Synthesis of Interleukin-1 Receptor Antagonist by Thy-1+and Thy-1-Murine Lung Fibroblast Subsets

Abstract

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 fibroblasts 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-1-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.