TGF-beta differentially modulates epidermal growth factor-mediated increases in leukemia-inhibitory factor, IL-6,...

The regulation of cytokine production by thymic epithelial cells (TEC) in the thymus is under coordinated and temporal control and is important for the development of T cells. Human TEC express TGF-beta R and epidermal growth factor (EGF) receptor, and produce TGF-beta 3 in vitro and in vivo. Furthermore, EGF has been shown to increase IL-1 alpha, IL-1 beta, IL-6 mRNA and protein levels in human TEC. Since EGF has been shown to modulate TGF-beta effector functions, we determined whether TGF-beta can modulate EGF-mediated increases in cytokine gene expression in human TEC. We established that a single TEC expresses both EGF receptor and TGF-beta R. TGF-beta plus EGF synergistically increased leukemia-inhibitory factor (LIF), additively increased IL-6, but had little effect on IL-1 alpha and IL-1 beta mRNA levels. In contrast, TGF-beta alone increased LIF and IL-6, had little effect on IL-1 alpha, and slightly decreased IL-1 beta mRNA levels. The increases in LIF and IL-6 mRNA levels by TGF-beta plus EGF correlate with the increases in LIF and IL-6 concentrations in TEC culture supernatants as detected by ELISA. We also determined the mechanism responsible for the increases in cytokine mRNA levels. TGF-beta plus EGF did not affect transcription of LIF and IL-6 genes; this suggests that the increases in the steady state levels of cytokine mRNA were mediated post-transcriptionally, most likely at the level of mRNA stability. Our data demonstrate that TGF-beta modulates TEC cytokine production. We speculate that TGF-beta produced in situ plays a role in thymocyte development by directly affecting thymocyte differentiation and by indirectly modulating TEC cytokine production.