Am. J. Respir. Cell Mol. Biol., Volume 21, Number 3, September, 1999 418-427

Mechanisms and Regulation of Polymorphonuclear Leukocyte and Eosinophil Adherence to Human Airway Epithelial Cells

Mark A. Jagels, Pamela J. Daffern, Bruce L. Zuraw, and Tony E. Hugli

Departments of Immunology and Molecular and Experimental Medicine, Scripps Research Institute, La Jolla, California

Polymorphonuclear leukocytes (PMN) and eosinophils (Eos) are important cellular participants in a variety of acute and chronic inflammatory reactions in the airway. Histologic evidence has implicated direct interactions between these two subsets of leukocytes and airway epithelial cells during inflammation. A comprehensive characterization and comparison of physiologic stimuli and adhesion molecule involvement in granulocyte-epithelial-cell interactions done with nontransformed human airway epithelial cells has not been reported. We therefore examined the regulation and biochemical mechanisms governing granulocyte-epithelial-cell adhesion, using either purified PMN or Eos and primary cultures of human bronchial epithelial cells (HBECs). We investigated the involvement of a number of proinflammatory signals associated with allergic and nonallergic airway inflammation, as well as the contribution of several epithelial and leukocyte adhesion molecules, including intercellular adhesion molecule-1 (ICAM-1), vascular cell adhesion molecule-1 (VCAM-1), and members of the ₁, ₂, and ₇ integrin families. ICAM-1 was expressed at low levels on cultured HBECs and was markedly upregulated after stimulation with interferon (IFN)- or, to a lesser extent, with tumor necrosis factor (TNF)- or interleukin (IL)-1. VCAM-1 was not present on resting HBECs, and was not upregulated after stimulation with IFN-, IL-1, IL-4, or TNF-. PMN adhesion to HBECs could be induced either through activation of PMN with IL-8, granulocyte-macrophage colony-stimulating factor (GM-CSF), or C5a, but not with IL-5 or by preactivation of HBECs with TNF- or IFN-. Blocking antibody studies indicated that PMN-HBEC adherence depended on ₂ integrins, primarily _M2 (Mac-1). Adherence of Eos to HBECs could be induced through activation of Eos with IL-5, GM-CSF, or C5a, but not with IL-8 or by prior activation of HBECs with TNF- of IFN-. Maximal adhesion of Eos and PMN required pretreatment of HBECs with either TNF- or IFN- in addition to leukocyte activation. Adherence of Eos to unstimulated HBECs was mediated through both ₁ and ₂ integrins, whereas adhesion of Eos to activated HBECs was dominated by ₂ integrins. Adhesion of both Eos and PMN was inhibited by treatment of HBECs with blocking antibodies to ICAM-1. Differential utilization of ₁ and ₂ integrins by Eos, depending on the activation state of the epithelium, is a novel finding and may affect activation and/or recruitment of Eos in airway tissue. Mechanisms of adhesion of HBECs to Eos and PMN, as evidenced by the different responsiveness of the two latter types of cells to IL-8 and IL-5, may account for a prevalence of Eos over PMN in certain airway diseases.

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