Anti-neuroinflammatory effect of curcumin on Pam3CSK4-stimulated microglial cells

Jin,Meiling; Park,Sun Young; Shen,Qian; Lai,Yihong; Ou,Xingmei; Mao,Zhuo; Lin,Dongxu; Yu,Yangyang; Zhang,Weizhen

doi:10.3892/ijmm.2017.3217

Anti-neuroinflammatory effect of curcumin on Pam3CSK4-stimulated microglial cells

Authors:
- Meiling Jin
- Sun Young Park
- Qian Shen
- Yihong Lai
- Xingmei Ou
- Zhuo Mao
- Dongxu Lin
- Yangyang Yu
- Weizhen Zhang
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Affiliations: Center for Diabetes, Obesity and Metabolism, Department of Physiology, Shenzhen University Health Science Center, Shenzhen, Guangdong 518060, P.R. China, Bio-IT Fusion Technology Research Institute, Pusan National University, Busan 609-735, Republic of Korea
Published online on: October 27, 2017 https://doi.org/10.3892/ijmm.2017.3217
Pages: 521-530

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Abstract

Curcumin is the main curcuminoid present in Curcuma longa and it has been previously reported to exhibit a wide range of pharmacological activities. In the present study, the inhibitory effects of curcumin on the inflammatory mediators released by Pam3CSK4-stimulated BV-2 microglial cells were investigated. The production of pro-inflammatory mediators and cytokines, including tumor necrosis factor-α (TNF-α) and prostaglandin E2 (PGE2), were measured by enzyme‑linked immunosorbent assay (ELISA). The expression of inflammatory genes, including inducible nitric oxide synthase and cyclooxygenase-2, were further investigated using reverse transcription-quantitative polymerase chain reaction. The effects of curcumin on heme oxygenase-1 (HO-1), nuclear factor (erythroid-derived 2)-like 2 (Nrf2), mitogen-activated protein kinase (MAPK) and nuclear factor-κB (NF-κB) signaling pathways were analyzed by western blotting. The results revealed that curcumin dose-dependently inhibited Pam3CSK4-induced nitric oxide, PGE2, and TNF-α secretion. Curcumin suppressed the secretion of inflammatory mediators through an increase in the expression of HO-1. Curcumin induced HO-1 transcription and translation through the Nrf2/antioxidant response element signaling pathway. Inhibitory experiments revealed that HO-1 was required for the anti-inflammatory effects of curcumin. Further mechanistic studies demonstrated that curcumin inhibited neuroinflammation by suppressing NF-κB and MAPK signaling pathways in Pam3CSK4-activated microglial cells. The results of the present study suggest that curcumin may be a novel treatment for neuroinflammation-mediated neurodegenerative disorders.

