内吗啡肽和Mu阿片受体在小鼠树突状细胞的表达及其相关功能的研究
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摘要
目的:研究内吗啡肽-1和内吗啡肽-2以及Mu阿片受体在小鼠树突状细胞的表达及其相关的功能。
方法:从7-8周龄的C57BL/6J小鼠骨髓提取骨髓前体细胞培养,经CD11c免疫磁珠分选,获得纯化的树突状细胞。流式细胞仪分析表明,CD11c(树突状细胞的特异性标记)阳性细胞纯度达95%以上。首先,研究Mu阿片受体是否在鼠树突状细胞表达。用RT-PCR的方法,检测Mu阿片受体基因在树突状细胞上的表达;用激光共聚焦显微镜观察免疫荧光染色,观察Mu阿片受体蛋白在树突状细胞上的表达;同时,用定量PCR的方法,研究了不同Toll样受体(TLR)的配体对Mu阿片受体基因表达的调控。其次,研究树突状细胞是否产生内吗啡肽-1和内吗啡肽-2。用免疫荧光染色研究了内吗啡肽-1和内吗啡肽-2在树突状细胞的表达;用酶免疫测定(EIA)的方法,检测了培养树突状细胞的上清中的内吗啡肽-1和内吗啡肽-2的含量,反映内吗啡肽从树突状细胞的分泌。最后,在证实了树突状细胞表达内吗啡肽-1、内吗啡肽-2和Mu阿片受体的基础上,进一步探讨树突状细胞内吗啡肽/Mu阿片受体的功能意义。用脂多糖(LPS)激活树突状细胞,用naloxone作为阿片受体非特异性拮抗剂,用CTOP作为Mu阿片受体特异性拮抗剂,用竞争结合的方法检测了树突状细胞内由forskolin引起的cAMP的生成;用Western blot的方法,观察了内吗啡肽-1对树突状细胞内磷酸化p38 MAPK和ERK的表达,以判断p38 MAPK和ERK两条信号通路的活化状态;运用酶联免疫吸附试验(ELISA)的方法,检测了内吗啡肽-1促使树突状细胞分泌的细胞因子IL-10、IL-12和IL-23的浓度;在树突状细胞和T淋巴细胞共培养的条件下,用氚标记胸腺嘧啶核苷(3H-TdR)掺入测定的方法检测了T淋巴细胞的增殖能力。
结果:在Mu阿片受体方面,RT-PCR的结果表明,经LPS活化的树突状细胞表达Mu阿片受体的mRNA。免疫荧光双标染色的结果表明,Mu阿片受体蛋白与树突状细胞的CD11c分子共表达于细胞膜上;而且,定量PCR的结果表明,不同的TLR配体均可显著上调Mu阿片受体基因的表达,特别是LPS和Poly (I:C)上调更为明显;LPS活化的树突状细胞在6小时后便出现Mu阿片受体mRNA的表达,表达水平逐步升高,于24小时达到顶峰,并在随后的12-24小时内维持在较高的表达水平。在内吗啡肽方面,免疫荧光染色表明,活化的树突状细胞内产生内吗啡肽-1和内吗啡肽-2;酶免疫测定(EIA)检测的结果表明,不同的TLR配体活化树突状细胞促使分泌不同浓度的内吗啡肽-1和内吗啡肽-2。对内吗啡肽/Mu阿片受体在树突状细胞的功能研究表明,内吗啡肽-1可显著降低胞内forskolin引起的cAMP的生成;能降低p38MAPK信号通路的活化,增加ERK信号通路的活化;相应地,经过内吗啡肽-1处理的LPS活化的树突状细胞,增强IL-10的产生和分泌,降低IL-12和IL-23的产生和分泌;与T淋巴细胞体外共培养时,经内吗啡肽-1或内吗啡肽-2处理的树突状细胞能抑制T淋巴细胞的增殖反应。上述内吗啡肽的作用都能被阿片受体非特异性拮抗剂naloxone和Mu阿片受体特异性拮抗剂CTOP翻转或部分翻转,提示内吗啡肽的作用都是由Mu受体介导的。
结论:活化的树突状细胞诱导性表达Mu阿片受体和内吗啡肽。内吗啡肽可通过Mu阿片受体影响胞内的信号通路,改变树突状细胞的功能特性,调节免疫反应。
Objective: The aim of the present study was to investigate the expression of endomorphins and their high affinity mu-opioid receptors on murine dendritic cells, as well as their functions.
Methods: Bone marrow dendritic cells were extracted from normal, 7- to 8-week-old C57 BL/6J mice, purified with anti-CD11c (a specific marker for dendritic cells) antibody-coated magnetic beads and cultured in the presence of GM-CSF. FACS analysis indicated that the purity of dendritic cells was more than 95%. At first, we investigated whether the dendritic cells express the mu-opioid receptors. RT-PCR was used to detect the mu-receptor gene expression on the dendritic cells. Immunofluorescence double staining combined with confocal microscopic observation was used to detect the mu-opioid receptor protein expression with CD11c marker. Quantitative PCR was used to examine the control of mu-opioid receptor expression by different Toll-like receptor ligands. Secondly, we investigated whether the dendritic cells produce and secrete the endomorphins. Immunofluorescence staining was used to detect to expression of endomorphins in the dendritic cells. The enzyme immunoassay (EIA) was used to determine the contents of endomorphins secreted in the supernatant. Finally, on the base of confirmation of the presence of mu-opioid receptor and endomorphins in dendritic cells, we investigated their functional significances. Competitive binding assay was used to measure the forskolin-induced cAMP formation. Western blot was used to determine the phosphorylation of p38MAPK and ERK in the signal pathways. ELISA was used to measure the concentration of various cytokines in the supernatant. 3H-thymidine incorporation was used to detect the proliferation of T cells under the condition of co-culture of T lymphocytes with endomorphin-treated dendritic cells.
