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TNF- Potentiates C5a-Stimulated Eosinophil Adhesion to Human Bronchial Epithelial Cells: A Role for ₅₁ Integrin¹

Anne Burke-Gaffney^2,*,, Kate Blease^3,*, Adele Hartnell^4,* and Paul G. Hellewell

^* Applied Pharmacology and Unit of Critical Care, National Heart and Lung Institute Division, Imperial College of Science, Technology and Medicine, London, United Kingdom; and Cardiovascular Research Group, University of Sheffield, Clinical Sciences Center, Northern General Hospital, Sheffield, United Kingdom

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- 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- nor IL-5, a known eosinophil-priming agent. Priming caused activation of _M2 integrin; mAb against either the common ₂ integrin subunit or its ICAM-1 ligand reduced the primed component of adhesion. Using mAbs against ₁ or ₅, but not ₄ integrin subunit, together with anti-₂ integrin mAb, reduced stimulated adhesion to basal levels. Cross-linking ₅₁ integrin increased _M2 integrin-dependent adhesion of eosinophils. There are no known adhesion molecule ligands of ₅₁ integrin expressed on HBEC; however, fibronectin, the major matrix protein ligand for ₅₁ integrin, was detected in association with HBEC monolayers. A mAb against fibronectin, in combination with anti-₂ integrin mAb, reduced adhesion to basal levels. In conclusion, ₅₁ integrin may provide a contact-dependent costimulus for eosinophil priming that, together with TNF-, potentiated C5a activation of _M2 integrin and increased eosinophil adhesion to ICAM-1. Fibronectin, associated with HBEC, may act as a ligand for ₅₁ integrin. Dual regulation of eosinophil priming may prevent inappropriate activation of eosinophils in the circulation.

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