Expression of TGF-beta isoforms by Thy-1+ and Thy-1- pulmonary fibroblast subsets: evidence for TGF-beta as a regulator of IL-1-dependent stimulation of IL-6.
Transforming growth factor-beta (TGF-beta) and interleukin-1 (IL-1) are essential participants in the development of pulmonary fibrosis. Administration of inhibitors to either cytokine can prevent the onset and progression of lung fibrosis in animal models. In this report, stable Thy-1+ and Thy-1- murine lung fibroblast subpopulations were analyzed for expression of the three mammalian TGF-beta isoforms. TGF-beta 1, TGF-beta 2, and TGF-beta 3 mRNA transcripts were detected by reverse transcriptase-PCR in both murine fibroblast subsets. Most of the TGF-beta produced by fibroblasts is latent; however, a small amount of active TGF-beta can be detected using a sensitive mink lung cell bioassay. By incorporating neutralizing anti-TGF-beta isoform-specific antibodies, it was determined that TGF-beta 1 is the predominant isoform present in both the active and the latent forms. Overall, Thy-1- fibroblasts secrete twice as much latent TGF-beta as the Thy-1+ subset. To investigate whether a link exists between TGF-beta and IL-1, the effect of TGF-beta 1 on the expression of IL-1 receptor type I (IL-1RtI) by fibroblast subsets was assessed by flow cytometry and Scatchard analysis. TGF-beta 1 significantly down-regulates the expression of IL-1RtI by Thy-1+ fibroblasts, but not by Thy-1- fibroblasts. A functional consequence of this down-regulation of the IL-1RtI is that it makes Thy-1+ fibroblasts less responsive to IL-1-mediated induction of IL-6 protein synthesis.(ABSTRACT TRUNCATED AT 250 WORDS)
Silvera, MR; Sempowski, GD; Phipps, RP
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