Thymic epithelial cells (TEC) are known to secrete thymic hormones that influence maturation of T lym- [2884][2885][2886][2887][2888][2889][2890] showed that interleukin 1 (IL-i) in vivo stimulates zinc uptake by the thymus. Both the a and J forms of IL-1, which stimulate proliferation of human TEC, also stimulate their uptake of zinc in vitro, and this latter stimulation is both dependent and independent of proliferation. Zinc induces zinc accumulation without proliferation. Two other stimulants of proliferation, bovine pituitary extract and epidermal growth factor, stimulate zinc uptake by TEC, but only in a manner dependent on proliferation. Utilizing in situ hybridization, we show that the IL-1 a and P forms and zinc induce metallothionein mRNA expression in TEC. Metallothionein is thought to be involved in the transfer of zinc to thymulin. IL-1 was shown to stimulate the secretion of thymulin as measured both by its ability to smulate induction of IL-2 receptor-positive lymphocytes from human peripheral blood lymphocytes and by the azathioprinesensitive rosette assay. In addition, the zinc-thymul complex in the presence, but not absence, of IL-1 stimulates nuclear protein kinase C in isolated lymphocyte nuclei. IL-1 apparently regulates the synthesis or secretion and delivery of zincthymulin complex to the T-lymphocyte system.

The thymus produces several putative thymic hormones: thymosin alpha 1, thymulin, and thymopoietin, which have been reported to circulate and to act on both prothymocytes and mature T cells in the periphery, thus maintaining their commitment to the T cell system. These endocrine influences decline with age and are associated with "thymic menopause" and cellular immune senescence, which contribute to the development of diseases in the aged. Thymus endocrinology is characterized by the action of many hormones and hormone-like substances on the cellular components of the thymus, including thymocytes, thymic epithelial cells, and thymic stromal cells. The intrathymic environment is characterized by a complex network of paracrine, autocrine, and endocrine signals involving both interleukins and thymic peptides, which can be envisioned to operate in a synergistic network to carry the evolving T cell through its stepwise development to a mature T cell. Extrathymic influences regulating the secretory function of thymic epithelial cells and the stepwise evolution of T cells can be ascribed to circulating interleukins, mainly IL1 and IL2, derived from activation and secretion of leukocytes in the periphery. These interleukins act in a synergistic fashion at all levels of T cell development by the induction of high-affinity IL2 receptors and the resultant IL2-dependent proliferative responses. To determine whether exogenous administration of interleukins would induce T lymphocyte development in aged mice, we chemically thymectomized aged mice with a steroid hormone and treated them with mixed interleukins or thymic hormones such as thymosin. We found that mixed interleukins, but not thymosin, restored thymic weight and cellularity and enhanced thymocyte responses to interleukins and mitogen. Thymosin potentiated the effect.

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