生物活性肽调节NF-κB信号通路的研究进展

doi:10.7506/spkx1002-6630-201321075

摘要/Abstract

摘要：

核转录因子-κB(nuclear factor-κB，NF-κB)是通过调节其靶基因的表达，在机体免疫应答、炎症与肿瘤的发生发展过程中发挥着重要功能，因此也被认为是调控免疫应答、预防和治疗肿瘤与炎症的理想靶点。生物活性肽具有许多的生理活性功能和独特的营养特性，可广泛地应用于保健食品和医药产品。本文首先概括NF-κB的组成、结构特点及其激活途径，从肽类调节NF-κB的机制出发，结合本实验室和国外学者最新的研究成果，对生物活性肽调节NF-κB相关研究进行系统的介绍，提出生物活性肽在一定程度上可以干预NF-κB信号通路，为生物活性肽作为相关疾病生物免疫治疗提供新的途径。

关键词: NF-&kappa, B；生物活性肽；调节机制；免疫应答

Abstract:

Nuclear factor-κB (NF-κB) has been reported to play an important role in immunity, inflammation and carcinogenesis
by regulating the expression of its target genes. Thus, NF-κB was recognized as a promising target for the prevention
and treatment of cancer and inflammation. Because bioactive peptides have many physiological functions and unique nutritional
properties, it can be widely used in the fields of functional foods and medicinal products. In this paper, the compositions,
structural characteristics and activation pathways of NF-κB are outlined. Recent research advances in the regulation
and therapeutic effects of bioactive peptides on NF-κB pathways are reviewed. Moreover, the future development prospects
of bioactive peptides are also proposed.

Key words: nuclear factor-&kappa, B (NF-&kappa, B)；bioactive peptide；regulatory mechanism；immune response

中图分类号:

R151

龚建苗，陈庆森*，阎亚丽，庞广昌. 生物活性肽调节NF-κB信号通路的研究进展[J]. 食品科学, 2013, 34(21): 379-388.

GONG Jian-miao，CHEN Qing-sen*，YAN Ya-li，PANG Guang-chang. Research Progress in Immune Regulation of Bioactive Peptides on NF-κB[J]. FOOD SCIENCE, 2013, 34(21): 379-388.

参考文献

1.A.S.A nucleosomal function for I kappa B kinase-alpha in NF-kappa B-dependent gene expression. Nature,2003,423,659-663.

2.ATHMAN R,PHILPOT T D.Innate immunity via Toll-like receptors and Nod proteins[J].Current opinion in microbiology,2004,7(1):25-32.

3.BEINKE S,LEY SC.Functions of NF-κB1 and NF-κB2 in immune cell biology[J]. Biochemical Journal, 2004,382(2):393-409.

4.DOYLE D A,CHAO J,HEIMANN D,etal.Effect of an NF-kB inhibitor on the cell population in the fibroblast-populated collagen matrix[J].Journal of Surgical Research, 2013,179(2):267.

5. GIESSEN T W, MARAHIEL M A. Ribosome-independent biosynthesis of biologically active peptides: application of synthetic biology to generate structural diversity[J]. FEBS letters, 2012, 586(15): 2065-2075.

6.庞广昌，陈庆森，胡志和,等.蛋白质的消化吸收及其功能评述[J]，食品科学，2013，34（09）：375-391

7.SEN R,BALTIMORE D.Multiple nuelear faetors inieraet with the irnmunoglobulin enhancer sequenees.Cell,1986,46(5):705-716.

8.GHOSH S,MAY MJ,KOPP EB. NF-kappa B and Rel proteins：evolutionardy conserved mediators of immune responses[J]A Rev Immunol.1998,16:225.

9.MILYAMOTO S,VERMAL M.REL/NF-κB/IκB story[J]Adv Cancer Res .1995,66:255-292.

10. MORRISON DC,BRADE H,OPAL S ,etal. Role of NF-κB in macrophage activation (review) in endotoxin in health and disease [M]．Marcel Dekker, N.Y.1999,502-520.

11.KARIN M.BEN-NERIAH Y.Phosphorylation meets ubiquitination:the control of NF-κB activity.Annu Rev Immunol,2000,18:621-663.

