An area of major interest to us is the mechanisms involved in heterologous regulation of adrenergic receptors and the relevance of such regulation to disease conditions. Loss of beta-adrenergic receptors and receptor reactivity is a pathogenic feature in bronchial asthma. Glucocorticoids are effective in the treatment of asthma, which has been attributed to their ability to upregulate pulmonary beta-adrenergic receptors. In a study of glucocorticoid- beta-adrenergic interactions in cultured human lung cells we made the accidental observation that the beta-receptors of these cells were upregulated by serum-free medium conditioned with EBV- transformed human lymphocytes. The effect of the conditioned medium (LCM) could be attributed to a mixture of proteins, with approximate molecular weights of 70, 35 and 15 kD. Glucocorticoids also increased the density of beta-receptors in lung cells, and markedly potentiated the similar action of LCM. Human monocytic interleukin-1 (IL-1) as well as recombinant IL-lalpha and IL-lbeta also upregulated beta-receptors in the lung cells, and this effect was similarly potentiated by glucocorticoids. A neutralizing antibody against IL-1 blocked the effect of the 15 kD protein from LCM, but not the effects of the 35 and 70 kD proteins. These results indicate that lymphocytes release protein factors including IL-1, which up-regulate pulmonary beta-adrenergic receptors. As the major source of IL-1 in the body is macrophages including pulmonary macrophages, these findings suggest the existence of a novel, paracrine mechanism for the regulation of beta-receptors in the lung.