Results: RT-PCR analysis and double immunofluroscence staining revealed the expression of mu-opioid receptor gene and protein in activated murine dendritic cells. Various ligands of Toll-like receptors could regulate the dynamic expression of mu-opioid receptor in murine dendritic cells. Similarly, we observed that activated murine dendritic cells produce endomorphin in cytoplasm and secrete into the supernatant. Functionally, treatment of DCs with endomorphin-1, one specific agonist of mu-opoid receptor, could inhibit forskolin-induced increase of cAMP levels in activated DCs. The signaling which was triggered by endomorphin-1 could suppress the activation of p38 MAPK and enhance the activation of ERK signaling in LPS-stimulated DCs. Treatment of DCs with endomorphin-1 could increase the production of IL-10 and decrease the production of IL-12 and IL-23. Consistently endomorphins-treated dendritic cells could inhibit the proliferation of T lymphocytes. All the above-mentioned effects of endomorphin-1could be reversed by naloxone (non-specific opioid receptor antagonist) and CTOP (specific mu-opioid receptor antagonist), suggesting that these effects of endomorphin-1 were mediated by mu-opioid receptors.
Conclusion: The results demonstrated the inducible expression of functional mu-opioid receptor and endomorphins on activated dendritic cells and the secretion of endomorphins, suggesting that the signaling initiated by endomorphin can alter cellular signaling pathways, modulate the functional properties of dendritic cells and modulate immune response, and impling the involvement of dendritic cells in the crosstalk among the nervous, endocrine and immune systems
方法:从7-8周龄的C57BL/6J小鼠骨髓提取骨髓前体细胞培养,经CD11c免疫磁珠分选,获得纯化的树突状细胞。流式细胞仪分析表明,CD11c(树突状细胞的特异性标记)阳性细胞纯度达95%以上。首先,研究Mu阿片受体是否在鼠树突状细胞表达。用RT-PCR的方法,检测Mu阿片受体基因在树突状细胞上的表达;用激光共聚焦显微镜观察免疫荧光染色,观察Mu阿片受体蛋白在树突状细胞上的表达;同时,用定量PCR的方法,研究了不同Toll样受体(TLR)的配体对Mu阿片受体基因表达的调控。其次,研究树突状细胞是否产生内吗啡肽-1和内吗啡肽-2。用免疫荧光染色研究了内吗啡肽-1和内吗啡肽-2在树突状细胞的表达;用酶免疫测定(EIA)的方法,检测了培养树突状细胞的上清中的内吗啡肽-1和内吗啡肽-2的含量,反映内吗啡肽从树突状细胞的分泌。最后,在证实了树突状细胞表达内吗啡肽-1、内吗啡肽-2和Mu阿片受体的基础上,进一步探讨树突状细胞内吗啡肽/Mu阿片受体的功能意义。用脂多糖(LPS)激活树突状细胞,用naloxone作为阿片受体非特异性拮抗剂,用CTOP作为Mu阿片受体特异性拮抗剂,用竞争结合的方法检测了树突状细胞内由forskolin引起的cAMP的生成;用Western blot的方法,观察了内吗啡肽-1对树突状细胞内磷酸化p38 MAPK和ERK的表达,以判断p38 MAPK和ERK两条信号通路的活化状态;运用酶联免疫吸附试验(ELISA)的方法,检测了内吗啡肽-1促使树突状细胞分泌的细胞因子IL-10、IL-12和IL-23的浓度;在树突状细胞和T淋巴细胞共培养的条件下,用氚标记胸腺嘧啶核苷(3H-TdR)掺入测定的方法检测了T淋巴细胞的增殖能力。
结果:在Mu阿片受体方面,RT-PCR的结果表明,经LPS活化的树突状细胞表达Mu阿片受体的mRNA。免疫荧光双标染色的结果表明,Mu阿片受体蛋白与树突状细胞的CD11c分子共表达于细胞膜上;而且,定量PCR的结果表明,不同的TLR配体均可显著上调Mu阿片受体基因的表达,特别是LPS和Poly (I:C)上调更为明显;LPS活化的树突状细胞在6小时后便出现Mu阿片受体mRNA的表达,表达水平逐步升高,于24小时达到顶峰,并在随后的12-24小时内维持在较高的表达水平。在内吗啡肽方面,免疫荧光染色表明,活化的树突状细胞内产生内吗啡肽-1和内吗啡肽-2;酶免疫测定(EIA)检测的结果表明,不同的TLR配体活化树突状细胞促使分泌不同浓度的内吗啡肽-1和内吗啡肽-2。对内吗啡肽/Mu阿片受体在树突状细胞的功能研究表明,内吗啡肽-1可显著降低胞内forskolin引起的cAMP的生成;能降低p38MAPK信号通路的活化,增加ERK信号通路的活化;相应地,经过内吗啡肽-1处理的LPS活化的树突状细胞,增强IL-10的产生和分泌,降低IL-12和IL-23的产生和分泌;与T淋巴细胞体外共培养时,经内吗啡肽-1或内吗啡肽-2处理的树突状细胞能抑制T淋巴细胞的增殖反应。上述内吗啡肽的作用都能被阿片受体非特异性拮抗剂naloxone和Mu阿片受体特异性拮抗剂CTOP翻转或部分翻转,提示内吗啡肽的作用都是由Mu受体介导的。
结论:活化的树突状细胞诱导性表达Mu阿片受体和内吗啡肽。内吗啡肽可通过Mu阿片受体影响胞内的信号通路,改变树突状细胞的功能特性,调节免疫反应。
Objective: The aim of the present study was to investigate the expression of endomorphins and their high affinity mu-opioid receptors on murine dendritic cells, as well as their functions.