12.JANG IL,PHARM D,GILBERTil JB,eta1.Nuclear factor KappaB important transcription factor and therapeutic target[J].J Clin Pharmacol,1998,38:981-993.

13.ARENZANA-SEISDEDOS F,TURPIN P,RODRLGUEZ M,etal. Nuclear localization of I Kappa B alpha promotes active transport of NF-kappa B from the nucleus to the cytoptasm[J]Cett Sci,1997,110:369.

14.ZANDI E,ROTHWARF DM,DELHASE M, etal.The IκB kinase complex(IKK) contains two kinase subunits,IKKα and IKΚbeta,neeessary for IκB phosphorylation and NF-κB activation.Cell,1997,91(2):243-252.

15.邢飞跃,赵克森,姜勇.NF-κB的信号通路与阻断策略[J].中国病理生理杂志,2003,19(6):849-855.

16.YAMAMOTO Y, GAYNOR RB.IkappaB kinase: key regulators of the NF-kappaB pathway.Trends Biochem,Sci.29,2004,72-79.

17.PAUL N,MOYNAGH.the NF-kappaB pathway,Journal of Cell Science,2005,118(20):4589-4592.

18.ROTHWARF DM,ZANDI E,NATOLI G, etal.IKK-gamma is an essential regulatory subunit of the IκB kinase complex.Nature,1998,395(6699):297-300.

19.PERKINS ND,GILMORE TD.Good cop,bad cop:the different faces of NF-κB.Cell Death Differ,2006,13(5):759-772.

20.XIAO G,HARHAJ EW,SUN SC.NF-κB-inducing kinase regulates the proeessing of NF-κB 2 p100.Mol Cell,2001,7(2):401-409.

21.YAMANOTO N, EJIRI M,MIZUNO S. Biogenic peptides and their potential use [J].Curt Pharma Design,2003,9(16):1345-1355.

22.CLAREAND DA,SWAISGOOD HE. Bioactive milk peptides,a prospectus[J].JDairy Sci,2000,82(1):1187-11951

23.姜晓光,宋博,迟春萍,等.生物活性肽的生理功能及研究进展[J].微生物学杂志,2006,5(26):82-85

24.BERMAY B, BAUDY-FLOCH M, ZANUTTINI B, etal. Ovarian and sperm regulatory peptides regulate ovuration in the oyster Crassostrea gigas.Mol Reprod Dev,2006,73(5):607-616.

25.疏秀林，施庆珊，黄小茉，等.γ-聚谷氨酸及其衍生物在生物医学领域中的应用.中国组织工程研究,2012,16(16):3009-3012．

26.郭海艳，周文达．精子肽的固相合成及其在免疫性不孕诊断中的应用研究[J].现代检验医学杂志，2008，23(2)：66-68．

27.PINS JJ,KEENAN JM.Effects of whey peptides on cardiovascular disease risk factors[J ].J Clin Hypertens(Greenwich),2006,8(11):89.

28.WANG J,GREEN K,MCGIBBO G,etal.Analysis of effect of casein phosphopeptides on zinc binding using mass spectromety[J].Rapid Commun Mass Spectrom,2007,21(9):1546.

29. HERNANDEZ-LEDESMA B, HSIEH CC,etal. Lunasin, a novel seed peptide for cancer prevention[J]. Peptides, 2009, 30(2): 426-430.

30.吴建中,赵谋明,宁正祥.食品中的生物活性多肽[J].食品与发酵工业,2002, 28(11):46-50.

31.李勇.生物活性肽研究现况和进展[J],食品与发酵工业,2007,33(1):3-9.

32.CHAN KM,DECKER EA,MEANS WJ.Extraction and activity of carnosine ,a naturally occurring antioxidant in beef muscle[J].J Food Sci,1993,58(1):1-41.

33.葛轶群,愈建瑛,宋聿文,等.生物活性肽的研究进展[J].中国生物药物杂志,1998,19(6):404-406.

34.DUNNIK CA,GIBRAN BS,HEIMBACH DM,etal.Substance Phas a role in neurogenic mediation of human burn wound healing.J Burn Care Rehabil 1996,17:390-396.

