Dopamine Alters Lipopolysaccharide-Induced Nitric Oxide Production in Microglial Cells via Activation of D1-Like Receptors
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Dopamine (DA) is important in the maintenance of normal nervous system function. DA is the target of multiple drugs, and it induces critical alterations in immune cells. However, these impacts are controversial, and the mechanism remains unclear. In the present study, we treated BV-2 microglial cells and primary microglia with DA and measured the changes in cytokines. We also identified the expression of DA receptors (DRs) using confocal and immunofluorescent microscopy. Specific agonists and antagonists of D1-like DRs (D1DR and D5DR) were used to observe alterations in cytokines. Western blot and siRNA interference were performed to investigate the involvement of the downstream signaling molecules of DRs. We also measured changes in mitogen-activated protein kinases (MAPKs) and the nuclear factor-kappa B (NF-κB) signaling pathway and assessed their involvement using inhibitors. We found that DA alone produced no effects on IL-6, TNF-α or nitric oxide (NO) production, and it inhibited lipopolysaccharide (LPS)-induced NO in microglial cells. Microglia expressed a high abundance of D1-like DRs (D1DR and D5DR). The agonists inhibited NO production, and antagonists reversed the DA-induced suppression of NO. Adenylatec cyclase (AC), cyclic adenosine monophosphate (cAMP) and protein kinase A (PKA) mediated DA function, and cAMP-response element binding protein (CREB) was not involved. ERK1/2 and NF-κB, but not p-38 or JNK, played roles in DA-suppressed NO generation via altering inducible nitric oxide synthase (iNOS) transcription. These data illustrate that DA modulates LPS-induced NO production via the AC/cAMP-PKA-ERK1/2-NF-κB-iNOS axis in mouse microglia, and D1-like DRs are involved. The present study provides functional evidence for an essential role of DA in immunoregulation.
KeywordsDopamine Dopamine receptors Nitric oxide iNOS NF-κB
The authors thank Drs. Wu Feng and Ren Huixun in the Department of Immunology and Pathogenic Biology of Xi’an Jiaotong University for the great help in the modification of the manuscript.
This work was supported by the National Natural Science Foundation of China (Grant Numbers: 81273196, 81430048, 81772034).
Compliance with Ethical Standards
Conflict of interest
The authors declare that they have no conflict of interests.
Ethics Approval and Consent to Participate
All protocols were approved by the Ethics Committee of Xi’an Jiaotong University.
Informed consent was obtained from all individual participants included in the study.
- 1.Romanov RA, Zeisel A, Bakker J, Girach F, Hellysaz A, Tomer R, Alpar A, Mulder J, Clotman F, Keimpema E, Hsueh B, Crow AK, Martens H, Schwindling C, Calvigioni D, Bains JS, Mate Z, Szabo G, Yanagawa Y, Zhang MD, Rendeiro A, Farlik M, Uhlen M, Wulff P, Bock C, Broberger C, Deisseroth K, Hokfelt T, Linnarsson S, Horvath TL, Harkany T (2017) Molecular interrogation of hypothalamic organization reveals distinct dopamine neuronal subtypes. Nat Neurosci 20(2):176–188. https://doi.org/10.1038/nn.4462 CrossRefPubMedGoogle Scholar
- 2.Milienne-Petiot M, Groenink L, Minassian A, Young JW (2017) Blockade of dopamine D1-family receptors attenuates the mania-like hyperactive, risk-preferring, and high motivation behavioral profile of mice with low dopamine transporter levels. J Psychopharmacol (Oxford England) 31(10):1334–1346. https://doi.org/10.1177/0269881117731162 CrossRefGoogle Scholar
