INTERLEUKIN-4 AND INTERFERON-GAMMA DISCORDANTLY REGULATE COLLAGEN BIOSYNTHESIS BY FUNCTIONALLY DISTINCT LUNG FIBROBLAST SUBSETS

Pulmonary fibrosis is a potentially fatal consequence of treatments fo r malignancy and is an increasing problem in bone marrow transplant pa tients and in cases of allogeneic lung transplant. The fibrotic respon se is characterized by increases in lung fibroblast number and collage n synthesis. This laboratory previously isolated stable, functionally distinct, murine lung fibroblast subsets (Thy-(1+) and Thy-1(-)) to st udy the contribution of fibroblast subpopulations in lung fibrosis. Th e fibroblast fibrotic response may be induced by cytokines secreted by infiltrating cells such as T lymphocytes and mast cells. In the curre nt study two key regulatory cytokines, interferon-gamma (IFN-gamma) an d interleukin-4 (IL-4), were investigated for their effects on the col lagen synthesis of murine lung fibroblast subsets. IL-4 and IFN-gamma are putatively characterized as fibrogenic and anti-fibrogenic cytokin es, respectively, and are found in repairing lung tissue. Stimulation with recombinant IL-4 induced a 100% increase in total collagen produc tion only by Thy-1(+) fibroblasts. Types I and III collagen mRNA were increased in the Thy-1(+) fibroblasts, unlike the Thy-1(-) subset. In contrast, IFN-gamma decreased constitutive collagen production by more than 50% in Thy-1(+) and Thy-1(-) fibroblasts. Interestingly, the two subsets utilized their collagen production machinery (collagenase, ti ssue inhibitors of metalloproteinases) differently to further regulate collagen turnover in response to IL-4 and IFN-gamma. Overall, our dat a support the hypothesis that IL-4 is fibrogenic and IFN-gamma is anti -fibrogenic. Moreover, selective expansion of IL-4 responsive fibrobla sts (e.g., Thy-1(+)) may be important in the transition from repair to chronic fibrosis. In addition, these data suggest that an inflammator y response dominated by IL-4-producing Th-2 lymphocytes and/or mast ce lls will promote fibrosis development. (C) 1996 Wiley-Liss, Inc.