Methods: Bone marrow dendritic cells were extracted from normal, 7- to 8-week-old C57 BL/6J mice, purified with anti-CD11c (a specific marker for dendritic cells) antibody-coated magnetic beads and cultured in the presence of GM-CSF. FACS analysis indicated that the purity of dendritic cells was more than 95%. At first, we investigated whether the dendritic cells express the mu-opioid receptors. RT-PCR was used to detect the mu-receptor gene expression on the dendritic cells. Immunofluorescence double staining combined with confocal microscopic observation was used to detect the mu-opioid receptor protein expression with CD11c marker. Quantitative PCR was used to examine the control of mu-opioid receptor expression by different Toll-like receptor ligands. Secondly, we investigated whether the dendritic cells produce and secrete the endomorphins. Immunofluorescence staining was used to detect to expression of endomorphins in the dendritic cells. The enzyme immunoassay (EIA) was used to determine the contents of endomorphins secreted in the supernatant. Finally, on the base of confirmation of the presence of mu-opioid receptor and endomorphins in dendritic cells, we investigated their functional significances. Competitive binding assay was used to measure the forskolin-induced cAMP formation. Western blot was used to determine the phosphorylation of p38MAPK and ERK in the signal pathways. ELISA was used to measure the concentration of various cytokines in the supernatant. 3H-thymidine incorporation was used to detect the proliferation of T cells under the condition of co-culture of T lymphocytes with endomorphin-treated dendritic cells.
Results: RT-PCR analysis and double immunofluroscence staining revealed the expression of mu-opioid receptor gene and protein in activated murine dendritic cells. Various ligands of Toll-like receptors could regulate the dynamic expression of mu-opioid receptor in murine dendritic cells. Similarly, we observed that activated murine dendritic cells produce endomorphin in cytoplasm and secrete into the supernatant. Functionally, treatment of DCs with endomorphin-1, one specific agonist of mu-opoid receptor, could inhibit forskolin-induced increase of cAMP levels in activated DCs. The signaling which was triggered by endomorphin-1 could suppress the activation of p38 MAPK and enhance the activation of ERK signaling in LPS-stimulated DCs. Treatment of DCs with endomorphin-1 could increase the production of IL-10 and decrease the production of IL-12 and IL-23. Consistently endomorphins-treated dendritic cells could inhibit the proliferation of T lymphocytes. All the above-mentioned effects of endomorphin-1could be reversed by naloxone (non-specific opioid receptor antagonist) and CTOP (specific mu-opioid receptor antagonist), suggesting that these effects of endomorphin-1 were mediated by mu-opioid receptors.
Conclusion: The results demonstrated the inducible expression of functional mu-opioid receptor and endomorphins on activated dendritic cells and the secretion of endomorphins, suggesting that the signaling initiated by endomorphin can alter cellular signaling pathways, modulate the functional properties of dendritic cells and modulate immune response, and impling the involvement of dendritic cells in the crosstalk among the nervous, endocrine and immune systems
引文
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1. Zadina JE, Hackler L, Ge J, et al. A potent and selective endogenous agonist for the mu-opiate receptor. Nature, 1997, 386: 499-502.
2. Fichna J, Janecka A, Costentin J,et al. The endomorphin system and its evolving neurophysiological role. Pharmacol. Rev, 2007, 59:88-123.
3. Jessop DS, Richards LJ, Harbuz MS. Opioid peptides endomorphin-1 and endomorphin-2 in the immune system in humans and in a rodent model of inflammation. Ann. N. Y. Acad. Sci, 2002, 966: 456-463.
4. Mousa SA, Machelska H, Schafe M, et al. Immunohistochemical localization of endomorphin-1 and endomorphin-2 in immune cells and spinal cord in a model of inflammatory pain. J. Neuroimmunol, 2002, 126:5-15.
5. Seale JV, Jessop DS, Harbu MS. Immunohistochemical staining of endomorphin 1 and 2 in the immune cells of the spleen. Peptides, 2004, 25: 91-94.
6. Inui Y, Azuma Y, Ohura K. Differential alteration of functions of rat peritoneal macrophages responsive to endogenous opioid peptide endomorphin-1. Int. Immunopharmacol, 2002, 2:1133-1142.
7. Azuma Y, Ohura K. Endomorphin-2 modulates productions of TNF-alpha, IL-1beta, IL-10, and IL-12, and alters functions related to innate immune of macrophages. Inflammation, 2002b, 26:223-232.
8. Azuma Y, Ohura K. Endomorphins 1 and 2 inhibit IL-10 and IL-12 production and innate immune functions, and potentiate NF-kappaB DNA binding in THP-1 differentiated to macrophage-like cells. Scand. J. Immunol, 2002a, 56:260-269.
9. Gaveriaux-Ruff C, Matthes HW, Peluso J,et al. Abolition of morphine-immunosuppression in mice lacking the mu-opioid receptor gene. Proc. Natl. Acad. Sci. USA, 1998, 95: 6326-6330.
