EXTRACELLULAR RELEASE OF THE TYPE-I INTRACELLULAR IL-1 RECEPTOR ANTAGONIST FROM HUMAN AIRWAY EPITHELIAL-CELLS - DIFFERENTIAL-EFFECTS OF IL-4, IL-13, IFN-GAMMA, AND CORTICOSTEROIDS

Three IL-1R antagonists (IL-1Ra) exist: secreted IL-1Ra and intracellu lar IL-1Ra (icIL-1Ra) types I and II. We have previously reported that human airway epithelial cells (HAEC) express icIL-1Ra type I, which c an be up-regulated by corticosteroids. This study assessed whether cyt okines and corticosteroids differentially effect icIL-1Ra type I prote in release from HAEC to the extracellular compartment. We report that icIL-1Ra type I mRNA and intracellular protein are up-regulated in NCI -H292 cells, a human pulmonary mucoepidermoid carcinoma cell line, in response to IL-4, IL-13, IFN-gamma, and dexamethasone. The icIL-1Ra ty pe I protein was detected in concentrated cell culture supernatants fr om NCI-H292 cells and normal human bronchial epithelial cells. The rel ease of biologically relevant concentrations of active IL-1Ra from nor mal human bronchial epithelial cells was demonstrated by the ability o f a neutralizing anti-IL-1Ra Ab to augment IL-1 beta-mediated IL-8 sec retion. IL-4, IL-13, and IFN-gamma induced immunoreactive IL-1Ra relea se into supernatants from NCI-H292 cells, Dexamethasone inhibited cons titutive and cytokine-induced release of immunoreactive IL-1Ra. The re lease of icIL-1Ra type I protein was not related to cytotoxicity, as m easured by lactate dehydrogenase. We propose that icIL-1Ra type I rele ase from HAEC represents a novel mechanism by which IL-1 bioactivity i n the airway microenvironment may be modulated, Cytokine-mediated icIL -1Ra type I synthesis may increase both intracellular protein and rele ase to the extracellular space, where cell surface IL-1R can be antago nized, In contrast, corticosteroid-induced increases in icIL-1Ra type I synthesis and inhibition of extracellular protein release promote ac cumulation of icIL-1Ra type I protein within the intracellular compart ment.