- 3.Torres-Rosas R, Yehia G, Pena G, Mishra P, del Rocio Thompson-Bonilla M, Moreno-Eutimio MA, Arriaga-Pizano LA, Isibasi A, Ulloa L (2014) Dopamine mediates vagal modulation of the immune system by electroacupuncture. Nat Med 20(3):291–295. https://doi.org/10.1038/nm.3479 CrossRefPubMedCentralPubMedGoogle Scholar
- 4.Miyagi J, Oshibuchi H, Kasai A, Inada K, Ishigooka J (2014) Valproic acid inhibits excess dopamine release in response to a fear-conditioned stimulus in the basolateral complex of the amygdala of methamphetamine-sensitized rats. Eur J Pharmacol 730:20–25. https://doi.org/10.1016/j.ejphar.2014.01.020 CrossRefPubMedGoogle Scholar
- 11.Xie F, Zhang F, Min S, Chen J, Yang J, Wang X (2018) Glial cell line-derived neurotrophic factor (GDNF) attenuates the peripheral neuromuscular dysfunction without inhibiting the activation of spinal microglia/monocyte. BMC Geriatr 18(1):110. https://doi.org/10.1186/s12877-018-0796-1 CrossRefPubMedCentralPubMedGoogle Scholar
- 14.Zhu C, Kros JM, van der Weiden M, Zheng P, Cheng C, Mustafa DA (2017) Expression site of P2RY12 in residential microglial cells in astrocytomas correlates with M1 and M2 marker expression and tumor grade. Acta neuropathol Commun 5(1):4. https://doi.org/10.1186/s40478-016-0405-5 CrossRefPubMedCentralPubMedGoogle Scholar
- 17.Yoshioka Y, Sugino Y, Tozawa A, Yamamuro A, Kasai A, Ishimaru Y, Maeda S (2016) Dopamine inhibits lipopolysaccharide-induced nitric oxide production through the formation of dopamine quinone in murine microglia BV-2 cells. J Pharmacol Sci 130(2):51–59. https://doi.org/10.1016/j.jphs.2015.11.002 CrossRefPubMedGoogle Scholar
- 18.Wang B, Chen T, Wang J, Jia Y, Ren H, Wu F, Hu M, Chen Y (2018) Methamphetamine modulates the production of interleukin-6 and tumor necrosis factor-alpha via the cAMP/PKA/CREB signaling pathway in lipopolysaccharide-activated microglia. Int Immunopharmacol 56:168–178. https://doi.org/10.1016/j.intimp.2018.01.024 CrossRefPubMedGoogle Scholar
- 21.Basu B, Sarkar C, Chakroborty D, Ganguly S, Shome S, Dasgupta PS, Basu S (2010) D1 and D2 dopamine receptor-mediated inhibition of activated normal T cell proliferation is lost in jurkat T leukemic cells. J Biol Chem 285(35):27026–27032. https://doi.org/10.1074/jbc.M110.144022 CrossRefPubMedCentralPubMedGoogle Scholar
- 22.Shao QH, Zhang XL, Chen Y, Zhu CG, Shi JG, Yuan YH, Chen NH (2018) Anti-neuroinflammatory effects of 20C from Gastrodia elata via regulating autophagy in LPS-activated BV-2 cells through MAPKs and TLR4/Akt/mTOR signaling pathways. Mol Immunol 99:115–123. https://doi.org/10.1016/j.molimm.2018.04.014 CrossRefPubMedGoogle Scholar
- 23.Hu W, Shi L, Li MY, Zhou PH, Qiu B, Yin K, Zhang HH, Gao Y, Kang R, Qin SL, Ning JZ, Wang W, Zhang LJ (2017) Adrenomedullin protects Leydig cells against lipopolysaccharide-induced oxidative stress and inflammatory reaction via MAPK/NF-kappaB signalling pathways. Sci Rep 7(1):16479. https://doi.org/10.1038/s41598-017-16008-x CrossRefPubMedCentralPubMedGoogle Scholar
- 25.Somalwar AR, Choudhary AG, Sharma PR, Sagarkar BN, Sakharkar S, Subhedar AJ, Kokare NK DM (2018) Cocaine- and amphetamine-regulated transcript peptide (CART) induced reward behavior is mediated via Gi/o dependent phosphorylation of PKA/ERK/CREB pathway. Behav Brain Res 348:9–21. https://doi.org/10.1016/j.bbr.2018.03.035 CrossRefPubMedGoogle Scholar
- 26.Moon SK, Cha BY, Kim CH (2004) ERK1/2 mediates TNF-alpha-induced matrix metalloproteinase-9 expression in human vascular smooth muscle cells via the regulation of NF-kappaB and AP-1: involvement of the ras dependent pathway. J Cell Physiol 198(3):417–427. https://doi.org/10.1002/jcp.10435 CrossRefPubMedGoogle Scholar
