TGF-BETA DIFFERENTIALLY MODULATES EPIDERMAL GROWTH FACTOR-MEDIATED INCREASES IN LEUKEMIA-INHIBITORY FACTOR, IL-6, IL-1-ALPHA, AND IL-1-BETAIN HUMAN THYMIC EPITHELIAL-CELLS

The regulation of cytokine production by thymic epithelial cells (TEC) in the thymus is under coordinated and temporal control and is import ant for the development of T cells. Human TEC express TGF-beta R and e pidermal 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 be en shown to modulate TGF-beta effector functions, we determined whethe r TGF-beta can modulate EGF-mediated increases in cytokine gene expres sion human TEC. We established that a single TEC expresses both EGF re ceptor and TGF-beta R. TGF-beta plus EGF synergistically increased leu kemia-inhibitory factor (LIF), additively increased IL-6, but had litt le effect on IL-1 alpha and IL-1 beta mRNA levels. In contrast, TGF-be ta 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 EL ISA. 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, mo st likely at the level of mRNA stability. Our data demonstrate that TG F-beta modulates TEC cytokine production. We speculate that TGF-beta p roduced in situ plays a role in thymocyte development by directly affe cting thymocyte differentiation and by indirectly modulating TEC cytok ine production.