Corticosterone Suppresses the Proliferation of RAW264.7 Macrophage Cells via Glucocorticoid, But Not Mineralocorticoid, Receptor

Abstract

Macrophages are white blood cells within tissues that are produced by monocytes and help to protect against infection by bacteria through phagocytosis. Several studies have shown a correlation between the state of depression and abnormalities in the immune response. Corticosterone (CORT), which is often referred to as the stress hormone, is a well-known regulator of peripheral immune responses and also shows anti-inflammatory properties in the body. However, it is still unclear how CORT regulates macrophage function. In this study, we focused on the effects of CORT on the proliferation and survival of macrophage cells using the macrophage cell line RAW264.7. Under treatment with 10 µm CORT for 24 h, the proliferation of RAW264.7 cells decreased to 73.6% of that in the control. Moreover, this inhibition was blocked by treatment with mifepristone, a glucocorticoid receptor (GR) antagonist, but not by spironolactone, a mineralocorticoid receptor (MR) antagonist. In an lactate dehydrogenase (LDH) assay, CORT did not show any cytotoxic effect on RAW264.7 cells. JC-1 cell staining also showed that CORT did not influence mitochondrial dysfunction in RAW264.7 cells. In an investigation of the modulation of a signaling cascade by CORT, treatment with CORT promoted the translocation of GR, but not MR, from the cytosol to the nucleus in RAW264.7 cells. In conclusion, our findings suggest that CORT suppresses the proliferation of RAW264.7 cells by controlling the transcription of a particular gene, which is related to cell proliferation, through the formation of a CORT-GR complex.Key words glucocorticoid; mineralocorticoid; corticosterone; RAW264.7; mifepristone; spironolactone Corticosterone (CORT), which is classified as a steroid hormone, is an adrenal corticosteroid that plays a role in a wide range of phenomena, such as the regulation of glucose metabolism, the reaction of the immune system and the stress response. CORT is one of the main corticosteroids in rodents. There are two types of adrenal corticosteroid receptors: type II, or glucocorticoid receptor (GR), and type I, or mineralocorticoid receptor (MR).1,2) It has been demonstrated that CORT has greater affinity for MR than for GR. 3,4) In general, both GR and MR are localized in the cytosol. It has been demonstrated that a ligand-steroid hormone receptor complex forms a homodimer together with another chaperon protein once CORT binds to steroid hormone receptor. After it forms a homodimer complex, this complex translocates from the cytosol to the nucleus and binds to a particular motif of DNA to regulate DNA transcription.5) In the case of GR, intracellular GR is inactivated by the formation of complexes with several proteins, such as heat-shock proteins.6,7) After the active ligand-steroid hormone receptor complex forms a homodimer and translocates to the nucleus from the cytosol, it modulates the transcriptional responses of inflammatory genes, either by binding directly to DNA or by cooperating with some other protein or signal cascade, such as nuclear facto...

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