Direct contact between T lymphocytes and human dermal fibroblasts or synoviocytes down-regulates types I and III collagen production via cell-associated cytokines

Abstract

In many inflammatory diseases where tissue remodeling occurs, T cells are in close contact with mesenchymal cells. We investigated the effect of direct cell-cell contact between peripheral blood T lymphocytes or HUT-78 lymphoma cells and dermal fibroblasts or synoviocytes on the deposition of the major extracellular matrix components: types I and III collagen. Incubation of dermal fibroblasts and synoviocytes with plasma membrane preparations from resting T cells slightly increased the production of collagen I but did not significantly affect that of collagen III. Conversely, direct contact with either plasma membranes or fixed phytohemagglutinin/phorbol myristate acetate-activated T cells markedly inhibited the synthesis of types I and III collagen by 60-70% in untreated dermal fibroblasts and synoviocytes and by 85% in transforming growth factor beta-stimulated fibroblasts. This decrease of collagen synthesis was abrogated when fixed T cells were separated physically from fibroblasts, demonstrating that direct contact between the two cell types was necessary. This inhibition was associated with a marked decrease in steady-state levels of pro-alpha1(I) and pro-alpha1(III) collagen mRNAs. T cell contact decreased the transcription rate but did not significantly alter the stability of the alpha1(I) and alpha1(III) transcripts. Finally, using neutralizing antibodies or cytokine inhibitors we provide evidence that this inhibition of extracellular matrix production mediated by T cell contact was partially due to additive effects of T cell membrane-associated interferon gamma, tumor necrosis factor alpha, and interleukin-1alpha.