Am. J. Respir. Cell Mol. Biol., Volume 20, Number 5, May, 1999 964-975

Extracellular Regulation of Interleukin (IL)-1 through Lung Epithelial Cells and Defective IL-1 Type II Receptor Expression

Kristin R. Coulter, Mark D. Wewers, Melissa P. Lowe, and Daren L. Knoell

Departments of Pharmacy and Internal Medicine, College of Pharmacy, and Pulmonary and Critical Care Division, College of Medicine, Ohio State University, Columbus, Ohio

Interleukin (IL)-1 is produced primarily by activated mononuclear phagocytic cells in the lung airway and functions as a potent proinflammatory cytokine. Release of IL-1 in the airway microenvironment induces the production of proinflammatory factors from parenchymal airway cells, including IL-8. To study the regulation of lung epithelial cell responsiveness to IL-1, the human type II-like airway epithelial cell line A549 and primary normal human bronchial epithelial (NHBE) cells were assayed for IL-1-specific response modifiers. Specifically, the IL-1 type I receptor (IL-1RI), IL-1 type II receptor (IL-1RII), IL-1 receptor accessory protein (IL-1RAcP), and IL-1 receptor antagonist (IL-1Ra) were analyzed. Constitutive expression of IL-1RI, IL-1RAcP, and IL-1Ra was detected in both immortalized and primary human airway epithelial cells. Interestingly, a complete absence of IL-1RII expression was demonstrated under all study conditions in both A549 and NHBE cells. Both cell types were responsive to IL-1 at concentrations as low as 50 to 500 pg/ml when measured by IL-8 release into cell supernatants. IL-1-induced chemokine production and release were inhibited by a 10- to 1,000-fold molar excess of recombinant IL-1RII or IL-1Ra, whereas IL-1RI was a less effective inhibitor. On the basis of our results, we propose that human lung epithelial cells lack the ability to downregulate IL-1 activity extracellularly because of an inability to express IL-1RII. Release of extracellular IL-1 inhibitors, including soluble IL-1Ra and soluble IL-1RII, by other inflammatory cells present in the airway may be critical for regulation of IL-1 activity in the airway microenvironment.

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