Glucocorticoids exert opposing effects on macrophage function dependent on their concentration.
Glucocorticoids (GCs) are involved in the modulation of macrophage function and thereby control the host's immune responses to pathogens. However, neither the role of hormone concentration nor the differential contribution of the glucocorticoid (GR) and the mineralocorticoid receptors (MR) to these activities are known. Here we show that low levels of corticosterone enhance NO production as well as mRNA expression of pro-inflammatory cytokines, chemokines and enzymes required for mediator synthesis. In contrast, at high corticosterone concentrations macrophage function was strongly repressed. Importantly, inactivation of the GR by lentiviral delivery of siRNAs abrogated both the immunostimulatory and the immunosuppressive GC actions whereas inactivation of the MR had no effect. Furthermore, removal of endogenous GCs by adrenalectomy in vivo induced a preactivated state in macrophages that could be modulated by corticosterone. We conclude that GCs exert distinct effects on macrophage function dependent on their concentration, and that they primarily act through the GR despite concomitant expression of the MR.
Lim
Hee-Young
HY
Institute for Virology and Immunobiology, University of Würzburg, Würzburg, Germany.
Müller
Nora
N
Herold
Marco J
MJ
van den Brandt
Jens
J
Reichardt
Holger M
HM
D000311:Adrenal Glands / Q000502:physiology; D000818:Animals; D000893:Anti-Inflammatory Agents / Q000494:pharmacology*; D002478:Cells, Cultured; D003345:Corticosterone / Q000494:pharmacology*; D004305:Dose-Response Relationship, Drug; D005786:Gene Expression Regulation / Q000187:drug effects; D020868:Gene Silencing; D005822:Genetic Vectors; D016086:Lentivirus / Q000235:genetics; D008262:Macrophage Activation / Q000187:drug effects; D017737:Macrophages, Peritoneal / Q000187:drug effects* / Q000378:metabolism; D012333:RNA, Messenger / Q000235:genetics; D034741:RNA, Small Interfering / Q000235:genetics; D051381:Rats; D011919:Rats, Inbred Strains; D011965:Receptors, Glucocorticoid / Q000235:genetics / Q000378:metabolism; D018161:Receptors, Mineralocorticoid / Q000235:genetics / Q000378:metabolism
D000893:Anti-Inflammatory Agents; D012333:RNA, Messenger; D034741:RNA, Small Interfering; D011965:Receptors, Glucocorticoid; D018161:Receptors, Mineralocorticoid; D003345:Corticosterone