Extracellular regulation of interleukin (IL)-1 beta through lung epithelial cells and defective IL-1 type II receptor expression

Interleukin (IL)-1 beta is produced primarily by activated mononuclear phag ocytic cells in the lung airway and functions as a potent proinflammatory c ytokine. Release of IL-1 beta in the airway microenvironment induces the pr oduction of proinflammatory factors from parenchymal airway cells, includin g IL-8. To study the regulation of lung epithelial cell responsiveness to I L-1 beta, the human type II-like airway epithelial cell line A549 and prima ry normal human bronchial epithelial (NHBE) cells were assayed for IL-1-spe cific response modifiers. Specifically, the IL-1 type I receptor (IL-IRI), IL-1 type II receptor (IL-1RII), IL-1 receptor accessory protein (IL-1RAcP) , and IL-1 receptor antagonist (IL-1Ra) were analyzed. Constitutive express ion of IL-1RI, IL-1RAcP, and IL-1Ra was detected in both immortalized and p rimary 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 beta at concentrat ions as low as 50 to 500 pg/ml when measured by IL-8 release into cell supe rnatants. IL-1 beta-induced chemokine production and release were inhibited by a 10- to 1,000-fold molar excess of recombinant IL-1RII or IL-1Ra, wher eas 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 I L-1 beta activity extracellularly because of an inability to express IL-1RI I. Release of extracellular IL-1 inhibitors, including soluble IL-1Ra and s oluble IL-1RII, by other inflammatory cells present in the airway may be cr itical for regulation of IL-1 beta activity in the airway microenvironment.