Lipoxins and aspirin-triggered lipoxin alleviate bone cancer pain in association with suppressing expression of spinal proinflammatory cytokines

Journal of Neuroinflammation

Yan-Qing Wang¹  Gen-Cheng Wu¹  Ya-Lin Huang²  Jian-Wei Jiang¹  Xiao-Wei Wang¹  Wen-Li Mi¹  Zhi-Fu Wang¹  Jun Wang¹  Qi-Liang Mao-Ying¹  Shan Hu¹ 

[1] Department of Integrative Medicine and Neurobiology, State Key Laboratory of Medical Neurobiology, Institute of Acupuncture Research (WHO Collaborating Center for Traditional Medicine), School of Basic Medical Sciences, Shanghai Medical College, Institutes of Brain Science, Fudan University, 138 Yi Xue Yuan Road, P.O. Box 291, Shanghai 200032, China;Institutes of Biomedical Sciences, Institute of Stem Cell and Regeneration Medicine, Fudan University, Shanghai, 200032, P. R. China

关键词: Rats;    Spinal cord;    Cancer-induced bone pain;    Proinflammatory cytokines;    Neurons;    Astrocytes;    Aspirin-triggered-15-epi-lipoxinA4;    Lipoxins;   

Others  :  1160094
DOI  :  10.1186/1742-2094-9-278

 received in 2011-11-21, accepted in 2012-12-04,  发布年份 2012

【 摘 要 】

Background

The neuroinflammatory responses in the spinal cord following bone cancer development have been shown to play an important role in cancer-induced bone pain (CIBP). Lipoxins (LXs), endogenous lipoxygenase-derived eicosanoids, represent a unique class of lipid mediators that possess a wide spectrum of anti-inflammatory and pro-resolving actions. In this study, we investigated the effects of intrathecal injection with lipoxin and related analogues on CIBP in rats.

Methods

The CIBP model was induced by intra-tibia inoculation of Walker 256 mammary gland carcinoma cells. Mechanical thresholds were determined by measuring the paw withdrawal threshold to probing with a series of calibrated von Frey filaments. Lipoxins and analogues were administered by intrathecal (i.t.) or intravenous (i.v.) injection. The protein level of LXA4 receptor (ALX) was tested by western blot. The localization of lipoxin receptor in spinal cord was assessed by fluorescent immunohistochemistry. Real-time PCR was carried out for detecting the expression of pro-inflammatory cytokines.

Results

Our results demonstrated that: 1) i.t. injection with the same dose (0.3 nmol) of lipoxin A4 (LXA4), lipoxin B4 (LXB4) or aspirin-triggered-15-epi-lipoxin A4 (ATL) could alleviate the mechanical allodynia in CIBP on day 7 after surgery. ATL showed a longer effect than the others and the effect lasted for 6 hours. ATL administered through i.v. injection could also attenuate the allodynia in cancer rats. 2) The results from western blot indicate that there is no difference in the expression of ALX among the naive, sham or cancer groups. 3) Immunohistochemistry showed that the lipoxin receptor (ALX)-like immunoreactive substance was distributed in the spinal cord, mainly co-localized with astrocytes, rarely co-localized with neurons, and never co-localized with microglia. 4) Real-time PCR analysis revealed that, compared with vehicle, i.t. injection with ATL could significantly attenuate the expression of the mRNA of proinflammatory cytokines (IL-1β and TNF-α) in the spinal cord in CIBP.

Conclusions

Taken together, the results of our study suggest that LXs and analogues exert strong analgesic effects on CIBP. These analgesic effects in CIBP are associated with suppressing the expression of spinal proinflammatory cytokines.

【 授权许可】

   
2012 Hu et al.; licensee BioMed Central Ltd.

【 图 表 】

Figure 2.

Figure 3.

Figure 4.

Figure 5.

Figure 6.

