Glucocorticoids and interferon-alpha in the acquired immunodeficiency syndrome.
Some patients with acquired immunodeficiency syndrome (AIDS) develop glucocorticoid resistance characterized by low receptor affinity (Kd) for glucocorticoids in mononuclear, cells and high values of ACTH and cortisol. As glucocorticoids regulate interferon-alpha (IFN alpha) production, we hypothesized that IFN alpha, a cytokine produced predominantly by monocytes in AIDS, should be increased in cortisol-resistant AIDS, attributing the lack of cortisol inhibition to IFN alpha production. Therefore, we examined glucocorticoid receptor characteristics on monocytes by [3H]dexamethasone binding and measured IFN alpha, cortisol, and ACTH in AIDS patients with (AIDS-GR) or without glucocorticoid resistance (AIDS-C) and controls (C). Monocytes of AIDS-GR patients had a receptor Kd of 10.5 +/- 4.2 nmol/L that was higher than that in the AIDS-C group (2.9 +/- 0.8 nmol/L) and normal subjects (2.0 +/- 0.8 nmol/L; P < 0.01). IFN alpha levels were increased in the AIDS-GR group (17 +/- 6 vs. 4 +/- 1 U/mL in the AIDS-C group and 2 +/- 0.5 U/mL in the C group; P < 0.01). Correlations were found between plasma IFN alpha and receptor Kd on monocytes of AIDS-GR (r = 0.77) and between IFN alpha and plasma cortisol in the same group (r = 0.74). The poly(I)-poly(C)-induced IFN alpha production by monocytes was inhibited by glucocorticoids in the C and AIDS-C groups (approximately 80% inhibition in both groups); the effect was reversed by the receptor antagonist RU-38486. By contrast, glucocorticoids failed to inhibit IFNalpha production from AIDS-GR monocytes (approximately 20% inhibition). In conclusion, elevated IFN alpha levels in AIDS-GR may be due to the lack of inhibitory effect of cortisol on IFN alpha production due to cortisol resistance in monocytes.
Norbiato
G
G
Department of Endocrinology, University Hospital L. Sacco (Vialba), Milan, Italy.
Bevilacqua
M
M
Vago
T
T
Clerici
M
M
D000163:Acquired Immunodeficiency Syndrome / Q000378:metabolism*; D000324:Adrenocorticotropic Hormone / Q000097:blood / Q000652:urine; D000328:Adult; D003907:Dexamethasone / Q000378:metabolism / Q000494:pharmacology; D004351:Drug Resistance; D005260:Female; D005938:Glucocorticoids / Q000494:pharmacology*; D006801:Humans; D006854:Hydrocortisone / Q000097:blood / Q000652:urine; D016898:Interferon-alpha / Q000096:biosynthesis / Q000097:blood / Q000378:metabolism*; D008297:Male; D008875:Middle Aged; D009000:Monocytes / Q000187:drug effects / Q000378:metabolism; D011965:Receptors, Glucocorticoid / Q000502:physiology; D014280:Triglycerides / Q000097:blood; D014316:Tritium
D005938:Glucocorticoids; D016898:Interferon-alpha; D011965:Receptors, Glucocorticoid; D014280:Triglycerides; D014316:Tritium; D003907:Dexamethasone; D000324:Adrenocorticotropic Hormone; D006854:Hydrocortisone