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15. Azuma Y, Ohura K, Wang PL, et al. Endomorphins 1 and 2 modulate chemotaxis, phagocytosis and superoxide anion production by microglia. J Neuroimmunol, 2001, 119: 51-56.
1. Zadina JE, Hackler L, Ge LJ, et al. A potent and selective endogenous agonist for the mu-opiate receptor. Nature, 1997, 386: 499-502.
2. Bidlack JM, Khimich M, Parkhill AL,et al. Opioid receptors and signaling on cells from the immune system.J Neuroimmune Pharmacol, 2006,1(3):260-269
3. Belcheva MM, Haas PD, Tan Y, et al. The fibroblast growth factor receptor is at the site of convergence between mu-opioid receptor and growth factor signaling pathways in rat C6 glioma cells. J.Pharmacol.Exp.Ther, 2002, 303(3): 909-918.
4. Rozenfeld-Granot G, Toren A, Amariglio N, et al. MAP kinase activation by mu opioid receptor in cord blood CD34(+)CD38(-) cells. Exp.Hematol, 2002, 30(5): 473-480.
5. Fichna J, Janecka A, Costentin J, et al. The endomorphin system and its evolving neurophysiological role. Pharmacol.Rev, 2007, 59(1): 88-123.
6. Husted TL, Govindaswami M, Oeltgen PR, et al. A delta2-opioid agonist inhibits p38 MAPK and suppresses activation of murine macrophages. J.Surg.Res, 2005, 128 (1): 45-49.
7. Korzh A, Keren O, Gafni M, et al. Modulation of extracellular signal-regulated kinase (ERK) by opioid and cannabinoid receptors that are expressed in the same cell. Brain Res, 2008, 1189: 23-32.
8. Macey TA, Lowe JD, Chavkin C. Mu opioid receptor activation of ERK1/2 is GRK3 and arrestin dependent in striatal neurons. J.Biol.Chem, 2006, 281(45): 34515-34524.
9. Messmer D, Hatsukari I, Hitosugi N, et al. Morphine reciprocally regulates IL-10 and IL-12 production by monocyte-derived human dendritic cells and enhances T cell activation. Mol.Med, 2006, 12 (11-12): 284-290.
10. Fr?ssdorf J, Weber NC, Obal D, et al. Morphine induces late cardioprotection in rat hearts in vivo: the involvement of opioid receptors and nuclear transcription factor kappaB. Anesth.Analg, 2005, 101 (4): 934-41.
11. Azuma Y, Ohura K. Endomorphins 1 and 2 inhibit IL-10 and IL-12 production and innate immune functions, and potentiate NF-kappaB DNA binding in THP-1 differentiated to macrophage-like cells. Scand.J.Immunol, 2002, 56 (3): 260-269.
12. Roy S, Cain KJ, Chapin RB, et al. Morphine modulates NF kappa B activation in macrophages. Biochem.Biophys.Res.Commun, 1998, 245 (2): 392-396.
13. Qian C, Jiang X, An H, et al. TLR agonists promote ERK-mediated preferential IL-10 production of regulatory dendritic cells (diffDCs), leading to NK-cell activation. Blood, 2006,108 (7): 2307-2315.
14. Li Y, Chu N, Hu A, et al. Inducible IL-23p19 expression in human microglia via p38 MAPK and NF-kappaB signal pathways. Exp.Mol.Pathol, 2008,84 (1): 1-8.
15. Azuma Y, Ohura K, Wang PL, et al. Endomorphins 1 and 2 modulate chemotaxis, phagocytosis and superoxide anion production by microglia. J.Neuroimmunol, 2001, 119 (1): 51-56.
1. Wybran J, Plotnikoff NP. Methionine enkephalin,a new lymphokine for the treatment of ARC patients. In (Plotnikoff. N. Murgo. A,Faith R,Wybran,Jeds)Stress and Immun,CRC Press,Boca Raton,FL,1991:417-432.
2. Carr DJJ, Serou M. Exogenous and endogenous opioids as biological response modifiers. Immunopharmacology, 1995,31:59-71.
3. Roy S,Ramakrishnan S,Loh HH ,et al. Chronic morphine treatment: selectively suppress macrophage colony formation in bone marrow. Eur. J. Pharmacol, 1991a,195:359-363.
4. Sibinga NES and Goldstein A. Opioid peptides and opioid receptors in cells of the immune system. Ann. Rev. Immu nol,1988,6:219-249.
5. Zadina JE, Hackler L, Ge LJ, et al. A potent and selective endogenous agonist for theμ-opioid receptor. Nature,1997, 386: 499-502.
6. Fichna J, Janecka A, Costentin J, et al. The endomorphin system and its evolving neurophysiological role. Pharmacol Rev, 2007, 59: 88-123.
7. Liu H, Yang Y, Xin R, et al. Differential cardiovascular effects of synthetic peptides derived from endomorphin-1 in anesthetized rats. Peptides, 2008, 29(6):1048-1056.
8. Gyires K, Zádori Z. Analysis of central mechanisms involved in gastric mucosal integrity. Neuropsychopharmacol Hung, 2008, 10(3): 121-125.
9. Martin-Schild S, Gerall AA, Kastin AJ, et al. Differential distribution of endomorphin 1- and endomorphin 2-like immunoreactivities in the CNS of the rodent. J Comp Neurol, 1999, 405 (4): 450-471.
10. Wu SY, Dun SL, Wright MT, et al. Endomorphin-like immunoreactivity in the rat dorsal horn and inhibition of substantia gelatinosa neurons in vitro. Neuroscience, 1999, 89 (2): 317-321.