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1	Spangenberg EE and Green KN: Inflammation in Alzheimer's disease: Lessons learned from microglia-depletion models. Brain Behav Immun. 61:1–11. 2017. View Article : Google Scholar
2	De Hoz R, Salobrar-Garcia E, Salazar JJ, Roias B, Ajoy D, Lopez-Cuenca I, Rojas P, Trivino A and Ramierz JM: The role of microglial in retinal neurodegeneration: Alzheimer's disease, Parkinson, and glaucoma. Front Aging Neurosci. 9:2142017. View Article : Google Scholar
3	Larochelle A, Bellavance MA and Rivest S: Role of adaptor protein MyD88 in TLR-mediated preconditioning and neuro-protection after acute excitotoxicity. Brain Behav Immun. 46:221–231. 2015. View Article : Google Scholar : PubMed/NCBI
4	Tang Y and Le W: Differential role of M1 and M2 microglia in neurodegenerative diseases. Mol Neurobiol. 53:1181–1194. 2016. View Article : Google Scholar
5	Nakagawa Y and Chiba K: Diversity and plasticity of microglial cells in psychiatric and neurological disorders. Pharmacol Ther. 154:21–35. 2015. View Article : Google Scholar : PubMed/NCBI
6	Kaur CG, Rathnasamy and Ling EA: Biology of microglial in the developing Brain. J Neuropathol Exp Neurol. 76:736–753. 2017.PubMed/NCBI
7	Moss DW and Bates TE: Activation of murine microglial cell lines by lipopolysaccharide and interferon-gamma causes NO-mediated decreases in mitochondrial and cellular function. Eur J Neurosci. 13:529–538. 2001. View Article : Google Scholar : PubMed/NCBI
8	Rangarajan P, Karthikeyan A and Dheen ST: Role of dietary phenols in mitigating microglia-mediated neuroinflammation. Neuromolecular Med. 18:453–464. 2016. View Article : Google Scholar : PubMed/NCBI
9	Acharyya S, Villalta SA, Bakkar N, Bupha-Intr T, Janssen PM, Carathers M, Li ZW, Beg AA, Ghosh S, Sahenk Z, et al: Interplay of IKK/NF-kappaB signaling in macrophages and myofibers promotes muscle degeneration in Duchenne muscular dystrophy. J Clin Invest. 117:889–901. 2007. View Article : Google Scholar : PubMed/NCBI
10	Sweeney SE and Firestein GS: Signal transduction in rheumatoid arthritis. Curr Opin Rheumatol. 16:231–237. 2004. View Article : Google Scholar : PubMed/NCBI
11	Jangra A, Kwatra M, Singh T, Pant R, Kushwah P, Ahmed S, Dwivedi D, Saroha B and Lahkar M: Edaravone alleviates cisplatin-induced neurobehavioral deficits via modulation of oxidative stress and inflammatory mediators in the rat hippo-campus. Eur J Pharmacol. 791:51–61. 2016. View Article : Google Scholar : PubMed/NCBI
12	Koh K and Kim J, Jang YJ, Yoon K, Cha Y, Lee HJ and Kim J: Transcription factor Nrf2 suppresses LPS-induced hyperactivation of BV-2 microglial cells. J Neuroimmunol. 233:160–167. 2011. View Article : Google Scholar : PubMed/NCBI
13	Talalay P: Chemoprotection against cancer by induction of phase 2 enzymes. Biofactors. 12:5–11. 2000. View Article : Google Scholar
14	Zhang J, Fu B, Zhang X, Zhang L, Bai X, Zhao X, Chen L, Cui L, Zhu C, Wang L, et al: Bicyclol upregulates transcription factor Nrf2, HO-1 expression and protects rat brains against focal ischemia. Brain Res Bull. 100:38–43. 2014. View Article : Google Scholar
15	Innamorato NG, Rojo AI, García-Yagüe AJ, Yamamoto M, de Ceballos ML and Cuadrado A: The transcription factor Nrf2 is a therapeutic target against brain inflammation. J Immunol. 181:680–689. 2008. View Article : Google Scholar : PubMed/NCBI
16	Parada E, Buendia I, Navarro E, Avendaño C, Egea J and López MG: Microglial HO-1 induction by curcumin provides antioxidant, antineuroinflammatory, and glioprotective effects. Mol Nutr Food Res. 59:1690–1700. 2015. View Article : Google Scholar : PubMed/NCBI
17	Kunnumakkara AB, Bordoloi D, Padmavathi G, Monisha J, Roy NK, Prasad S and Aggarwal BB: Curcumin, the golden nutraceutical: Multitargeting for multiple chronic diseases. Br J Pharmacol. 174:1325–1348. 2017. View Article : Google Scholar
18	Tsai YM, Chien CF, Lin LC and Tsai TH: Curcumin and its nano-formulation: The kinetics of tissue distribution and blood-brain barrier penetration. Int J Pharm. 416:331–338. 2011. View Article : Google Scholar : PubMed/NCBI
19	Garcia-Alloza M, Borrelli LA, Rozkalne A, Hyman BT and Bacskai: Curcumin labels amyloid pathology in vivo, disrupts existing plaques, and partially restores distorted neurites in an Alzheimer mouse model. J Neurochem. 102:1095–1104. 2007. View Article : Google Scholar : PubMed/NCBI
20	Prakobwong S, Khoontawad J, Yongvanit P, Pairojkul C, Hiraku Y, Sithithaworn P, Pinlaor P, Aggarwal BB and Pinlaor S: Curcumin decreases cholangiocarcinogenesis in hamsters by suppressing inflammation-mediated molecular events related to multistep carcinogenesis. Int J Cancer. 129:88–100. 2011. View Article : Google Scholar
