Dexmedetomidine suppresses interleukin-1β-induced interleukin-6 synthesis in rat glial cells

Tanabe,Kumiko; Matsushima-Nishiwaki,Rie; Kozawa,Osamu; Iida,Hiroki

doi:10.3892/ijmm.2014.1863

Dexmedetomidine suppresses interleukin-1β-induced interleukin-6 synthesis in rat glial cells

Authors:
- Kumiko Tanabe
- Rie Matsushima-Nishiwaki
- Osamu Kozawa
- Hiroki Iida
View Affiliations

Affiliations: Department of Anesthesiology and Pain Medicine, Gifu University Graduate School of Medicine, Gifu 501-1194, Japan, Department of Pharmacology, Gifu University Graduate School of Medicine, Gifu 501-1194, Japan
Published online on: July 24, 2014 https://doi.org/10.3892/ijmm.2014.1863
Pages: 1032-1038

Metrics: Total Views: 0 (Spandidos Publications: | PMC Statistics: )

Metrics: Total PDF Downloads: 0 (Spandidos Publications: | PMC Statistics: )

Cited By (CrossRef): 0 citations Loading Articles...

Abstract

Dexmedetomidine, an α2-adrenoceptor agonist, is used as a sedative medication for criticalyl ill patients and is known to exert neuroprotective effects by direct action on neurons and indirect action on neurons through astrocytes. Interleukin (IL)-6 plays a key role in neuroinflammation, which accompanies infection, traumatic brain injury, ischemia, neurodegenerative disorders, as both a pro-inflammatory cytokine and an anti-inflammatory cytokine. Dexmedetomidine suppresses immune function. However, the effects of dexmedetomidine on cytokine synthesis in the central nervous system (CNS) remain elusive. We previously reported that IL-1β stimulates IL-6 synthesis in the rat C6 glioma cell line through the phosphorylation of p38 mitogen-activated protein (MAP) kinase, stress-activated protein kinase (SAPK)/c-Jun N-terminal kinase (JNK) and IκB. In the present study, we investigated the effects of dexmedetomidine on the IL-1β-induced IL-6 synthesis in C6 cells. Dexmedetomidine inhibited the IL-1β-stimulated IL-6 release and mRNA expression in C6 cells. 8-Bromo-adenosine-3',5'-cyclic monophosphate, but not 8-bromo-guanosine 3',5'-cyclic monophosphate, significantly enhanced the IL-1β-induced IL-6 release and mRNA expression. However, dexmedetomidine failed to affect cAMP accumulation in the cells treated with IL-1β or forskolin, an activator of adenylyl cyclase. Yohimbine, an α2-adrenoceptor antagonist, did not reverse the suppressive effects of dexmedetomidine on the IL-1β-induced IL-6 release. Dexmedetomidine did not affect the IL-1β-induced phosphorylation of p38 MAP kinase, SAPK/JNK, IκB, nuclear factor (NF)-κB or c-Jun. Our findings strongly suggest that dexmedetomidine inhibits the IL-1β-induced IL-6 synthesis independently of the adenylyl cyclase-cAMP pathway through α2-adrenoceptors in C6 glioma cells. It is possible that dexmedetomidine may affect the immune system in the CNS by regulating the production of IL-6.