11. Jessop DS, Major GN, Coventry TL, et al. Opioid peptides endomorphin-1 and endomorphin-1 are present in mammalian immune tissues. J Neuroimmunol, 2000,106: 53-59.
12. Jessop DS, Richards LJ, Harbuz MS. Opioid peptides endomorphin -1 and endomorphin -2 in the immune system in humans and in a rodent model of inflammation. Ann N Y Acad Sci, 2002, 966: 456-463.
13. Mousa SA, Machelska H, Schafer M, et al. Immunohistochemical localization of endomorphin-1 and endomorphin-2 in immune cells and spinal cord in a model of inflammatory pain. J Neuroimmunol, 2002, 126: 5-15.
14. Seale JV, Jessop DS, Harbuz MS. Immunohistochemical staining of endomorphin 1 and 2 in the immune cells of the spleen. Peptides, 2004, 25: 91-94.
15. Cabot PJ, Carter L, Gaiddon C, et al. Immune cell-derivedβ-endorphin: production, release, and control of inflammatory pain in rats. J Clin Invest, 1997, 100:142-148.
16. Machelska H, Cabot PJ, Mousa SA, et al. Pain control in inflammation governed by selections. Nat Med, 1998, 4: 1425-1428.
17. Puehler W, Stein C. Controlling pain by influencing neurogenic pathways. RheumDis Clin North Am,2005, 31 (1): 103-113.
18. Sanderson N K, Skinner K, Julius D, et al. Co-localization of endomorphin-2 and substance P in primary afferent nociceptors and effects of injury: a light and electron microscopic study in the rat. Eur J Neurosci ,2004, 19 (7): 1789-1799.
19. Azuma Y, Ohura K, Wang PL, et al. Endomorphins delay constitutive apoptosis and alter the innate host defense functions of neutrophils. Immunol Lett, 2002, 81(1):31-40.
20. Azuma Y, Wang PL, Shinohara M, et al. Immunomodulation of the neutrophil respiratory burst by endomorphins 1 and 2. Immunol Lett, 2000,75(1):55-59.
21. Izzi V, ChiurchiùV, Aquilio FD, et al. Endomorphin-1 inhibits the activation and the development of a hyporesponsive-like phenotype in lipopolysaccharide- stimulated THP-1 monocytes. Int J Immunopathol Pharmacol, 2008, 21(4): 833-843.
22. Inui Y, Azuma Y, Ohura K. Differential alteration of functions of rat peritoneal macrophages responsive to endogenous opioid peptide endomorphin-1. Int Immunopharmacol, 2002, 2: 1133-1142.
23. Azuma Y, Ohura K. Endomorphin-2 modulates productions of TNF-alpha, IL-1beta, IL-10, and IL-12, and alters functions related to innate immune of macrophages. Inflammation, 2002b, 26: 223-232.
24. Azuma Y, Ohura K. Endomorphins 1 and 2 inhibit IL-10 and IL-12 production and innate immune functions, and potentiate NF-kappaB DNA binding in THP-1 differentiated to macrophage-like cells. Scand J Immunol, 2002a, 56: 260-269.
25. Neudeck BL, Loeb JM. Endomorphin-1 alters interleukin-8 secretion in Caco-2 cells via a receptor mediated process. Immunol Lett, 2002, 84(3):217-221.
26. Sari? A, Balog T, Sobocanec S, et al. Endomorphin 1 activates nitric oxide synthase 2 activity and down regulates nitric oxide synthase 2 mRNA expression. Neuroscience, 2007, 144(4):1454-1461.
27. Anton B, Leff P, Calva JC, et al. Endomorphin 1 and endomorphin 2 suppress in vitro antibody formation at ultra-low concentrations: anti-peptide antibodies but not opioid antagonists block the activity. Brain Behav Immun, 2008, 22(6): 824-832.
28. Bidlack JM, Khimich M, Parkhill AL, et al. Opioid receptors and signaling on cells from the immune system. J. Neuroimmuμne Pharmacol, 2006,1: 260-269.
29. Belcheva MM, Haas PD, Tan Y, et al. The fibroblast growth factor receptor is at the site of convergence between mu-opioid receptor and growth factor signaling pathways in rat C6 glioma cells. J. Pharmacol. Exp. Ther, 2002, 303: 909-918.
30. Rozenfeld-Granot G, Toren A, Amariglio N, et al. MAP kinase activation by mu-opioid receptor in cord blood CD34+CD38- cells. Exp. Hematol, 2002,30: 473-480.
20. Azuma Y, Wang PL, Shinohara M, et al. Immunomodulation of the neutrophil respiratory burst by endomorphins 1 and 2. Immunol Lett, 2000,75(1):55-59.
21. Izzi V, ChiurchiùV, Aquilio FD, et al. Endomorphin-1 inhibits the activation and the development of a hyporesponsive-like phenotype in lipopolysaccharide- stimulated THP-1 monocytes. Int J Immunopathol Pharmacol, 2008, 21(4): 833-843.
22. Inui Y, Azuma Y, Ohura K. Differential alteration of functions of rat peritoneal macrophages responsive to endogenous opioid peptide endomorphin-1. Int Immunopharmacol, 2002, 2: 1133-1142.
23. Azuma Y, Ohura K. Endomorphin-2 modulates productions of TNF-alpha, IL-1beta, IL-10, and IL-12, and alters functions related to innate immune of macrophages. Inflammation, 2002b, 26: 223-232.
