NLRP3炎性小体介导的炎性过程在肠易激综合征发生中的作用
|
摘要
研究背景：
肠道菌群失调及炎性反应在肠易激综合征IBS中的作用机制尚不完全清楚。IL-lbeta是主要由单核巨噬细胞合成分泌的重要炎性介质,它对胃肠分泌和运动有影响,还可使胃肠道胆碱能神经对乙酰胆碱及其他炎性介质的敏感性增高。IBS患者单核细胞给予脂多糖LPS的诱导后IL-lbeta基线水平则会较健康对照显著增高。这让我们关注到了IL-1beta释放的信号传导通路,第一信号由Toll样受体和细菌LPS结合,诱导IL-1beta前体合成；第二信号通过激活NLRP3炎性小体使IL-lbeta前体转化成有生物活性的IL-lbeta. NLRP3炎性小体是一种多蛋白复合物,可以被多种细菌所激活,它在IBS患者和健康对照组之间的差异对于我们研究肠道菌群失调在IBS中的作用具有重要的意义。
目的：
通过检测IBS患者NLRP3信号传导通路改变分析NLRP3炎性小体介导的IL-lbeta的释放的炎性过程在IBS发生机制中的作用。(?)方法：
乙状结肠粘膜标本取自36例IBS患者(腹泻型16例,便秘型20例)、18例正常对照、18例溃疡性结肠炎患者(阳性对照)。应用免疫组织化学法测定结肠粘膜NLRP3的表达量,应用ELISA法检测结肠粘膜中caspase-1和IL-1beta含量。
结果：
腹泻组和便秘组结肠粘膜IL-1beta含量均值(48.33±15.72 VS 49.46±23.47 VS 38.26±13.24)和caspase-1含量均值(527.24±381.60 VS 559.45±299.28 VS 426.06±274.49)较正常组升高,但无显著性差异(P>0.05)。
溃结组、腹泻组、便秘组分别与正常对照组比较结肠粘膜NLRP3免疫组织化学染色间质阳性细胞计数(248.62±34.91 VS 109.88±33.71 VS115.50±31.37 VS 27.38±10.86)和平均光密度(225.20±19.04VS 178.37±23.85VS180.62±39.07VS 153.87±20.03)均有显著差异(P值均<0.05)。
正常对照组的结肠粘膜IL-1beta含量分别与结肠粘膜NLRP3免疫组织化学染色间质阳性细胞计数和结肠粘膜NLRP3免疫组织化学染色间质平均光密度有很好的相关性(P<0.05),而腹泻组和便秘组中结肠粘膜IL-1beta含量与结肠粘膜NLRP3免疫组织化学染色间质阳性细胞计数和结肠粘膜NLRP3免疫组织化学染色间质平均光密度无相关性(P>0.05)。
结论：
IBS患者乙状结肠粘膜间质中NLRP3含量高于正常对照组,其乙状结肠粘膜中caspase-1和IL-1beta的含量部分患者较正常对照组增加。
与正常对照组相比,IBS患者乙状结肠粘膜间质中NLRP3表达量与结肠粘膜IL-1beta含量不成比例,这提示IBS患者肠粘膜单核巨噬细胞NLRP3表达量增加,但只有部分IBS患者被激活。
单核、巨噬细胞中NLRP3表达量增高,提高了肠易激综合征患者对病原微生物刺激的敏感性,从而导致有病原微生物的作用的患者或肠段,存在NLRP3炎性小体介导的IL-1beta合成分泌的显著增加。
Objective:
Detect changes of NLRP3 signal transduction pathway to analyze NLRP3-mediated IL-lbeta release inflammatory process in the irritable bowel syndrome pathogenesis.
Methods:
Sigmoid colon mucosa specimens were collection from 36 patients with IBS (16 cases of diarrhea IBS, constipation IBS in 20 cases) and 18 normal controls,18 patients with ulcerative colitis (positive control). Immunohistochemical staining determined the NLRP3 expression of colonic mucosa and we applied ELISA assay to detact caspase-1 and IL-lbeta levels of the mucosa.
Result:
Caspase-1 and IL-lbeta levels of sigmoid colon mucosa increased in patients with irritable bowel syndrome, but no statistical significance,
In the NLRP3 Immunohistochemistry staining,the positive cells number and the mean density of the colon interstitial mucosa was higher in the IBS group than the normal control group.
IL-lbeta levels and NLRP3 expression of interstitial colon,including positive cells and mean density, had good correlation in the normal control group. IL-1beta levels and NLRP3 expression of interstitial colon had poor correlation in the IBS group.
