Comparative and combined effects of transforming growth factors ? and ?, interleukin-1 and interferon-? on rheumatoid synovial cell proliferation, glycolysis and prostaglandin E production

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Abstract
Enhanced cell proliferation, glycolysis and prostaglandin E production are all characteristic features of rheumatoid synovial tissue. The interrelationships of these three cellular parameters have been examined using rheumatoid synovial fibroblasts and their responses to specific cytokines in vitro. Transforming growth factor α (TGFα) caused a more than threefold increase in synovial cell proliferation whilst transforming growth factor β (TGFβ), interleukin-1α (IL-1α) and interferon-γ (IFN-γ) produced only marginal changes. The combined addition of IL-1α with TGFβ resulted in an enhanced proliferative response comparable with that produced by TGFα. Glycolysis, estimated by glucose utilisation and measurements of the glycolytic regulatory metabolite fructose 2,6-bisphosphate was significantly stimulated by TGFβ, IL-1α and IFN-γ, but less so by TGFα. Prostaglandin E production was significantly increased by IL-1α to an extent much greater than that produced by TGFα or TGFβ, although the combined addition of IL-1α with either TGFα or β resulted in a synergistic increase in PGE production, a response partly diminished by the addition of IFN-γ. These findings suggest that the extent to which a cytokine stimulates glycolysis is not consistently related to its mitogenicity, and that cytokine combinations which stimulate high levels of PGE production (a growth inhibitor) will not necessarily be associated with a reduced rate of cellular proliferation in cultured, adherent, rheumatoid synovial fibroblasts.