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 intracellular IL-1Ra (icIL-1Ra) types I and II. We have previously reported that human airway epithelial cells (HAEC) express icIL-1Ra type I, which can be up-regulated by corticosteroids. This study assessed whether cytokines and corticosteroids differentially effect icIL-1Ra type I protein 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 type I protein was detected in concentrated cell culture supernatants from NCI-H292 cells and normal human bronchial epithelial cells. The release of biologically relevant concentrations of active IL-1Ra from normal human bronchial epithelial cells was demonstrated by the ability of a neutralizing anti-IL-1Ra Ab to augment IL-1beta-mediated IL-8 secretion. IL-4, IL-13, and IFN-gamma induced immunoreactive IL-1Ra release into supernatants from NCI-H292 cells. Dexamethasone inhibited constitutive and cytokine-induced release of immunoreactive IL-1Ra. The release of icIL-1Ra type I protein was not related to cytotoxicity, as measured by lactate dehydrogenase. We propose that icIL-1Ra type I release from HAEC represents a novel mechanism by which IL-1 bioactivity in the airway microenvironment may be modulated. Cytokine-mediated icIL-1Ra type I synthesis may increase both intracellular protein and release to the extracellular space, where cell surface IL-1R can be antagonized. In contrast, corticosteroid-induced increases in icIL-1Ra type I synthesis and inhibition of extracellular protein release promote accumulation of icIL-1Ra type I protein within the intracellular compartment.
Levine
S J
SJ
Critical Care Medicine Department, Warren G. Magnuson Clinical Center, National Institutes of Health, Bethesda, MD 20892, USA. slevine@nih.gov
Wu
T
T
Shelhamer
J H
JH
D001980:Bronchi / Q000378:metabolism*; D002478:Cells, Cultured; D003907:Dexamethasone / Q000494:pharmacology*; D004848:Epithelium / Q000378:metabolism; D006801:Humans; D007371:Interferon-gamma / Q000494:pharmacology*; D053590:Interleukin 1 Receptor Antagonist Protein; D018793:Interleukin-13 / Q000494:pharmacology*; D015847:Interleukin-4 / Q000494:pharmacology*; D007770:L-Lactate Dehydrogenase / Q000378:metabolism; D012333:RNA, Messenger / Q000032:analysis; D017472:Receptors, Interleukin-1 / Q000037:antagonists & inhibitors*; D012795:Sialoglycoproteins / Q000378:metabolism*; D015854:Up-Regulation
C507763:IL1RN protein, human; D053590:Interleukin 1 Receptor Antagonist Protein; D018793:Interleukin-13; D012333:RNA, Messenger; D017472:Receptors, Interleukin-1; D012795:Sialoglycoproteins; D015847:Interleukin-4; D003907:Dexamethasone; D007371:Interferon-gamma; D007770:L-Lactate Dehydrogenase