21	Zhou J, Miao H, Li X, Hu Y, Sun H and Hou Y: Curcumin inhibits placental inflammation to ameliorate LPS-induced adverse pregnancy outcomes in mice via upregulation of phosphorylated Akt. Inflamm Res. 66:177–185. 2017. View Article : Google Scholar
22	Livak KJ and Schmittgen TD: Analysis of relative gene expression data using real-time quantitative PCR and the 2(-Delta Delta C(T)) method. Methods. 25:402–408. 2001. View Article : Google Scholar
23	Zhou D, Huang C, Lin Z, Zhan S, Kong L, Fang C and Li J: Macrophage polarization and function with emphasis on the evolving roles of coordinated regulation of cellular signaling pathways. Cell Signal. 26:192–197. 2014. View Article : Google Scholar
24	Jung JS, Choi MJ, Lee YY, Moon BI, Park JS and Kim HS: Suppression of lipopolysaccharide-induced neuroinflammation by Morin via MAPK, PI3K/Akt, and PKA/HO-1 signaling pathway modulation. J Agric Food Chem. 65:373–382. 2017. View Article : Google Scholar
25	Brown GC: Nitric oxide and neuronal death. Nitric Oxide. 23:153–165. 2010. View Article : Google Scholar : PubMed/NCBI
26	Dzamko N, Gysbers A, Perera G, Bahar A, Shankar A, Gao J, Fu Y and Halliday GM: Toll-like receptor 2 is increased in neurons in Parkinson's disease brain and may contribute to alpha-synuclein pathology. Acta Neuropathol. 133:303–319. 2017. View Article : Google Scholar
27	Fallarino F, Gargaro M, Mondanell G, Downer EJ, Hossain MJ and Gran B: Delineating the role of Toll-like receptors in the neuro-inflammation model EAE. Methods Mol Biol. 1390:383–411. 2016. View Article : Google Scholar : PubMed/NCBI
28	Hossain MJ, Tanasescu R and Gran B: Innate immune regulation of autoimmunity in multiple sclerosis: Focus on the role of Toll-like receptor 2. J Neuroimmunol. 304:11–20. 2017. View Article : Google Scholar
29	Jin S, Kim JG, Park JW, Koch M, Horvath TL and Lee BJ: Hypothalamic TLR2 triggers sickness behavior via a microglia-neuronal axis. Sci Rep. 6:294242016. View Article : Google Scholar : PubMed/NCBI
30	Geloso MC, Corvino V, Marchese E, Serrano A, Michetti F and D' Ambrosi N: The dual role of microglia in ALS: Mechanisms and therapeutic approaches. Front Aging Neurosci. 9:2422017. View Article : Google Scholar : PubMed/NCBI
31	Xia Q, Hu Q, Wang H, Yang H, Gao F, Ren H, Chen D, Fu C, Zheng L, Zhen X, et al: Induction of COX-2-PGE₂ synthesis by activation of the MAPK/ERK pathway contributes to neuronal death triggered by TDP-43-depleted microglia. Cell Death Dis. 6:e17022015. View Article : Google Scholar
32	Liu Y and Zhang Z, Luo B, Schluesener HJ and Zhang Z: Lesional accumulation of heme oxygenase-1⁺ microglia/macrophages in rat traumatic brain injury. Neuroreport. 24:281–286. 2013. View Article : Google Scholar : PubMed/NCBI
33	Fernández P, Guillén MI, Gomar F and Alcaraz MJ: Expression of heme oxygenase-1 and regulation by cytokines in human osteoarthritic chondrocytes. Biochem Pharmacol. 66:2049–2052. 2003. View Article : Google Scholar : PubMed/NCBI
34	Jayasooriya RG, Lee KT, Choi YH, Moon SK, Kim WJ and Kim GY: Antagonistic effects of acetylshikonin on LPS-induced NO and PGE₂ production in BV2 microglial cells via inhibition of ROS/PI3K/Akt-mediated NF-κB signaling and activation of Nrf2-dependent HO-1. In Vitro Cell Dev Biol Anim. 51:975–986. 2015. View Article : Google Scholar : PubMed/NCBI
35	Rojo AI, Innamorato NG, Martín-Moreno AM, De Ceballos ML, Yamamoto M and Cuadrado A: Nrf2 regulates microglial dynamics and neuroinflammation in experimental Parkinson's disease. Glia. 58:588–598. 2010. View Article : Google Scholar
36	Kobayashi EH, Suzuki T, Funayama R, Nagashima T, Hayashi M, Sekine H, Tanaka N, Moriguchi T, Motohashi H, Nakayama K, et al: Nrf2 suppresses macrophage inflammatory response by blocking proinflammatory cytokine transcription. Nat Commun. 7:116242016. View Article : Google Scholar : PubMed/NCBI
37	Wardyn JD, Ponsford AH and Sanderson CM: Dissecting molecular cross-talk between Nrf2 and NF-kappaB response pathways. Biochem Soc Trans. 43:621–626. 2015. View Article : Google Scholar : PubMed/NCBI
38	Chantong B, Kratschmar DV, Lister A and Odermatt A: Dibutyltin promotes oxidative stress and increases inflammatory mediators in BV-2 microglia cells. Toxicol Lett. 230:177–187. 2014. View Article : Google Scholar : PubMed/NCBI
39	Liou CJ, Len WB, Wu SJ, Lin CF, Wu XL and Huang WC: Casticin inhibits COX-2 and iNOS expression via suppression of NF-kappaB and MAPK signaling in lipopolysaccharide-stimulated mouse macrophages. J Ethnopharmacol. 158:310–316. 2014. View Article : Google Scholar