35.蒋伟，王正国，赖西南,等.感觉神经肽SP在伤口愈合细胞因子网络调控中的作用[J].创伤外科杂志,2002,4(4):250-252．

36.LIEB K,FIEBICHi BL,BERGER M,etal. The neuropeptide substance P activates transcription factor NF-kappa B and kappa B-dependent gene expression in human astrocytoma cells[J]. The Journal of Immunology,1997,159(10):4952-4958.

37.IAN MARRIOTT,MICHAEL J MASON ,ADAM ELHOFY,etal.Substance P activates NF-κB independent of elevations in intracellular calcium in murine macrophages and dendritic cells[J]. Journal of Neuroimmunology，2000,102(2000):163-171.

38.蒋伟, 王正国, 赖西南,等.钙拮抗剂在P物质激活肉芽组织成纤维细胞核因子-κB中的作用[J].中华实验外科杂志,2004, 21(010):1194-1196.

39.SONHN S J. Substance P upregulates osteoclastogenesis by activating nuclear factor kappa B in osteoclast precursors[J].Actaoto-laryngologica,2005,125(2):130-133.

40.ESTEBAN F, MUNOZ M, GONZALEZ-MOLES MA, etal. A role for substance P in cancer promotion and progression: a mechanism to counteract intracellular death signals following oncogene activation or DNA damage[J]. Cancer and metastasis reviews, 2006, 25(1): 137-145.

41.SHARMA R,RAJPUT YS,MANN B.Chemical and functional properties of glycomacropeptide (GMP) and its role in the detection of cheese whey adulteration in milk:a review[J].Dairy science & technology,2013,93(1):21-43.

42.FAYED AE.Healthy multifunctional spectra of milk glycoproteins and their fragments-a review article[J].Polish Journal of Food and Nutrition Sciences,2012,62(3):125-142.

43.YANG Z.Endothelial NF-κB:the remote controller of the backyard fire in the vascular wall?[J]. Cardiovascular research,2013,97(1):8-9.

44.朱晨晨,陈庆森.乳源酪蛋白糖巨肽改善炎症性肠病的研究进展[J].食品科学,2012,33(01):262-266.

45.REQUENA P,DADDAOUA A,GUADIX E,etal.Bovine glycomacropeptide induces cytokine production in human monocytes through the stimulation of the MAPK and the NF‐κB signal transduction pathways[J]. British journal of pharmacology, 2009, 157(7):1232-1240.

46.尹俐.含硒谷胱甘肽硫转移酶的真核表达及抗氧化作用研究[D].吉林大学,2012.

47.胡圣尧,聂志妍,袁勤生.还原型谷胱甘肽的研究进展[J].食品与药品,2009,11(1):69-71.

48.江洁,单谚峰.谷胱甘肽的制备及其应用[J].饲料工业,2007,28(15):15-17．

49.BANDYOPADHYAY S, STARKE DW, MIEYAL JJ,etal. Thioltransferase (glutaredoxin) reactivates the DNA-binding activity of oxidation- inactivated nuclear factor I[J].J Biol Chem, 1998,273(1):392-397.

50.HADDAD JJ, LAND SC. Redox signaling-mediated regulation of lipopolysaccharide-induced proinflammatory cytokine biosynthesis in alveolar epithelial cells [J]. Antioxid Redox Signal, 2002,4(1):179-193.

51.ARMSTRONG JS,STEINAUER KK,HORNUNG B,etal.Role of glutathione depletion and reactive oxygen species generation in apoptotic signaling in a human B lymphoma cell line[J].Cell Death Differ,2002,9(3):252-263.

52.赵兵,张华茹,李海明,等.还原型谷胱甘肽在不同潮气量机械通气对大鼠肺细胞凋亡的影响[J].中国实用医刊,2011,38(8):40-41.

53.RAHMAN I. Regulation of nuclear factor-kappa B, activator protein-1, and glutathione levels by tumor necrosis factor-alpha and dexamethasone in alveolar epithelial cells[J].Biochemical pharmacology,2000,60(8):1041.

54.FRATERNAL A,CRINELLI R,CASABIANCA A,etal.Molecules Altering the Intracellular Thiol Content Modulate NF-κB and STAT-1/IRF-1 Signalling Pathways and IL-12 p40 and IL-27 p28 Production in Murine Macrophages[J].PLOS ONE,2013,8(3):e57866.