24. Azuma Y, Ohura K. Endomorphins 1 and 2 inhibit IL-10 and IL-12 production and innate immune functions, and potentiate NF-kappaB DNA binding in THP-1 differentiated to macrophage-like cells. Scand J Immunol, 2002a, 56: 260-269.
25. Neudeck BL, Loeb JM. Endomorphin-1 alters interleukin-8 secretion in Caco-2 cells via a receptor mediated process. Immunol Lett, 2002, 84(3):217-221.
26. Sari? A, Balog T, Sobocanec S, et al. Endomorphin 1 activates nitric oxide synthase 2 activity and down regulates nitric oxide synthase 2 mRNA expression. Neuroscience, 2007, 144(4):1454-1461.
27. Anton B, Leff P, Calva JC, et al. Endomorphin 1 and endomorphin 2 suppress in vitro antibody formation at ultra-low concentrations: anti-peptide antibodies but not opioid antagonists block the activity. Brain Behav Immun, 2008, 22(6): 824-832.
28. Bidlack JM, Khimich M, Parkhill AL, et al. Opioid receptors and signaling on cells from the immune system. J. Neuroimmuμne Pharmacol, 2006,1: 260-269.
29. Belcheva MM, Haas PD, Tan Y, et al. The fibroblast growth factor receptor is at the site of convergence between mu-opioid receptor and growth factor signaling pathways in rat C6 glioma cells. J. Pharmacol. Exp. Ther, 2002, 303: 909-918.
30. Rozenfeld-Granot G, Toren A, Amariglio N, et al. MAP kinase activation by mu-opioid receptor in cord blood CD34+CD38- cells. Exp. Hematol, 2002,30: 473-480.
43. Hassan AHS, Ableitner A, Stein C, et al. Inflammation of the rat paw enhances axonal transport of opioid receptors in the sciatic nerve and increases their density in the inflamed tissue. Neuroscience, 1993, 55 (1): 185-195.
44. Li Z, Proud D, Zhang C, et al. Chronic arthritis down-regulates peripheralμ- opioid receptor expression with concomitant loss of endomorphin 1 antinociception. Arthritis Rheum, 2005, 52 (10): 3210-3219.
45. Straub RH, Wolff C, Fassold A, et al. Antiinflammatory role of endomorphins in osteoarthritis ,rheumatoid arthritis and adjuvant-induced polyarthritis. Arthritis Rheum, 2008, 58(2):456-466.
46. Azuma Y, Ohura K, Wang PL, et al. Endomorphins 1 and 2 modulate chemotaxis, phagocytosis and superoxide anion production by microglia. J Neuroimmunol, 2001,119 (1): 51-56.
47. Sharp BM. Multiple opioid receptors on immune cells modulate intracellular signaling. Brain Behav Immun, 2006, 20: 9-14.
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53. Gaveriaux-Ruff C, Matthes HW, Peluso J, et al. Abolition of morphine- immunosuppression in mice lacking the mu-opioid receptor gene. Proc. Natl. Acad. Sci. USA,1998,95: 6326-6330.
54. Cabot PJ, Carter L, Schafer M, et al. Methionine-enkephalin-and Dynorphin A-release from immune cells and control of inflammatory pain. Pain, 2001,93: 207-212
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2. Ghiringhelli F, Apetoh L, Housseau F, et al. Links between innate and cognate tumor immunity. Curr. Opin. Immunol, 2007, 19: 224-231.
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5. Hackstein H, Thomson AW. Dendritic cells: emerging pharmacological targets of immunosuppressive drugs. Nat. Rev. Immunol, 2004, 4: 24-34.
6. Zadina JE, Hackler L, Ge LJ et al. A potent and selective endogenous agonist for the mu-opiate receptor. Nature, 1997, 386: 499-502.
7. Fichna J, Janecka A, Costentin J, et al. The endomorphin system and its evolving neurophysiological role. Pharmacol. Rev. 2007, 59: 88-123.
8. Liu H, Yang Y, Xin R, et al. Differential cardiovascular effects of synthetic peptides derived from endomorphin-1 in anesthetized rats. Peptides, 2008, 29 (6):1048-1056.
9. Gyires K, Zádori Z. Analysis of central mechanisms involved in gastric mucosal integrity. Neuropsychopharmacol Hung, 2008, 10(3): 121-125.
10. Jessop DS, Richards LJ, Harbuz MS. Opioid peptides endomorphin-1 and endomorphin-2 in the immune system in humans and in a rodent model of inflammation. Ann. N. Y. Acad. Sci, 2002, 966: 456-463.
11. Mousa SA, Machelska H, Schafer M, et al. Immunohistochemical localization of endomorphin-1 and endomorphin-2 in immune cells and spinal cord in a model of inflammatory pain. J. Neuroimmunol, 2002, 126: 5-15.
12. Seale JV, Jessop DS, Harbuz MS. Immunohistochemical staining of endomorphin 1 and 2 in the immune cells of the spleen. Peptides, 2004, 25: 91-94.
13. Inui Y, Azuma Y, Ohura K. Differential alteration of functions of rat peritoneal macrophages responsive to endogenous opioid peptide endomorphin-1. Int. Immunopharmacol, 2002, 2: 1133-1142.
14. Azuma Y, Ohura K. Endomorphin-2 modulates productions of TNF-alpha, IL-1beta, IL-10, and IL-12, and alters functions related to innate immune of macrophages. Inflammation, 2002b, 26: 223-232.