- 32.McKenna F, McLaughlin PJ, Lewis BJ, Sibbring GC, Cummerson JA, Bowen-Jones D, Moots RJ (2002) Dopamine receptor expression on human T- and B-lymphocytes, monocytes, neutrophils, eosinophils and NK cells: a flow cytometric study. J Neuroimmunol 132(1–2):34–40. https://doi.org/10.1016/S0165-5728(02)00280-1 CrossRefPubMedGoogle Scholar
- 33.Wedel J, Hottenrott MC, Stamellou E, Breedijk A, Tsagogiorgas C, Hillebrands JL, Yard BA (2014) N-Octanoyl dopamine transiently inhibits T cell proliferation via G1 cell-cycle arrest and inhibition of redox-dependent transcription factors. J Leukoc Biol 96(3):453–462. https://doi.org/10.1189/jlb.3A0813-455R CrossRefPubMedCentralPubMedGoogle Scholar
- 34.Ferreira TB, Barros PO, Teixeira B, Cassano T, Centuriao N, Kasahara TM, Hygino J, Vasconcelos CC, Filho HA, Alvarenga R, Wing AC, Andrade RM, Andrade AF, Bento CA (2014) Dopamine favors expansion of glucocorticoid-resistant IL-17-producing T cells in multiple sclerosis. Brain Behav Immun 41:182–190. https://doi.org/10.1016/j.bbi.2014.05.013 CrossRefPubMedGoogle Scholar
- 36.Brustolim D, Ribeiro-dos-Santos R, Kast RE, Altschuler EL, Soares MBP (2006) A new chapter opens in anti-inflammatory treatments: the antidepressant bupropion lowers production of tumor necrosis factor-alpha and interferon-gamma in mice. Int Immunopharmacol 6(6):903–907. https://doi.org/10.1016/j.intimp.2005.12.007 CrossRefPubMedGoogle Scholar
- 38.Ruggiero C, Doghman-Bouguerra M, Ronco C, Benhida R, Rocchi S, Lalli E (2018) The GRP78/BiP inhibitor HA15 synergizes with mitotane action against adrenocortical carcinoma cells through convergent activation of ER stress pathways. Mol Cell Endocrinol 474:57–64. https://doi.org/10.1016/j.mce.2018.02.010 CrossRefPubMedGoogle Scholar
- 39.Nelson M, Adams T, Ojo C, Carroll MA, Catapane EJ (2018) Manganese toxicity is targeting an early step in the dopamine signal transduction pathway that controls lateral cilia activity in the bivalve mollusc Crassostrea virginica. Comp Biochem Physiol C Toxicol Pharmacol 213:1–6. https://doi.org/10.1016/j.cbpc.2018.07.002 CrossRefPubMedGoogle Scholar
- 41.Zhu T, Wu XL, Zhang W, Xiao M (2015) Glucagon like peptide-1 (GLP-1) modulates OVA-induced airway inflammation and mucus secretion involving a protein kinase A (PKA)-dependent nuclear factor-kappaB (NF-kappaB) signaling pathway in mice. Int J Mol Sci 16(9):20195–20211. https://doi.org/10.3390/ijms160920195 CrossRefPubMedCentralPubMedGoogle Scholar
- 46.Filip GA, Postescu ID, Bolfa P, Catoi C, Muresan A, Clichici S (2013) Inhibition of UVB-induced skin phototoxicity by a grape seed extract as modulator of nitrosative stress, ERK/NF-kB signaling pathway and apoptosis, in SKH-1 mice. Food Chem Toxicol 57:296–306. https://doi.org/10.1016/j.fct.2013.03.031 CrossRefPubMedGoogle Scholar
- 48.Basudhar D, Somasundaram V, de Oliveira GA, Kesarwala A, Heinecke JL, Cheng RY, Glynn SA, Ambs S, Wink DA, Ridnour LA (2017) Nitric oxide synthase-2-derived nitric oxide drives multiple pathways of breast cancer progression. Antioxid Redox Signal 26(18):1044–1058. https://doi.org/10.1089/ars.2016.6813 CrossRefPubMedCentralPubMedGoogle Scholar
- 50.Dietz AK, Robinson RR, Forsthuber T (2018) Protective effect of IFN-γ during experimental autoimmune encephalomyelitis is associated with the induction of inducible nitric oxide synthase. J Immunol 200(1 Supplement):54.10Google Scholar