55.DESTOUMIEUX D, MUNOZ M, BULET P, etal. Penaeidins, a family of antimicrobial peptides from penaeid shrimp (Crustacea, Decapoda)[J]. Cellular and Molecular Life Sciences CMLS,2000,57(8-9): 1260-1271.

56.舒黛廉，任敏，王珏.抗菌肽研究现状及其在畜牧业中的应用前景[J].中国畜牧医药,2007,34（6）:100-106.

57.吴甜甜，赵景.天然抗菌肽的研究进展及应用前景[J].新疆大学生命科学与技术学院.生物技术通报,2009（1）:27-29.

58.李曼,曹晓梅,陈薇.昆虫抗菌肽的生物学特点及药物研发进展[J].生物技术通讯,2007,18（4）:706-709.

59.PENG KS,SHE RP,YANG YR,etal. Anti-adherence of antibacterial peptides and oligosaccharides and promotion of growth and disease resistance in tilapia[J].Asian-Australasian Journal of Animal Sciences,2007,20(4):569-576.

60.KIMBRELL DAM,BEUTLER B. The evolution and genetics of innate immunity[J].Nature Rev Genet,2001(2):256-267.

61.CHEN JY,LIN WJ,LIN TL.A fish antimicrobial peptide，tilapia hepeidin TH2-3,shows potent antitumor activity against human fibrosarcoma cells[J].Peptides,2009.30:1636-1642．

62.CHEN JY,LIN WJ,WU JL,eta1.Epinecidin-1 peptide induces apoptosis which enhances antitumor efects in human leukemia U937 cells[J].Peptides,2009,30:2365-2373．

63.LIN WJ,CHIEN YL,PAN CY,eta1.Epinecidin-1,an antimicrobial peptide from fish(inephelus coioides)which has an antitumor efect like lytic peptides in human fibrosarcoma cell[J].Peptides,2009,30:283-290.

64.GAO Y,LECKER S,POST MJ,etal.Inhibition of ubiquitin-proteasome pathway–mediated IκBα degradation by a naturally occurring antibacterial peptide[J].Journal of Clinical Investigation,2000,106(3):439.

65.BAO J,SATO K,LI M,etal.PR-39 and PR-11 peptides inhibit ischemia-reperfusion injury by blocking proteasome-mediated IκBα degradation[J]. American Journal of Physiology-Heart and Circulatory Physiology,2001,281(6):H2612-H2618.

66.HATTORI Y,JOJIMA T,TOMIZAWA A,etal.RETRACTED ARTICLE: A glucagon-like peptide-1 (GLP-1) analogue, liraglutide, upregulates nitric oxide production and exerts anti-inflammatory action in endothelial cells[J]. Diabetologia, 2010, 53(10): 2256-2263.

67.HUANG J,Li X,Li M,etal.Mitochondria-Targeted Antioxidant Peptide SS31 Protects the Retinas of Diabetic Rats[J].Current molecular medicine,2013,13(6):935-945.

68.JEON BJ,YANG Y,KYUNG SHIM S,etal.Thymosin Beta-4 Promotes Mesenchymal Stem Cell Proliferation Via An Interleukin-8-Dependent Mechanism[J].Experimental cell research,2013,4(14):1-9.

69.李辉,曹建国.重组血管基膜衍生多功能肽对肺腺癌A549细胞信号蛋白磷酸化水平的影响[J].中南药学,2012,10(2):85-88.

70.HADDAD JJ,HANBALI LH.The Anti-inflammatory and immunomodulatory activity of thymulin peptide is NF-κB-dependent and involves the downregulation of IκB-α[J]. American Journal of Medical and Biological Research,2013,1(2):41-49.

71.YANG R, PEI X, WANG J, etal. Protective effect of a marine oligopeptide preparation from Chum Salmon (Oncorhynchus keta) on radiation‐induced immune suppression in mice[J]. Journal of the science of food and agriculture, 2010, 90(13): 2241-2248.

72. MILLER SC,HUANG R,SAKAMURU S,etal.Identification of known drugs that act as inhibitors of NF-κB signaling and their mechanism of action[J].Biochemical pharmacology,2010,79(9):1272-1280.