鸡IL-18和IFN-γ协同抗病毒机制分析
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摘要
禽病毒性疾病如禽传染性法氏囊病(Infectious Bursal Disease,IBD)一直困扰着养禽业的健康、快速发展。在其他抗病毒感染的药物效果不理想时,有必要应用细胞因子制剂来改善机体免疫并提高抗病毒能力。已证明,鸡白细胞介素18(Chicken interleukin-18,Ch IL-18)和鸡干扰素γ(Chicken interferon,Ch IFN-γ)对多种病毒感染具有抑制作用。为了研究新型细胞因子制剂,该实验分析了鸡白细胞介素18(Chicken interleu-kin-18,Ch IL-18)和鸡干扰素γ(Chicken interferon,Ch IFN-γ)以及二者混合后的抗病毒机制。Ch IL-18和Ch IFN-γ蛋白注射雏鸡后7d内,应用试剂盒检测雏鸡体内血清中细胞因子的变化情况。利用鸡外周血单核细胞分析Ch IL-18和Ch IFN-γ对细胞内NO、几种Toll样受体(Toll-like receptors,TLR)及下游信号通路的影响。实验结果表明,混合组蛋白可刺激雏鸡血清中产生高水平IL-6,IL-12,及IL-17。混合组蛋白可以诱导巨噬细胞中NO的分泌水平显著升高,TLR 2、TLR 3、TLR 4和MHC-II的表达量升高,MAPK和NFκB信号通路被激活。综上结果表明,Ch IL-18和Ch IFN-γ以及二者协同可诱导机体对病毒感染产生有效的防御作用,为新型细胞因子制剂的研究提供参考。
The healthy and rapid development of poultry industry was troubled by avian viral diseases such as Infec-tious Bursal Disease(IBD). With other anti-viral drug effect is not ideal,it is necessary to use cytokine preparationsto improve the immune system and improve the anti-virus ability. Chicken interleukin-18(Ch IL-18)and chickeninterferon gamma(Ch IFN-γ)have been shown to inhibit a variety of viral infections. In order to study the novel cyto-kine preparations,the effects of Ch IL-18 and Ch IFN-γ and the two mixed antiviral mechanism was analyzed. The re-sults of this laboratory had showed that Ch IL-18 and Ch IFN-γ can inhibit IBDV proliferation in chickens,especial-ly with the mixed group,which indicates that the mixed group has better antiviral effect. Within 7 days after Ch IL-18 and Ch IFN-γ injection of chickens,the kit was used to detect the changes of cytokines in the chicks. The effects ofCh IL-18 and Ch IFN-γ on intracellular NO,several Toll-like receptors(TLR)and downstream signaling pathwayswere analyzed by using peripheral blood mononuclear cells of chickens. The results showed that the levels of IL-6,IL-12 and IL-17 in the serum stimulated by mixed group ware significantly different from those in the PBS group.Mixed group proteins could induce NO production,the expression levels of TLR2,TLR3,TLR4 and MHC-II were in-creased and MAPK and NFκB signaling were activated. These results indicated that the mixed group had a better the-oretical basis for antiviral ability,Ch IL-18 and Ch IFN-γ,both of which could induce the body to produce effectivedefense against virus infection and provide reference for the study of new cytokine preparations.
The healthy and rapid development of poultry industry was troubled by avian viral diseases such as Infec-tious Bursal Disease(IBD). With other anti-viral drug effect is not ideal,it is necessary to use cytokine preparationsto improve the immune system and improve the anti-virus ability. Chicken interleukin-18(Ch IL-18)and chickeninterferon gamma(Ch IFN-γ)have been shown to inhibit a variety of viral infections. In order to study the novel cyto-kine preparations,the effects of Ch IL-18 and Ch IFN-γ and the two mixed antiviral mechanism was analyzed. The re-sults of this laboratory had showed that Ch IL-18 and Ch IFN-γ can inhibit IBDV proliferation in chickens,especial-ly with the mixed group,which indicates that the mixed group has better antiviral effect. Within 7 days after Ch IL-18 and Ch IFN-γ injection of chickens,the kit was used to detect the changes of cytokines in the chicks. The effects ofCh IL-18 and Ch IFN-γ on intracellular NO,several Toll-like receptors(TLR)and downstream signaling pathwayswere analyzed by using peripheral blood mononuclear cells of chickens. The results showed that the levels of IL-6,IL-12 and IL-17 in the serum stimulated by mixed group ware significantly different from those in the PBS group.Mixed group proteins could induce NO production,the expression levels of TLR2,TLR3,TLR4 and MHC-II were in-creased and MAPK and NFκB signaling were activated. These results indicated that the mixed group had a better the-oretical basis for antiviral ability,Ch IL-18 and Ch IFN-γ,both of which could induce the body to produce effectivedefense against virus infection and provide reference for the study of new cytokine preparations.
