title: 1,25-Dihydroxyvitamin D3 attenuates endotoxin-induced production of inflammatory mediators by inhibiting MAPK activation in primary cortical neuron-glia cultures.
abstract: BACKGROUND
  Neuroinflammation occurs in insulted regions of the brain and may be due to reactive oxygen species (ROS), nitric oxide (NO), cytokines, and chemokines produced by activated glia. Excessive production of neurotoxic molecules causes further neuronal damage. Low levels of vitamin D3 are a risk factor for various brain diseases.
  
  
  METHODS
  Using the bacterial endotoxin, lipopolysaccharide (LPS), to induce neuroinflammation in primary cortical neuron-glia cultures, we investigated how 1,25-dihydroxyvitamin D3 (1,25(OH)2D3) affected neuroinflammation.
  
  
  RESULTS
  LPS (100 ng/ml) induced the accumulation of nitrite and the production of ROS, interleukin (IL)-6, and macrophage inflammatory protein (MIP)-2 in time-dependent manners. Inhibition of p38 and extracellular signal-regulated kinase (ERK) but not c-Jun N-terminal kinase (JNK) mitogen-activated protein kinase (MAPK) by 20 μM of SB203580, PD98059, and SP600125, significantly reduced LPS-induced ROS production, NO accumulation, and inducible NO synthase (iNOS) expression, respectively. LPS-induced IL-6 and MIP-2 were significantly attenuated by inhibition of p38, ERK, and JNK MAPK. Cotreatment with 1,25(OH)2D3 attenuated LPS-induced ROS production, NO accumulation, and iNOS expression in concentration-dependent manners. 1,25(OH)2D3 also reduced LPS-induced production of IL-6 and MIP-2. Similarly, iNOS, IL-6, and MIP-2 mRNA expression in cells treated with LPS significantly increased, whereas this effect was attenuated by 1,25(OH)2D3. Moreover, LPS-induced phosphorylation of p38, ERK, and JNK MAPK was significantly inhibited by 1,25(OH)2D3.
  
  
  CONCLUSIONS
  Our findings indicate that 1,25(OH)2D3 reduced the LPS-stimulated production of inflammatory molecules in neuron-glia cultures by inhibiting MAPK pathways and the production of downstream inflammatory molecules. We suggest that 1,25(OH)2D3 can be used to alleviate neuroinflammation in various brain injuries.
authors.affiliation: Department of Nursing, Hsin Sheng Junior College of Medical Care and Management, Taoyuan City, Taiwan. yani0106@gmail.com.
authors.forename: Ya-Ni
authors.initials: YN
authors.lastname: Huang
authors.affiliation: Institute of Preventive Medicine, National Defense Medical Center, Taipei, Taiwan. ejung330@gmail.com.|Graduate Institute of Life Sciences, National Defense Medical Center, Taipei, Taiwan. ejung330@gmail.com.
authors.forename: Yi-Jung
authors.initials: YJ
authors.lastname: Ho
authors.affiliation: Division of Orthopedics, Department of Surgery, Far Eastern Memorial Hospital, New Taipei City, Taiwan. popula180@gmail.com.
authors.forename: Chien-Cheng
authors.initials: CC
authors.lastname: Lai
authors.affiliation: Department of Neurosurgery, En Chu Kong Hospital, New Taipei City, Taiwan. chientsaichiu@hotmail.com.
authors.forename: Chien-Tsai
authors.initials: CT
authors.lastname: Chiu
authors.affiliation: Graduate Institute of Medical Sciences and Department of Physiology, College of Medicine, Taipei Medical University, 250 Wu-Hsing Street, Taipei, 110, Taiwan. jywang2010@tmu.edu.tw.
authors.forename: Jia-Yi
authors.initials: JY
authors.lastname: Wang
mesh_terms: D000818:Animals; D000975:Antioxidants / Q000494:pharmacology; D002117:Calcitriol / Q000494:pharmacology*; D002540:Cerebral Cortex / Q000166:cytology / Q000187:drug effects / Q000201:enzymology*; D054426:Chemokine CXCL2 / Q000378:metabolism; D004789:Enzyme Activation / Q000187:drug effects; D018836:Inflammation Mediators / Q000037:antagonists & inhibitors* / Q000378:metabolism*; D015850:Interleukin-6 / Q000096:biosynthesis; D008070:Lipopolysaccharides / Q000037:antagonists & inhibitors* / Q000633:toxicity*; D020935:MAP Kinase Signaling System / Q000187:drug effects; D020928:Mitogen-Activated Protein Kinases / Q000378:metabolism*; D009457:Neuroglia / Q000187:drug effects / Q000201:enzymology*; D009474:Neurons / Q000187:drug effects / Q000201:enzymology*; D052247:Nitric Oxide Synthase Type II / Q000037:antagonists & inhibitors; D061251:Primary Cell Culture; D051381:Rats; D017207:Rats, Sprague-Dawley; D017382:Reactive Oxygen Species / Q000378:metabolism; D014815:Vitamins / Q000494:pharmacology*
chemical_list: D000975:Antioxidants; D054426:Chemokine CXCL2; D018836:Inflammation Mediators; D015850:Interleukin-6; D008070:Lipopolysaccharides; D017382:Reactive Oxygen Species; D014815:Vitamins; D052247:Nitric Oxide Synthase Type II; D020928:Mitogen-Activated Protein Kinases; D002117:Calcitriol