SYNTHESIS OF INTERLEUKIN-1 RECEPTOR ANTAGONIST BY THY-1(-1(-) MURINE LUNG FIBROBLAST SUBSETS() AND THY)

IL-1 is a key cytokine that promotes pulmonary inflammation and fibros is, as a result of its ability to stimulate lung fibroblast proliferat ion and collagen synthesis, two hallmarks of fibrosis, The IL-1 recept or antagonist (IL-1Ra) is an important natural inhibitor of IL-1-media ted functions, In models of pulmonary fibrosis induced by chemotherape utic agents or noxious particles, administration of IL-1Ra significant ly ameliorates lung fibrosis, Lung tissue undergoing an inflammatory r esponse shows elevations in IL-1Ra, although it is not clear which pul monary cells are responsible for the IL-1Ra synthesis, The purpose of this research was to determine whether Thy-1(+) and Thy-1(-) subsets o f mouse lung fibrobiasts were capable of synthesizing IL-1Ra, In this report, it is demonstrated for the first time that lung fibroblasts ar e capable of synthesizing IL-1Ra, Both Thy-1(+) and Thy-1(-) parental lines and clones constitutively express IL-1Ra mRNA. Quantitation of I L-1Ra protein indicates that Thy-1(+) and Thy-1(-) fibroblasts secrete similar levels of secreted but not intracellular IL-1Ra, Thy-1(-) fib roblasts accumulate higher levels of IL-1Ra intracellularly. Moreover, fibroblast-conditioned supernatants containing IL-1Ra significantly s uppress the mitogenic response of a T cell clone, D10G4.1, to concanav alin A and IL-1 beta. Overall, our observations indicate that Thy-1(+) and Thy-1(-) fibroblasts release IL-1Ra and possess an IL-l-specific inhibitory activity in their supernatants, In vivo, fibroblast-derived IL-1Ra may serve to regulate IL-1-mediated effects in an autocrine an d/or paracrine fashion to maintain homeostasis in the pulmonary inters titium.