【 参考文献 】

• [1]Breivik H, Cherny N, Collett B, de Conno F, Filbet M, Foubert AJ, Cohen R, Dow L: Cancer-related pain: a pan-European survey of prevalence, treatment, and patient attitudes. Ann Oncol 2009, 20:1420-1433.
• [2]Paice JA, Ferrell B: The management of cancer pain. CA Cancer J Clin 2011, 61:157-182.
• [3]Goblirsch MJ, Zwolak P, Clohisy DR: Advances in understanding bone cancer pain. J Cell Biochem 2005, 96:682-688.
• [4]Zhang RX, Liu B, Wang L, Ren K, Qiao JT, Berman BM, Lao L: Spinal glial activation in a new rat model of bone cancer pain produced by prostate cancer cell inoculation of the tibia. Pain 2005, 118:125-136.
• [5]Mao-Ying QL, Zhao J, Dong ZQ, Wang J, Yu J, Yan MF, Zhang YQ, Wu GC, Wang YQ: A rat model of bone cancer pain induced by intra-tibia inoculation of Walker 256 mammary gland carcinoma cells. Biochem Biophys Res Commun 2006, 345:1292-1298.
• [6]Liu S, Liu WT, Liu YP, Dong HL, Henkemeyer M, Xiong LZ, Song XJ: Blocking EphB1 receptor forward signaling in spinal cord relieves bone cancer pain and rescues analgesic effect of morphine treatment in rodents. Cancer Res 2011, 71:4392-4402.
• [7]Paley CA, Bennett MI, Johnson MI: Acupuncture for cancer-induced bone pain? Evid Based Complement Alternat Med 2011, 2011:671043.
• [8]Mantyh PW, Clohisy DR, Koltzenburg M, Hunt SP: Molecular mechanisms of cancer pain. Nat Rev Cancer 2002, 2:201-209.
• [9]Cao H, Zhang YQ: Spinal glial activation contributes to pathological pain states. Neurosci Biobehav Rev 2008, 32:972-983.
• [10]Urch CE, Donovan-Rodriguez T, Dickenson AH: Alterations in dorsal horn neurones in a rat model of cancer-induced bone pain. Pain 2003, 106:347-356.
• [11]Gao YJ, Ji RR: Activation of JNK pathway in persistent pain. Neurosci Lett 2008, 437:180-183.
• [12]McMahon SB, Cafferty WB, Marchand F: Immune and glial cell factors as pain mediators and modulators. Exp Neurol 2005, 192:444-462.
• [13]Ji RR, Kawasaki Y, Zhuang ZY, Wen YR, Decosterd I: Possible role of spinal astrocytes in maintaining chronic pain sensitization: review of current evidence with focus on bFGF/JNK pathway. Neuron Glia Biol 2006, 2:259-269.
• [14]Chiang N, Arita M, Serhan CN: Anti-inflammatory circuitry: lipoxin, aspirin-triggered lipoxins and their receptor ALX. Prostaglandins Leukot Essent Fatty Acids 2005, 73:163-177.
• [15]Serhan CN, Savill J: Resolution of inflammation: the beginning programs the end. Nat Immunol 2005, 6:1191-1197.
• [16]Schwab JM, Serhan CN: Lipoxins and new lipid mediators in the resolution of inflammation. Curr Opin Pharmacol 2006, 6:414-420.
• [17]Yacoubian S, Serhan CN: New endogenous anti-inflammatory and proresolving lipid mediators: implications for rheumatic diseases. Nat Clin Pract Rheumatol 2007, 3:570-579.
• [18]Serhan CN, Hamberg M, Samuelsson B: Lipoxins: novel series of biologically active compounds formed from arachidonic acid in human leukocytes. Proc Natl Acad Sci U S A 1984, 81:5335-5339.
• [19]Serhan CN, Krishnamoorthy S, Recchiuti A, Chiang N: Novel anti-inflammatory–pro-resolving mediators and their receptors. Curr Top Med Chem 2011, 11:629-647.
• [20]Brady HR, Serhan CN: Lipoxins: putative braking signals in host defense, inflammation and hypersensitivity. Curr Opin Nephrol Hypertens 1996, 5:20-27.
• [21]Chiang N, Serhan CN, Dahlen SE, Drazen JM, Hay DW, Rovati GE, Shimizu T, Yokomizo T, Brink C: The lipoxin receptor ALX: potent ligand-specific and stereoselective actions in vivo. Pharmacol Rev 2006, 58:463-487.
• [22]Serhan CN: Lipoxins and aspirin-triggered 15-epi-lipoxins are the first lipid mediators of endogenous anti-inflammation and resolution. Prostaglandins Leukot Essent Fatty Acids 2005, 73:141-162.
• [23]Sun T, Yu E, Yu L, Luo J, Li H, Fu Z: LipoxinA(4) induced antinociception and decreased expression of NF-kappaB and pro-inflammatory cytokines after chronic dorsal root ganglia compression in rats. Eur J Pain 2012, 16:18-27.
