. Priming caused activation of alpha(M)beta(2) integrin; mAb against either the common beta(2) integrin subunit or its ICAM-1 ligand reduced the primed component of adhesion. Using mAbs against beta(1) or alpha(5), but not alpha(4) integrin subunit, together with anti-beta(2) integrin mAb, reduced stimulated adhesion to basal levels. Cross-linking alpha(5)beta(1) integrin increased alpha(M)beta(2) integrin-dependent adhesion of eosinophils. There are no known adhesion molecule ligands of alpha(5)beta(1) integrin expressed on HBEC; however, fibronectin, the major matrix protein ligand for alpha(5)beta(1) integrin, was detected in association with HBEC monolayers. A mAb against fibronectin, in combination with anti-beta(2) integrin mAb, reduced adhesion to basal levels. In conclusion, alpha(5)beta(1) integrin may provide a contact-dependent costimulus for eosinophil priming that, together with TNF-alpha, potentiated C5a activation of alpha(M)beta(2) integrin and increased eosinophil adhesion to ICAM-1. Fibronectin, associated with HBEC, may act as a ligand for alpha(5)beta(1) integrin. Dual regulation of eosinophil priming may prevent inappropriate activation of eosinophils in the circulation.
Burke-Gaffney
Anne
A
Applied Pharmacology and Unit of Critical Care, National Heart and Lung Institute Division, Imperial College of Science, Technology and Medicine, Dovehouse Street, London, SW3 6LY, United Kingdom. a.burke-gaffney@ic.ac.uk
Blease
Kate
K
Hartnell
Adele
A
Hellewell
Paul G
PG
D000276:Adjuvants, Immunologic / Q000502:physiology*; D000911:Antibodies, Monoclonal / Q000378:metabolism; D015703:Antigens, CD / Q000032:analysis / Q000096:biosynthesis; D001980:Bronchi / Q000166:cytology / Q000276:immunology* / Q000378:metabolism; D018821:CD18 Antigens / Q000502:physiology; D002448:Cell Adhesion / Q000276:immunology; D002450:Cell Communication / Q000276:immunology; D002478:Cells, Cultured; D054413:Chemokine CCL11; D019742:Chemokines, CC / Q000494:pharmacology; D015936:Complement C5a / Q000502:physiology*; D003432:Cross-Linking Reagents / Q000378:metabolism; D004804:Eosinophils / Q000276:immunology* / Q000378:metabolism; D006801:Humans; D039482:Integrin alpha5; D018799:Intercellular Adhesion Molecule-1 / Q000502:physiology; D017469:Receptors, Fibronectin / Q000276:immunology / Q000378:metabolism / Q000502:physiology*; D020545:Respiratory Mucosa / Q000166:cytology / Q000276:immunology* / Q000378:metabolism; D014409:Tumor Necrosis Factor-alpha / Q000502:physiology*
D000276:Adjuvants, Immunologic; D000911:Antibodies, Monoclonal; D015703:Antigens, CD; C515456:CCL11 protein, human; D018821:CD18 Antigens; D054413:Chemokine CCL11; D019742:Chemokines, CC; D003432:Cross-Linking Reagents; D039482:Integrin alpha5; D017469:Receptors, Fibronectin; D014409:Tumor Necrosis Factor-alpha; D018799:Intercellular Adhesion Molecule-1; D015936:Complement C5a