引文
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[25]Harrison OJ,Srinivasan N,Pott J,et al.Epithelial-derived IL-18regulates Th17 cell differentiation and Foxp3 Treg cell function in the intestine[J].Mucosal Immunol,2015,8(6):1226-1236.
[26]Moreira AP,Dias-Melicio LA,Soares AM.Interleukin-10 but not Transforming Growth Factor beta inhibits murine activated macrophages Paracoccidioides brasiliensis killing:effect on H2O2and NO production[J].Cell Immunol,2010,263(2):196-203.
[27]Tamai R,Sugawara S,Takeuchi O,et al.Synergistic effects of lipopolysaccharide and interferon-γin iinducing interleukin-8production inhuman monocytic THP-1 cell is accompanied by up-regulation of CD14,Toll-like receptor 4,MD-2 andMy D88 expression[J].J Endotoxin Res,2003,9(3):145-153.
[28]Sweet MJ,Campbell CC,Sester DP,et al.Colony-stimulating factor-1 suppresses responses to Cp G DNA and expression of tolllike receptor 9 butenhances responses to lipopolysaccharide in murine macrophages[J].J Immunol,2002,168(1):392-399.
[29]Radstake TR,Roelofs MF,Jenniskens YM,et al.Expression of toll-like receptors 2 and 4 in rheumatoid synovial tissue and regulation by proinflammatory cytokines interleukin-12 and interleukin-18 via interferon-gamma[J].Arthritis Rheum,2004,50(12):3856-3865.
[30]Barois N,Forquet F,Davoust J.Actin microfilaments control the MHC class II antigen presentation pathway in B cells[J].J Cell Sci.,1998,111(Pt13):1791-1800.
[31]Held TK,Weihua X,Yuan L,et al.Gamma interferon augments macrophage activation by lipopolysaccharide by two distinct mechanisms,at the signal transduction level and via an autocrine mechansim involving tumor necrosis factor alpha andinterleukin-1[J].Infect Immun,1999,67(1):206-212.
[2]Nagano Y,Kojima Y.Interference of the inactive vaccinia vi-rus with infection of skin by the active homologous virus[J].C R Seances Soc Biol Fil,1958,152(2):372-374.
[3]Billiau A.Interferon:the pathways of discovery I.Molecular and cellular aspects[J].Cytokine Growth Factor Rev,2006,17(5):381-409.
[4]van Boxel-Dezaire AH,Rani MR,Stark GR.Complex modulation of cell type-specific signaling in response to type I interferons[J].Immunity,2006,25(3):361-372.
[5]Khabar KS,Young HA.Post-transcriptional control of the interferon system[J].Biochimie,2007,89(6-7):761-769.
[6]Al-Yahya S,Mahmoud L,Al-Zoghaibi F,et al.Human Cytokinome Analysis for Interferon Response[J].J Virol,2015,89(14):7108-7119.
[7]Tian S,Jiang C,Liu X,et al.Hypermethylation of IFN-γin oral cancer tissues[J].Clin Oral Investig,2017.
[8]Chu M,Xu L,Zhang MB,et al.Role of Baicalin in Anti-Influenza Virus A as a Potent Inducer of IFN-Gamma[J].Biomed Res Int,2015,2015:263630.
[9]Schroder K,Sweet MJ,Hume DA.Signal integration between IFNgamma and TLR signalling pathways in macrophages[J].Immunobiology,2006,211(6-8):511-524.
[10]Schroder K,Hertzog PJ,Ravasi T,et al.Interferon-gamma:an overview of signals,mechansims and functions[J].J Leukoc Biol,2004,75(2):163-189.
[11]Bigley NJ.Complexity of Interferon-γInteractions with HSV-1[J].Front Immunol,2014,5:15.
[12]Okamura H,Nagata K,Komatsu T,et al.Anovel costimulatory factor for gamma interferon induction found in the livers of mice causes endotoxicshock[J].Infect Immun,1995,63(10):3966-3972.