View Figures

View References

1	Ma D, Rajakumaraswamy N and Maze M: α₂-Adrenoceptor agonists: shedding light on neuroprotection? Br Med Bull. 71:77–92. 2004.
2	Zhang Y and Kimelberg HK: Neuroprotection by alpha 2 adrenergic agonists in cerebral ischemia. Curr Neuropharmacol. 3:317–323. 2005. View Article : Google Scholar : PubMed/NCBI
3	Sanders RD and Maze M: α₂-Adrenoceptor agonists. Curr Opin Invest. 8:25–33. 2007.
4	Benarroch EE: Neuron-astrocyte interactions: partnership for normal function and disease in the central nervous system. Mayo Clin Proc. 80:1326–1338. 2005. View Article : Google Scholar : PubMed/NCBI
5	Talke P and Bickler PE: Effects of dexmedetomidine on hypoxia-evoked glutamate release and glutamate receptor activity in hippocampal slices. Anesthesiology. 85:551–557. 1996. View Article : Google Scholar : PubMed/NCBI
6	Yan M, Dai H, Ding T, Dai A, Zhang F, Yu L, Chen G and Chen Z: Effects of dexmedetomodine on the release of glial cell line-derived neurotrophic factor from rat astrocyte cells. Neurochem Int. 58:549–557. 2011. View Article : Google Scholar : PubMed/NCBI
7	Zhang F, Ding T, Yu L, Zhong Y, Dai H and Yan M: Dexmedetomidine protects against oxygen-glucose deprivation-induced injury through the I2 imidazoline receptor-PI3K/AKT pathway in rat C6 glioma cells. J Pharm Pharmacol. 64:120–127. 2012. View Article : Google Scholar
8	Allan SM, Tyrrell PJ and Rothwell NJ: Interleukin-1 and neuronal injury. Nat Rev Immunnol. 5:629–640. 2005. View Article : Google Scholar : PubMed/NCBI
9	Simi A, Tsakiri N, Wang P and Rothwell NJ: Interleukin-1 and inflammatory neurodegeneration. Biochem Soc Trans. 35:1122–1126. 2007. View Article : Google Scholar
10	Spooren A, Kolmus K, Laureys G, Clinckers R, De Keyser J, Haegeman G and Gerlo S: Interleukin-6, a mental cytokine. Brain Res Rev. 67:157–183. 2011. View Article : Google Scholar : PubMed/NCBI
11	Sanders RD, Hussell T and Maze M: Sedation & immunomodulation. Anesthesiol Clin. 29:687–706. 2011. View Article : Google Scholar
12	Eser O, Fidan H, Sahin O, Cosar M, Yaman M, Mollaoglu H, Songur A and Buyukbas S: The influence of dexmedtomidine on ischemic rat hippocampus. Brain Res. 1218:250–256. 2008. View Article : Google Scholar : PubMed/NCBI
13	Qiao H, Sanders RD, Ma D, Wu X and Maze M: Sedation improves early outcome in severely septic Sprague Dawley rats. Crit Care. 13:R1362009. View Article : Google Scholar : PubMed/NCBI
14	Venn RM, Bryant A, Hall GM and Grounds RM: Effects of dexmedetomidine on adrenocortical function, and the cardiovascular, endocrine and inflammatory responses in post-operative patients needing sedation in the intensive care unit. Br J Anaesth. 86:650–656. 2001. View Article : Google Scholar : PubMed/NCBI
15	Meniş D, Hekimoğlu S, Vatan İ, Yandım T, Yüksel M and Süt N: Effects of midazolam and dexmedetomidine on inflammatory responses and gastric intramucosal pH to sepsis, in critically ill patients. Br J Anaesth. 98:550–552. 2007.PubMed/NCBI
16	Kawashima A, Harada T, Imada K, Yano T and Mizuguchi K: Eicosapentaenoic acid inhibits interleukin-6 production in interleukin-1β-stimulated C6 glioma cells through peroxisome proliferator-activated receptor-gamma. Prostaglandins Leukot Essent Fatty Acids. 79:59–65. 2008.PubMed/NCBI
17	Tanabe K, Kozawa O and Iida H: Midazolam suppresses interleukin-1β-induced interleukin-6 release from rat glial cells. J Neuroinflammation. 8:682011.PubMed/NCBI