• [24]Svensson CI, Zattoni M, Serhan CN: Lipoxins and aspirin-triggered lipoxin inhibit inflammatory pain processing. J Exp Med 2007, 204:245-252.
• [25]Medhurst SJ, Walker K, Bowes M, Kidd BL, Glatt M, Muller M, Hattenberger M, Vaxelaire J, O'Reilly T, Wotherspoon G, Winter J, Green J, Urban L: A rat model of bone cancer pain. Pain 2002, 96:129-140.
• [26]Xu JJ, Walla BC, Diaz MF, Fuller GN, Gutstein HB: Intermittent lumbar puncture in rats: a novel method for the experimental study of opioid tolerance. Anesth Analg 2006, 103:714-720.
• [27]Pitcher GM, Ritchie J, Henry JL: Paw withdrawal threshold in the von Frey hair test is influenced by the surface on which the rat stands. J Neurosci Methods 1999, 87:185-193.
• [28]Chaplan SR, Bach FW, Pogrel JW, Chung JM, Yaksh TL: Quantitative assessment of tactile allodynia in the rat paw. J Neurosci Methods 1994, 53:55-63.
• [29]Wang J, Li J, Sheng X, Zhao H, Cao XD, Wang YQ, Wu GC: Beta-adrenoceptor mediated surgery-induced production of pro-inflammatory cytokines in rat microglia cells. J Neuroimmunol 2010, 223:77-83.
• [30]Livak KJ, Schmittgen TD: Analysis of relative gene expression data using real-time quantitative PCR and the 2(−Delta Delta C(T)) Method. Methods 2001, 25:402-408.
• [31]Schmittgen TD, Livak KJ: Analyzing real-time PCR data by the comparative C(T) method. Nat Protoc 2008, 3:1101-1108.
• [32]Brandenburg LO, Koch T, Sievers J, Lucius R: Internalization of PrP106-126 by the formyl-peptide-receptor-like-1 in glial cells. J Neurochem 2007, 101:718-728.
• [33]Decker Y, McBean G, Godson C: Lipoxin A4 inhibits IL-1beta-induced IL-8 and ICAM-1 expression in 1321 N1 human astrocytoma cells. Am J Physiol Cell Physiol 2009, 296:C1420-C1427.
• [34]Milligan ED, Watkins LR: Pathological and protective roles of glia in chronic pain. Nat Rev Neurosci 2009, 10:23-36.
• [35]Gao YJ, Ji RR: Targeting astrocyte signaling for chronic pain. Neurotherapeutics 2010, 7:482-493.
• [36]Das UN: Radiation resistance, invasiveness and metastasis are inflammatory events that could be suppressed by lipoxin A4. Prostaglandins Leukot Essent Fatty Acids 2012, 86:3-11.
• [37]Hao H, Liu M, Wu P, Cai L, Tang K, Yi P, Li Y, Chen Y, Ye D: Lipoxin A4 and its analog suppress hepatocellular carcinoma via remodeling tumor microenvironment. Cancer Lett 2011, 309:85-94.
• [38]Zhang B, Jia H, Liu J, Yang Z, Jiang T, Tang K, Li D, Huang C, Ma J, Shen GX, Ye D, Huang B: Depletion of regulatory T cells facilitates growth of established tumors: a mechanism involving the regulation of myeloid-derived suppressor cells by lipoxin A4. J Immunol 2010, 185:7199-7206.
• [39]Serhan CN, Fierro IM, Chiang N, Pouliot M: Cutting edge: nociceptin stimulates neutrophil chemotaxis and recruitment: inhibition by aspirin-triggered-15-epi-lipoxin A4. J Immunol 2001, 166:3650-3654.
• [40]Krebs DL, Hilton DJ: SOCS proteins: negative regulators of cytokine signaling. Stem Cells 2001, 19:378-387.
• [41]Wu SH, Liao PY, Dong L, Chen ZQ: Signal pathway involved in inhibition by lipoxin A(4) of production of interleukins induced in endothelial cells by lipopolysaccharide. Inflamm Res 2008, 57:430-437.
• [42]Leonard MO, Hannan K, Burne MJ, Lappin DW, Doran P, Coleman P, Stenson C, Taylor CT, Daniels F, Godson C, Petasis NA, Rabb H, Brady HR: 15-Epi-16-(para-fluorophenoxy)-lipoxin A(4)-methyl ester, a synthetic analogue of 15-epi-lipoxin A(4), is protective in experimental ischemic acute renal failure. J Am Soc Nephrol 2002, 13:1657-1662.
• [43]Diamond P, Doran P, Brady HR, McGinty A: Suppressors of cytokine signalling (SOCS): putative modulators of cytokine bioactivity in health and disease. J Nephrol 2000, 13:9-14.
• [44]Krebs DL, Hilton DJ: SOCS: physiological suppressors of cytokine signaling. J Cell Sci 2000, 113:2813-2819.