[13]Gracie JA,Robertson SE,Mc Innes IB.Interleukin-18[J].J Leukoc Biol,2003,73(2):213-224.
[14]Dinarello CA.Interleukin-18 and the pathogenesis of inflammatory diseases[J].Semin Nephrol,2007,27(1):98-114.
[15]Iannello A,Samarani S,Debbeche O,et al.Role of interleukin-18 in the development and pathogenesis of AIDS[J].AIDS Rev,2009,11(3):115-125.
[16]Smith DE.The biological paths of IL-1 family members IL-18 and IL-33[J].J Leukoc Biol,2011,89(3):383-392.
[17]Chaix J,Tessmer MS,Hoebe K,et al.Cutting edge:Priming of NK cells by IL-18[J].J Immunol,2008,181(3):1627-1631.
[18]Okamoto I,Kohno K,Tanimoto T,et al.Development of CD8+effector T cells is differentially regulated by IL-18 and IL-12[J].J Immunol,1999,162(6):3202-3211.
[19]Cao R,Farnebo J,Kurimoto M,et al.Interleukin-18 acts as an angiogenesis and tumor suppressor[J].FASEB J,1999,13(15):2195-2202.
[20]Szabo SJ,Sullivan BM,Peng SL,et al.Molecular mechanisms regulating Th1 immune responses[J].Annu Rev Immunol.2003;21:713-758.
[21]Sims JE,Smith DE.The IL-1 family:regulators of immunity[J].Nat Rev Immunol,2010,10(2):89-102.
[22]Qiao Y,Giannopoulou EG,Chan CH,et al.Synergistic activation of inflammatory cytokine genes by interferon-γ-induced chromatin remodeling and toll-like receptor signaling[J].Immunity,2013,39(3):454-469.
[23]Dias-Melicio LA,Fernandes RK,Rodrigues DR,et al.Interleukin-18 increase TLR4 and mannose receptor expression and modulates cytokine production inhuman monocytes[J].Mediators Inflamm,2015,2015:236839.
[24]Nakanishi K,Yoshimoto T,Tsutsui H,et al.Interleukin-18 is a unique cytokine that stimulates both Th1 and Th2 responses depending on its cytokinemilieu[J].Cytokine Growth Factor Rev,2001,12(1):53-72.
[25]Harrison OJ,Srinivasan N,Pott J,et al.Epithelial-derived IL-18regulates Th17 cell differentiation and Foxp3 Treg cell function in the intestine[J].Mucosal Immunol,2015,8(6):1226-1236.
[26]Moreira AP,Dias-Melicio LA,Soares AM.Interleukin-10 but not Transforming Growth Factor beta inhibits murine activated macrophages Paracoccidioides brasiliensis killing:effect on H2O2and NO production[J].Cell Immunol,2010,263(2):196-203.
[27]Tamai R,Sugawara S,Takeuchi O,et al.Synergistic effects of lipopolysaccharide and interferon-γin iinducing interleukin-8production inhuman monocytic THP-1 cell is accompanied by up-regulation of CD14,Toll-like receptor 4,MD-2 andMy D88 expression[J].J Endotoxin Res,2003,9(3):145-153.
[28]Sweet MJ,Campbell CC,Sester DP,et al.Colony-stimulating factor-1 suppresses responses to Cp G DNA and expression of tolllike receptor 9 butenhances responses to lipopolysaccharide in murine macrophages[J].J Immunol,2002,168(1):392-399.
[29]Radstake TR,Roelofs MF,Jenniskens YM,et al.Expression of toll-like receptors 2 and 4 in rheumatoid synovial tissue and regulation by proinflammatory cytokines interleukin-12 and interleukin-18 via interferon-gamma[J].Arthritis Rheum,2004,50(12):3856-3865.
[30]Barois N,Forquet F,Davoust J.Actin microfilaments control the MHC class II antigen presentation pathway in B cells[J].J Cell Sci.,1998,111(Pt13):1791-1800.
[31]Held TK,Weihua X,Yuan L,et al.Gamma interferon augments macrophage activation by lipopolysaccharide by two distinct mechanisms,at the signal transduction level and via an autocrine mechansim involving tumor necrosis factor alpha andinterleukin-1[J].Infect Immun,1999,67(1):206-212.