A regulatory role of prolactin, growth hormone, and corticosteroids for human T-cell production of cytokines.
The release of the pituitary hormones, prolactin and growth hormone (GH), and of adrenal corticosteroids is subject to a profound regulation by sleep. In addition these hormones are known to be involved in the regulation of the immune response. Here, we examined their role for in vitro production of T-cell cytokines. Specifically, we hypothesized that increased concentrations of prolactin and GH as well as a decrease in cortisol, i.e., hormonal changes characterizing early nocturnal sleep, could be responsible for a shift towards T helper 1 (Th1) cytokines during this time. Whole blood was sampled from 15 healthy humans in the morning after regular sleep and was activated in vitro with ionomycin and two concentrations of phorbol myrestate acetate (PMA, 8 and 25 ng/ml) in the absence or presence of prolactin, prolactin antibody, GH, glucocorticoid receptor (GR) antagonist RU-486, or mineralocorticoid receptor (MR) antagonist spironolactone. Hormones were examined at physiological concentrations. Production of T-cell derived cytokines was measured at the single cell level using multiparametric flow cytometry. Generally, effects were more pronounced after stimulation with 8 rather than 25 ng/ml PMA. The following changes reached significance (p <.05): prolactin (versus prolactin antibody) increased tumor necrosis factor-alpha (TNF-alpha) and interferon-gamma (IFN-gamma) producing CD4+ and CD8+ cells and interleukin-2 (IL-2) producing CD8+ cells. Compared with control, prolactin antibody decreased, whereas GH increased IFN-gamma+CD4+ cells. RU-486 increased TNF-alpha, IFN-gamma, and IL-2 producing CD4+ and CD8+ cells. Surprisingly strong effects were found after MR blocking with spironolactone which increased TNF-alpha, IFN-gamma, and IL-2 producing CD4+ and CD8+ cells. No effects on IL-4+CD4+ cells were observed, while the IFN-gamma/IL-4 ratio shifted towards Th1 after spironolactone and after RU-486 plus GH. Results suggest that enhanced prolactin and GH concentrations as well as low cortisol levels during early nocturnal sleep synergistically act to enhance Th1 cytokine activity.
Dimitrov
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Department of Neuroendocrinology, University of Lübeck, Ratzeburger Allee 160, Hs 23a, 23538 Lübeck, Germany.
Lange
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Fehm
H L
HL
Born
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J
D000305:Adrenal Cortex Hormones / Q000502:physiology; D000328:Adult; D002478:Cells, Cultured / Q000187:drug effects; D002940:Circadian Rhythm / Q000187:drug effects / Q000502:physiology; D016207:Cytokines / Q000187:drug effects / Q000378:metabolism*; D005434:Flow Cytometry; D006727:Hormone Antagonists / Q000494:pharmacology; D019382:Human Growth Hormone / Q000502:physiology*; D006801:Humans; D006854:Hydrocortisone / Q000502:physiology*; D007371:Interferon-gamma / Q000187:drug effects / Q000378:metabolism; D007375:Interleukin-1 / Q000378:metabolism; D007376:Interleukin-2 / Q000378:metabolism; D008297:Male; D015735:Mifepristone / Q000494:pharmacology; D011388:Prolactin / Q000502:physiology*; D011987:Receptors, Steroid / Q000037:antagonists & inhibitors; D012016:Reference Values; D012890:Sleep / Q000502:physiology; D013148:Spironolactone / Q000494:pharmacology; D016176:T-Lymphocyte Subsets / Q000187:drug effects / Q000378:metabolism*; D018417:Th1 Cells / Q000187:drug effects / Q000378:metabolism; D018418:Th2 Cells / Q000187:drug effects / Q000378:metabolism; D014409:Tumor Necrosis Factor-alpha / Q000187:drug effects / Q000378:metabolism
D000305:Adrenal Cortex Hormones; D016207:Cytokines; D006727:Hormone Antagonists; D007375:Interleukin-1; D007376:Interleukin-2; D011987:Receptors, Steroid; D014409:Tumor Necrosis Factor-alpha; D019382:Human Growth Hormone; D013148:Spironolactone; D015735:Mifepristone; D007371:Interferon-gamma; D011388:Prolactin; D006854:Hydrocortisone