Exogenous norepinephrine correlates with macrophage endoplasmic reticulum stress response in association with XBP-1.
BACKGROUND
The regulation of neuroendocrine hormones on the innate immune responses remains controversial. This report investigated the effects of exogenous norepinephrine with respect to macrophage function as well as to elucidate the underlying mechanism.


METHODS
The adherence, chemotaxis, phagocytosis, and cytokine production of macrophages were observed in the presence of increasing concentrations of norepinephrine. The expression of macrophage glucose response protein 78 (GRP78), X-box binding protein 1 (XBP1), activating transcription factor 6 (ATF6), and C-EBP homologous protein (CHOP) in macrophages was determined. The lentiviral vector pGCL-GFP-siXBP1 was cloned by inserting the annealed oligonucleotides encoding shRNAs specific for XBP1.


RESULTS
Norepinephrine exerted immunostimulatory effects on macrophage at low concentrations, while partial effects were observed at high concentrations. Low-dose norepinephrine induced an endoplasmic reticulum stress response, which was correlated with the immunostimulatory activities of norepinephrine. Levels of mRNA expression of XPB1, but not ATF6 or CHOP, was significantly increased only by low concentrations of norepinephrine. Inhibition of XBP1 expression with siRNA treatment significantly inhibited the immunostimulatory effects of low concentrations of norepinephrine.


CONCLUSIONS
Our data convincingly indicated that norepinephrine exerted immunostimulatory actions on macrophages at low concentrations, suggesting that the underlying mechanisms are related to endoplasmic reticulum stress via XBP1.
Yang
Ce
C
State Key Laboratory of Trauma, Burns, and Combined Injury, Research Institute of Surgery, Daping Hospital, Third Military Medical University, Chongqing, People's Republic of China.
Zhou
Jian-Yun
JY
Zhong
He-Jiang
HJ
Wang
Hai-Yan
HY
Yan
Jun
J
Liu
Qing
Q
Huang
Su-Na
SN
Jiang
Jian-Xin
JX
D000316:Adrenergic alpha-Agonists / Q000494:pharmacology*; D000818:Animals; D004268:DNA-Binding Proteins / Q000378:metabolism*; D004721:Endoplasmic Reticulum / Q000187:drug effects*; D000091342:Endoplasmic Reticulum Chaperone BiP; D007113:Immunity, Innate / Q000187:drug effects; D017737:Macrophages, Peritoneal / Q000187:drug effects*; D051379:Mice; D008810:Mice, Inbred C57BL; D009638:Norepinephrine / Q000494:pharmacology*; D000071701:Regulatory Factor X Transcription Factors; D013312:Stress, Physiological; D014157:Transcription Factors / Q000378:metabolism*; D000071717:X-Box Binding Protein 1
D000316:Adrenergic alpha-Agonists; D004268:DNA-Binding Proteins; D000091342:Endoplasmic Reticulum Chaperone BiP; C000717248:Hspa5 protein, mouse; D000071701:Regulatory Factor X Transcription Factors; D014157:Transcription Factors; D000071717:X-Box Binding Protein 1; C000605544:Xbp1 protein, mouse; D009638:Norepinephrine