15. Azuma Y, Ohura K. Endomorphin-1 and -2 inhibit IL-10 and IL-12 production and innate immune functions, and potentiate NF-kappa B DNA binding in THP-1 differentiated to macrophage-like cells. Scand. J. Immunol, 2002a, 56: 260-269.
16. Bidlack JM, Khimich M, Parkhill AL, et al. Opioid receptors and signaling on cells from the immune system. J. Neuroimmuμne. Pharmacol, 2006, 1: 260-269.
17. Gaveriaux-Ruff C, Matthes HW, Peluso J, et al. Abolition of morphine-immunosuppression in mice lacking the mu-opioid receptor gene. Proc. Natl. Acad. Sci. USA,1998, 95: 6326-6330.
18. Belcheva MM, Haas PD, Tan Y, et al. The fibroblast growth factor receptor is at the site of convergence between mu-opioid receptor and growth factor signaling pathways in rat C6 glioma cells. J. Pharmacol. Exp. Ther , 2002, 303: 909-918.
19. Rozenfeld-Granot G, Toren A, Amariglio N, et al. MAP kinase activation by mu-opioid receptor in cord blood CD34(+)CD38(-) cells. Exp. Hematol ,2002, 30: 473-480.
1. Gaveriaux-Ruff C, Matthes HW, Peluso J, et al. Abolition of morphine-immunosuppression in mice lacking the mu-opioid receptor gene. Proc. Natl. Acad. Sci. U SA, 1998,95: 6326-6330.
2. Borner C, Stumm R, Hollt V,et al. Comparative analysis of mu-opioid receptor expression in immune and neuronal cells. J. Neuroimmunol, 2007, 188: 56-63.
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13. Husted TL, Govindaswami M, Oeltgen PR, et al. A delta2-opioid agonist inhibits p38 MAPK and suppresses activation of murine macrophages. J. Surg. Res, 2005, 128: 45-49.
14. Korzh A, Keren O, Gafni M, et al. Modulation of extracellular signal-regulated kinase (ERK) by opioid and cannabinoid receptors that are expressed in the same cell. Brain Res, 2008, 1189: 23-32.
15. Macey TA, Lowe JD, Chavkin C. Mu opioid receptor activation of ERK1/2 is GRK3 and arrestin dependent in striatal neurons. J. Biol. Chem, 2006, 281: 34515-34524.
16. Messmer D, Hatsukari I, Hitosugi N, et al. Morphine reciprocally regulates IL-10 and IL-12 production by monocyte-derived human dendritic cells and enhances T cell activation. Mol. Med, 2006, 12: 284-290.
17. Frassdorf J, Weber NC, Obal D, et al. Morphine induces late cardioprotection in rat hearts in vivo: the involvement of opioid receptors and nuclear transcription factor kappaB. Anesth. Analg, 2005, 101: 934-941.
18. Azuma Y, Ohura K. Endomorphins 1 and 2 inhibit IL-10 and IL-12 production and innate immune functions, and potentiate NF-kappaB DNA binding in THP-1 differentiated to macrophage-like cells. Scand. J. Immunol, 2002, 56: 260-269.
19. Roy S, Cain KJ, Chapin RB, et al. Morphine modulates NF kappa B activation in macrophages. Biochem. Biophys. Res. Commun, 1998, 245: 392-396.
1. Zadina JE, Hackler L, Ge J, et al. A potent and selective endogenous agonist for the mu-opiate receptor. Nature, 1997, 386: 499-502.
2. Fichna J, Janecka A, Costentin J,et al. The endomorphin system and its evolving neurophysiological role. Pharmacol. Rev, 2007, 59:88-123.
3. Jessop DS, Richards LJ, Harbuz MS. Opioid peptides endomorphin-1 and endomorphin-2 in the immune system in humans and in a rodent model of inflammation. Ann. N. Y. Acad. Sci, 2002, 966: 456-463.
4. Mousa SA, Machelska H, Schafe M, et al. Immunohistochemical localization of endomorphin-1 and endomorphin-2 in immune cells and spinal cord in a model of inflammatory pain. J. Neuroimmunol, 2002, 126:5-15.
5. Seale JV, Jessop DS, Harbu MS. Immunohistochemical staining of endomorphin 1 and 2 in the immune cells of the spleen. Peptides, 2004, 25: 91-94.
6. Inui Y, Azuma Y, Ohura K. Differential alteration of functions of rat peritoneal macrophages responsive to endogenous opioid peptide endomorphin-1. Int. Immunopharmacol, 2002, 2:1133-1142.
7. Azuma Y, Ohura K. Endomorphin-2 modulates productions of TNF-alpha, IL-1beta, IL-10, and IL-12, and alters functions related to innate immune of macrophages. Inflammation, 2002b, 26:223-232.
8. Azuma Y, Ohura K. Endomorphins 1 and 2 inhibit IL-10 and IL-12 production and innate immune functions, and potentiate NF-kappaB DNA binding in THP-1 differentiated to macrophage-like cells. Scand. J. Immunol, 2002a, 56:260-269.
9. Gaveriaux-Ruff C, Matthes HW, Peluso J,et al. Abolition of morphine-immunosuppression in mice lacking the mu-opioid receptor gene. Proc. Natl. Acad. Sci. USA, 1998, 95: 6326-6330.
10. Makarenkova VP, Esche C, Kost NV, et al. Identification of delta- and mu-type opioid receptors on human and murine dendritic cells. J Neuroimmunol, 2001, 117: 68-77.
11. Akira S. Immunological mechanism in man against infection.Nippon Naika Gakkai Zasshi, 2001, 90(12):2360-2365.
12. Iwasaki A, Medzhitov R. Toll-like receptor control of the adaptive immune responses. Nat Immunol, 2004, 5(10):987-995.
