Synergistic regulation of pulmonary beta-adrenergic receptors by glucocorticoids and interleukin-1.
Coculturing IM9 human lymphocytes and A549 human lung adenocarcinoma cells results in a 2-3-fold increase in the density of beta-adrenergic receptors in the latter, as quantified by 125I-cyanopindolol binding. Lymphocyte-conditioned medium (LCM) has the same effect, which is moderately sensitive to heat, is retained by ultrafiltration over a Mr 10,000 cut-off filter, and is reduced by trypsin treatment or by preincubation of lymphocytes with 0.3 micrograms/ml cycloheximide. Treatment of lung cells with cycloheximide also prevents the effect of LCM. Glucocorticoids, which also increase beta-receptor density in A549 cells, markedly potentiate the effect of LCM. Gel permeation high pressure liquid chromatography of LCM yields three peaks of biological activity with Mr 70,000, 35,000, and 15,000. Monocytic interleukin-1 (IL-1) mimics the effect of LCM in that it increases beta-receptor density in A549 cells (EC50 0.3 pM), and its effect is potentiated by cortisol. Recombinant IL-1 alpha is somewhat more potent than IL-1 beta, while interleukin-2 and interferon-alpha are ineffective. Tumor necrosis factor alpha causes a small increase in beta-receptors, which is not influenced by glucocorticoids. A polyclonal anti-IL-1 antibody inhibits the effect of IL-1 and the effect of the 15-kDa but not the 35- and 70-kDa fractions of LCM. The activity of the latter two fractions is also unaffected by anti-tumor necrosis factor alpha antibody. These results indicate that lymphocytes release protein factors including IL-1 that up-regulate pulmonary beta-adrenergic receptors by an action that involves protein synthesis. The possible relevance of this regulatory mechanism for the pathomechanism of certain respiratory diseases is discussed.
Stern
L
L
Department of Pharmacology and Medicine, McGill University, Montreal, Canada.
Kunos
G
G
D000230:Adenocarcinoma; D002460:Cell Line; D003345:Corticosterone / Q000494:pharmacology*; D003470:Culture Media; D003907:Dexamethasone / Q000494:pharmacology*; D006801:Humans; D006854:Hydrocortisone / Q000494:pharmacology*; D007375:Interleukin-1 / Q000494:pharmacology*; D007700:Kinetics; D008175:Lung Neoplasms; D008214:Lymphocytes / Q000502:physiology; D011943:Receptors, Adrenergic, beta / Q000187:drug effects / Q000378:metabolism*
D003470:Culture Media; D007375:Interleukin-1; D011943:Receptors, Adrenergic, beta; D003907:Dexamethasone; D003345:Corticosterone; D006854:Hydrocortisone