Abstract
CX3CL1 (fractalkine) has been shown not only to be neuroprotective but also may play a role in HIV-1-associated neuropathogenesis. In this study, we found that production of CX3CL1 by human astrocytes stimulated with interleukin (IL)-1β was inhibited in a concentration-dependent manner following pretreatment with the synthetic cannabinoid WIN55,212-2. The CB2 receptor selective antagonist SR144528 significantly inhibited WIN55,212-2-mediated suppression of CX3CL1, suggesting a CB2-receptor-related mechanism. IL-1β triggered the activation of p38 and ERK1/2 (p44/42) MAP kinase (MAPK) signaling pathways, but WIN55,212-2 mainly inhibited p38 MAPK phosphorylation. This finding was mirrored in experiments using known inhibitors of these MAPKs, suggesting that the suppression of CX3CL1 production by WIN55,212-2 involves inhibition of signaling via p38 MAPK. Our results support the concept that synthetic cannabinoids have anti-inflammatory properties and that these agents may have therapeutic potential for certain neuroinflammatory disorders.
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References
Cabral GA, Raborn ES, Griffin L, Dennis J, Marciano-Cabral F (2008) CB2 receptors in the brain: role in central immune function. Br J Pharmacol 153:240–251. doi:10.1038/sj.bjp.0707584
Cardona AE, Pioro EP, Sasse ME, Kostenko V, Cardona SM, Dijkstra IM, Huang D, Kidd G, Dombrowski S, Dutta R, Lee JC, Cook DN, Jung S, Lira SA, Littman DR, Ransohoff RM (2006) Control of microglial neurotoxicity by the fractalkine receptor. Nat Neurosci 9:917–924. doi:10.1038/nn1715
Croxford JL (2003) Therapeutic potential of cannabinoids in CNS disease. CNS Drugs 17:179–202. doi:10.2165/00023210–200317030–00004
Croxford JL, Miller SD (2003) Immunoregulation of a viral model of multiple sclerosis using the synthetic cannabinoid R+WIN55,212. J Clin Invest 111:1231–1240
Erichsen D, Lopez AL, Peng H, Niemann D, Williams C, Bauer M, Morgello S, Cotter RL, Ryan LA, Ghorpade A, Gendelman HE, Zheng J (2003) Neuronal injury regulates fractalkine: relevance for HIV-1 associated dementia. J Neuroimmunol 138:144–155. doi:10.1016/S0165–5728(03)00117–6
Harrison JK, Jiang Y, Chen S, Xia Y, Maciejewski D, McNamara RK, Streit WJ, Salafranca MN, Adhikari S, Thompson DA, Botti P, Bacon KB, Feng L (1998) Role for neuronally derived fractalkine in mediating interactions between neurons and CX3CR1-expressing microglia. Proc Natl Acad Sci USA 95:10896–10901. doi:10.1073/pnas.95.18.10896
Hu S, Ali H, Sheng WS, Ehrlich LC, Peterson PK, Chao CC (1999) Gp-41-mediated astrocyte inducible nitric oxide synthase mRNA expression: involvement of interleukin-1beta production by microglia. J Neurosci 19:6468–6474
Hughes PM, Botham MS, Frentzel S, Mir A, Perry VH (2002) Expression of fractalkine (CX3CL1) and its receptor, CX3CR1, during acute and chronic inflammation in the rodent CNS. Glia 37:314–327. doi:10.1002/glia.10037
Klein TW (2005) Cannabinoid-based drugs as anti-inflammatory therapeutics. Nat Rev Immunol 5:400–411. doi:10.1038/nri1602
Klein TW, Newton C, Larsen K, Lu L, Perkins I, Nong L, Friedman H (2003) The cannabinoid system and immune modulation. J Leukoc Biol 74:486–496. doi:10.1189/jlb.0303101
Meucci O, Fatatis A, Simen AA, Miller RJ (2000) Expression of CX3CR1 chemokine receptors on neurons and their role in neuronal survival. Proc Natl Acad Sci USA 97:8075–8080. doi:10.1073/pnas.090017497
Pereira CF, Middel J, Jansen G, Verhoef J, Nottet HS (2001) Enhanced expression of fractalkine in HIV-1 associated dementia. J Neuroimmunol 115:168–175. doi:10.1016/S0165–5728(01)00262–4
Sheng WS, Hu S, Min X, Cabral GA, Lokensgard JR, Peterson PK (2005) Synthetic cannabinoid WIN55,212-2 inhibits generation of inflammatory mediators by IL-1beta-stimulated human astrocytes. Glia 49:211–219. doi:10.1002/glia.20108
Sunnemark D, Eltayeb S, Nilsson M, Wallstrom E, Lassmann H, Olsson T, Berg AL, Ericsson-Dahlstrand A (2005) CX3CL1 (fractalkine) and CX3CR1 expression in myelin oligodendrocyte glycoprotein-induced experimental autoimmune encephalomyelitis: kinetics and cellular origin. J Neuroinflammation 2:17. doi:10.1186/1742–2094–2–17
Tong N, Perry SW, Zhang Q, James HJ, Guo H, Brooks A, Bal H, Kinnear SA, Fine S, Epstein LG, Dairaghi D, Schall TJ, Gendelman HE, Dewhurst S, Sharer LR, Gelbard HA (2000) Neuronal fractalkine expression in HIV-1 encephalitis: roles for macrophage recruitment and neuroprotection in the central nervous system. J Immunol 164:1333–1339
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This study was supported in part by United States Public Health Service Grants DA00924 and DA025525.
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Sheng, W.S., Hu, S., Ni, H.T. et al. WIN55,212-2 Inhibits Production of CX3CL1 by Human Astrocytes: Involvement of p38 MAP Kinase. J Neuroimmune Pharmacol 4, 244–248 (2009). https://doi.org/10.1007/s11481-009-9147-5
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DOI: https://doi.org/10.1007/s11481-009-9147-5