13. Lehnardt S, Massillon L, Follett P, et al. Activation of innate immunity in the CNS triggers neurodegeneration through a Toll-like receptor 4-dependent pathway. Proc Natl. Acad. Sci. USA, 2003, 100(14):8514-8519.
14. Sharp BM, Roy S, Bidlack JM. Evidence for opioid receptors on cells involved in host defense and the immune system. J Neuroimmunol, 1998, 83: 45-56.
15. Azuma Y, Ohura K, Wang PL, et al. Endomorphins 1 and 2 modulate chemotaxis, phagocytosis and superoxide anion production by microglia. J Neuroimmunol, 2001, 119: 51-56.
1. Zadina JE, Hackler L, Ge LJ, et al. A potent and selective endogenous agonist for the mu-opiate receptor. Nature, 1997, 386: 499-502.
2. Bidlack JM, Khimich M, Parkhill AL,et al. Opioid receptors and signaling on cells from the immune system.J Neuroimmune Pharmacol, 2006,1(3):260-269
3. Belcheva MM, Haas PD, Tan Y, et al. The fibroblast growth factor receptor is at the site of convergence between mu-opioid receptor and growth factor signaling pathways in rat C6 glioma cells. J.Pharmacol.Exp.Ther, 2002, 303(3): 909-918.
4. Rozenfeld-Granot G, Toren A, Amariglio N, et al. MAP kinase activation by mu opioid receptor in cord blood CD34(+)CD38(-) cells. Exp.Hematol, 2002, 30(5): 473-480.
5. Fichna J, Janecka A, Costentin J, et al. The endomorphin system and its evolving neurophysiological role. Pharmacol.Rev, 2007, 59(1): 88-123.
6. Husted TL, Govindaswami M, Oeltgen PR, et al. A delta2-opioid agonist inhibits p38 MAPK and suppresses activation of murine macrophages. J.Surg.Res, 2005, 128 (1): 45-49.
7. Korzh A, Keren O, Gafni M, et al. Modulation of extracellular signal-regulated kinase (ERK) by opioid and cannabinoid receptors that are expressed in the same cell. Brain Res, 2008, 1189: 23-32.
8. Macey TA, Lowe JD, Chavkin C. Mu opioid receptor activation of ERK1/2 is GRK3 and arrestin dependent in striatal neurons. J.Biol.Chem, 2006, 281(45): 34515-34524.
9. Messmer D, Hatsukari I, Hitosugi N, et al. Morphine reciprocally regulates IL-10 and IL-12 production by monocyte-derived human dendritic cells and enhances T cell activation. Mol.Med, 2006, 12 (11-12): 284-290.
10. Fr?ssdorf J, Weber NC, Obal D, et al. Morphine induces late cardioprotection in rat hearts in vivo: the involvement of opioid receptors and nuclear transcription factor kappaB. Anesth.Analg, 2005, 101 (4): 934-41.
11. Azuma Y, Ohura K. Endomorphins 1 and 2 inhibit IL-10 and IL-12 production and innate immune functions, and potentiate NF-kappaB DNA binding in THP-1 differentiated to macrophage-like cells. Scand.J.Immunol, 2002, 56 (3): 260-269.
12. Roy S, Cain KJ, Chapin RB, et al. Morphine modulates NF kappa B activation in macrophages. Biochem.Biophys.Res.Commun, 1998, 245 (2): 392-396.
13. Qian C, Jiang X, An H, et al. TLR agonists promote ERK-mediated preferential IL-10 production of regulatory dendritic cells (diffDCs), leading to NK-cell activation. Blood, 2006,108 (7): 2307-2315.
14. Li Y, Chu N, Hu A, et al. Inducible IL-23p19 expression in human microglia via p38 MAPK and NF-kappaB signal pathways. Exp.Mol.Pathol, 2008,84 (1): 1-8.
15. Azuma Y, Ohura K, Wang PL, et al. Endomorphins 1 and 2 modulate chemotaxis, phagocytosis and superoxide anion production by microglia. J.Neuroimmunol, 2001, 119 (1): 51-56.
1. Wybran J, Plotnikoff NP. Methionine enkephalin,a new lymphokine for the treatment of ARC patients. In (Plotnikoff. N. Murgo. A,Faith R,Wybran,Jeds)Stress and Immun,CRC Press,Boca Raton,FL,1991:417-432.
2. Carr DJJ, Serou M. Exogenous and endogenous opioids as biological response modifiers. Immunopharmacology, 1995,31:59-71.
3. Roy S,Ramakrishnan S,Loh HH ,et al. Chronic morphine treatment: selectively suppress macrophage colony formation in bone marrow. Eur. J. Pharmacol, 1991a,195:359-363.
4. Sibinga NES and Goldstein A. Opioid peptides and opioid receptors in cells of the immune system. Ann. Rev. Immu nol,1988,6:219-249.
5. Zadina JE, Hackler L, Ge LJ, et al. A potent and selective endogenous agonist for theμ-opioid receptor. Nature,1997, 386: 499-502.
6. Fichna J, Janecka A, Costentin J, et al. The endomorphin system and its evolving neurophysiological role. Pharmacol Rev, 2007, 59: 88-123.
7. Liu H, Yang Y, Xin R, et al. Differential cardiovascular effects of synthetic peptides derived from endomorphin-1 in anesthetized rats. Peptides, 2008, 29(6):1048-1056.
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