18	Zumwalt JW, Thunstrom BJ and Spangelo BL: Interleukin-1β and catecholamines synergistically stimulate interleukin-6 release from rat C6 glioma cells in vitro: a potential role for lysophosphatidylcholine. Endocrinology. 140:888–896. 1999.
19	Laemmli UK: Cleavage of structural proteins during the assembly of the head of bacteriophage T4. Nature. 227:680–685. 1970. View Article : Google Scholar : PubMed/NCBI
20	Morioka N, Sugimoto T, Tokuhara M, Dohi T and Nakata Y: Noradrenaline induces clock gene Per1 mRNA expression in C6 glioma cells through β₂-adrenergic receptor coupled with protein kinase A-cAMP response element binding protein (PKA-CREB) and Src-tyrosine kinase-glycogen synthase kinase-3β (Src-GSK-3β). J Pharmacol Sci. 113:234–245. 2010.PubMed/NCBI
21	Aantaa R, Marjamäki A and Scheinin M: Molecular pharmacology of α2-adrenoceptor subtypes. Ann Med. 27:439–449. 1995.
22	Edwards LP, Brown-Bryan TA, McLean L and Ernsberger P: Pharmacological properties of the central antihypertensive agent, moxonidine. Cardiovasc Ther. 30:199–208. 2012. View Article : Google Scholar : PubMed/NCBI
23	Nishizuka Y: Studies and perspectives of protein kinase C. Science. 233:305–312. 1986. View Article : Google Scholar : PubMed/NCBI
24	Simonds WF: G protein regulation of adenylate cyclase. Trends Pharmacol Sci. 20:66–73. 1999. View Article : Google Scholar : PubMed/NCBI
25	Gallagher HC, Bacon CL, Odumeru OA, Gallagher KF, Fitzpatrick T and Regan CM: Valproate activates phosphodiesterase-mediated cAMP degradation: relevance to C6 glioma G1 phase progression. Neurotoxicol Teratol. 26:73–81. 2004. View Article : Google Scholar : PubMed/NCBI
26	Adcock IM and Caramori G: Cross-talk between pro-inflammatory transcription factors and glucocorticoids. Immunol Cell Biol. 79:376–384. 2001. View Article : Google Scholar : PubMed/NCBI
27	Iirola T, Ihmsen H, Laitio R, Kentala E, Aantaa R, Kurvinen JP, Scheinin M, Schwilden H, Schüttler J and Olkkola KT: Population pharmacokinetics of dexmedetomidine during long-term sedation in intensive care patients. Br J Anaesth. 108:460–468. 2012. View Article : Google Scholar : PubMed/NCBI
28	Huang R and Hertz L: Receptor subtype and dose dependence of dexmedetomidine-induced accumulation of [¹⁴C]glutamine in astrocytes suggests glial involvement in its hypnotic-sedative and anesthetic-sparing effects. Brain Res. 873:297–301. 2000.PubMed/NCBI
29	Chen Y, Zhao Z, Code WE and Hertz L: A correlation between dexmedetomidine-induced biphasic increases in free cytosolic calcium concentration and energy metabolism in astrocytes. Anesth Analg. 91:353–357. 2000.
30	Lambertsen KL, Biber K and Finsen B: Inflammatory cytokines in experimental and human stroke. J Cereb Blood Flow Metab. 32:1677–1698. 2012. View Article : Google Scholar : PubMed/NCBI
31	Bekker A, Haile M, Kline R, Didehvar S, Babu R, Martiniuk F and Urban M: The effect of intraoperative infusion of dexmedetomidine on the quality of recovery after major surgery. J Neurosurg Anesthesiol. 25:16–24. 2013. View Article : Google Scholar : PubMed/NCBI
32	Kang AH, Kim YS, Hong TH, Chae MS, Cho ML, Her YM and Lee J: Effects of dexmedetomidine on inflammatory responses in patients undergoing laparoscopic cholecystectomy. Acta Anaesthesiol Scand. 57:480–487. 2013. View Article : Google Scholar : PubMed/NCBI
33	Saavedra A, Baltazar G and Duarte EP: Driving GDNF expression: the green and the red traffic light. Prog Neurobiol. 86:186–215. 2008. View Article : Google Scholar : PubMed/NCBI