Corticosterone exerts immunostimulatory effects on macrophages via endoplasmic reticulum stress.
BACKGROUND
: Glucocorticoids are the central effector hormones for the hypothalamic-pituitary-adrenal axis. However, the effects of endogenous glucocorticoids on the immune system are not understood completely.


METHODS
: Macrophage function (adherence, chemotaxis and cytokine production) was assessed in the presence of increasing concentrations of corticosterone. The role of endoplasmic reticulum (ER) stress in corticosterone immunoregulation was determined with thapsigargin and plasmid pGCL-GFP-siXBP1. Mifepristone was used to determine the role of glucocorticoid receptor in the corticosterone-induced ER stress response.


RESULTS
: Corticosterone exerted immunostimulatory effects on macrophage function at low concentrations. No effects were observed at high concentrations in the absence of immunological stimulation. Low-dose corticosterone induced ER stress, which was correlated to the corticosterone immunostimulatory activities. Expression of X box-binding protein (XBP) 1, but not activating transcription factor 6, was significantly increased at both mRNA and protein levels only in the presence of low-dose corticosterone. Inhibition of XBP1 expression with small interfering RNA significantly inhibited the corticosterone immunostimulatory effects. In addition, pretreatment of macrophages with mifepristone significantly inhibited the expression of glucose response protein 78 and XBP1 in macrophages by low-dose corticosterone.


CONCLUSIONS
: At low concentrations, endogenous glucocorticoids exert immunostimulatory actions on macrophages. The underlying mechanisms may be correlated to ER stress via the glucocorticoid receptor, in which XBP1 plays an important role.
Zhou
J-Y
JY
State Key Laboratory of Trauma, Burns and Combined Injury, Research Institute of Surgery, Daping Hospital, Third Military Medical University, Chongqing, China.
Zhong
H-J
HJ
Yang
C
C
Yan
J
J
Wang
H-Y
HY
Jiang
J-X
JX
D000276:Adjuvants, Immunologic / Q000494:pharmacology*; D000818:Animals; D002448:Cell Adhesion / Q000187:drug effects; D002633:Chemotaxis / Q000187:drug effects; D003345:Corticosterone / Q000494:pharmacology*; D016207:Cytokines / Q000096:biosynthesis; D004268:DNA-Binding Proteins / Q000502:physiology; D004305:Dose-Response Relationship, Drug; D004721:Endoplasmic Reticulum / Q000187:drug effects*; D008264:Macrophages / Q000187:drug effects* / Q000276:immunology; D051379:Mice; D008810:Mice, Inbred C57BL; D015735:Mifepristone / Q000494:pharmacology; D010587:Phagocytosis / Q000187:drug effects; D011965:Receptors, Glucocorticoid / Q000502:physiology; D000071701:Regulatory Factor X Transcription Factors; D013312:Stress, Physiological / Q000187:drug effects*; D019284:Thapsigargin / Q000494:pharmacology; D014157:Transcription Factors / Q000502:physiology; D000071717:X-Box Binding Protein 1
D000276:Adjuvants, Immunologic; D016207:Cytokines; D004268:DNA-Binding Proteins; D011965:Receptors, Glucocorticoid; D000071701:Regulatory Factor X Transcription Factors; D014157:Transcription Factors; D000071717:X-Box Binding Protein 1; C000605544:Xbp1 protein, mouse; D015735:Mifepristone; D019284:Thapsigargin; D003345:Corticosterone