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

IL-1 is a key cytokine that promotes pulmonary inflammation and fibrosis, as a result of its ability to stimulate lung fibroblast proliferation and collagen synthesis, two hallmarks of fibrosis, The IL-1 receptor antagonist (IL-1Ra) is an important natural inhibitor of IL-1-mediated functions, In models of pulmonary fibrosis induced by chemotherapeutic agents or noxious particles, administration of IL-1Ra significantly ameliorates lung fibrosis, Lung tissue undergoing an inflammatory response shows elevations in IL-1Ra, although it is not clear which pulmonary cells are responsible for the IL-1Ra synthesis, The purpose of this research was to determine whether Thy-1(+) and Thy-1(-) subsets of mouse lung fibrobiasts were capable of synthesizing IL-1Ra, In this report, it is demonstrated for the first time that lung fibroblasts are capable of synthesizing IL-1Ra, Both Thy-1(+) and Thy-1(-) parental lines and clones constitutively express IL-1Ra mRNA. Quantitation of IL-1Ra protein indicates that Thy-1(+) and Thy-1(-) fibroblasts secrete similar levels of secreted but not intracellular IL-1Ra, Thy-1(-) fibroblasts accumulate higher levels of IL-1Ra intracellularly. Moreover, fibroblast-conditioned supernatants containing IL-1Ra significantly suppress the mitogenic response of a T cell clone, D10G4.1, to concanavalin 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 and/or paracrine fashion to maintain homeostasis in the pulmonary interstitium.