Regulation of cytokine production in the human thymus: epidermal growth factor and transforming growth factor alpha regulate mRNA levels of interleukin 1 alpha (IL-1 alpha), IL-1 beta, and IL-6 in human thymic epithelial cells at a post-transcriptional level

Human thymic epithelial (TE) cells produce interleukin 1 alpha (IL-1 alpha), IL-1 beta, and IL-6, cytokines that are important for thymocyte proliferation. The mRNAs for these cytokines are short-lived and are inducible by multiple stimuli. Thus, the steady-state levels for IL-1 and IL-6 mRNAs are critical in establishing the final cytokine protein levels. In this study we have evaluated the effect of epidermal growth factor (EGF), a growth factor for TE cells, and its homologue transforming growth factor alpha (TGF-alpha), on primary cultures of normal human TE cells for the levels of IL-1 alpha, IL-1 beta, IL-6, and TGF-alpha mRNA. We showed that TE cells expressed EGF receptors (EGF-R) in vitro and in vivo, and that treatment of TE cells with EGF or TGF-alpha increased IL-1 and IL-6 biological activity and mRNA levels for IL-1 alpha, IL-1 beta, and IL-6. Neither EGF nor TGF-alpha increased transcription rates of IL-1 alpha, IL-1 beta, and IL-6 genes, but rather both EGF and TGF-alpha increased cytokine mRNA stability. By indirect immunofluorescence assay, TGF-alpha was localized in medullary TE cells and thymic Hassall's bodies while EGF-R was localized to TE cells throughout the thymus. Thus, TGF-alpha and EGF are critical regulatory molecules for production of TE cell-derived cytokines within the thymus and may function as key modulators of human T cell development in vivo.