Conclusions:
NLRP3 expression of the sigmoid colon interstitial mucosa was higher in the IBS group than the normal control group. Caspase-1 and IL-lbeta levels of sigmoid colon mucosa increased iust in some patients with irritable bowel syndrome.
Compared with normal controls,the expression of NLRP3 in colon interstitial didn't match the colon IL-lbeta levels in patients with irritable bowel syndrome. This suggests that NLRP3 expression of monocytes and macrophages was higher in the IBS group,while NLRP3 inflammasome only activated in part of the patients.
Increased expression of NLRP3 in monocytes and macrophages improved the sensitivity to the stimulation of the pathogenic microorganisms. So when the pathogenic microorganisms interact with the intestinal mucosa,the NLRP3 inflammasome mediated synthesis and secretion of IL-lbeta significantly increasd in patients with IBS.
肠道菌群失调及炎性反应在肠易激综合征IBS中的作用机制尚不完全清楚。IL-lbeta是主要由单核巨噬细胞合成分泌的重要炎性介质,它对胃肠分泌和运动有影响,还可使胃肠道胆碱能神经对乙酰胆碱及其他炎性介质的敏感性增高。IBS患者单核细胞给予脂多糖LPS的诱导后IL-lbeta基线水平则会较健康对照显著增高。这让我们关注到了IL-1beta释放的信号传导通路,第一信号由Toll样受体和细菌LPS结合,诱导IL-1beta前体合成；第二信号通过激活NLRP3炎性小体使IL-lbeta前体转化成有生物活性的IL-lbeta. NLRP3炎性小体是一种多蛋白复合物,可以被多种细菌所激活,它在IBS患者和健康对照组之间的差异对于我们研究肠道菌群失调在IBS中的作用具有重要的意义。
目的：
通过检测IBS患者NLRP3信号传导通路改变分析NLRP3炎性小体介导的IL-lbeta的释放的炎性过程在IBS发生机制中的作用。(?)方法：
乙状结肠粘膜标本取自36例IBS患者(腹泻型16例,便秘型20例)、18例正常对照、18例溃疡性结肠炎患者(阳性对照)。应用免疫组织化学法测定结肠粘膜NLRP3的表达量,应用ELISA法检测结肠粘膜中caspase-1和IL-1beta含量。
结果：
腹泻组和便秘组结肠粘膜IL-1beta含量均值(48.33±15.72 VS 49.46±23.47 VS 38.26±13.24)和caspase-1含量均值(527.24±381.60 VS 559.45±299.28 VS 426.06±274.49)较正常组升高,但无显著性差异(P>0.05)。
溃结组、腹泻组、便秘组分别与正常对照组比较结肠粘膜NLRP3免疫组织化学染色间质阳性细胞计数(248.62±34.91 VS 109.88±33.71 VS115.50±31.37 VS 27.38±10.86)和平均光密度(225.20±19.04VS 178.37±23.85VS180.62±39.07VS 153.87±20.03)均有显著差异(P值均<0.05)。
正常对照组的结肠粘膜IL-1beta含量分别与结肠粘膜NLRP3免疫组织化学染色间质阳性细胞计数和结肠粘膜NLRP3免疫组织化学染色间质平均光密度有很好的相关性(P<0.05),而腹泻组和便秘组中结肠粘膜IL-1beta含量与结肠粘膜NLRP3免疫组织化学染色间质阳性细胞计数和结肠粘膜NLRP3免疫组织化学染色间质平均光密度无相关性(P>0.05)。
结论：
IBS患者乙状结肠粘膜间质中NLRP3含量高于正常对照组,其乙状结肠粘膜中caspase-1和IL-1beta的含量部分患者较正常对照组增加。
与正常对照组相比,IBS患者乙状结肠粘膜间质中NLRP3表达量与结肠粘膜IL-1beta含量不成比例,这提示IBS患者肠粘膜单核巨噬细胞NLRP3表达量增加,但只有部分IBS患者被激活。
单核、巨噬细胞中NLRP3表达量增高,提高了肠易激综合征患者对病原微生物刺激的敏感性,从而导致有病原微生物的作用的患者或肠段,存在NLRP3炎性小体介导的IL-1beta合成分泌的显著增加。
Objective:
Detect changes of NLRP3 signal transduction pathway to analyze NLRP3-mediated IL-lbeta release inflammatory process in the irritable bowel syndrome pathogenesis.
Methods:
Sigmoid colon mucosa specimens were collection from 36 patients with IBS (16 cases of diarrhea IBS, constipation IBS in 20 cases) and 18 normal controls,18 patients with ulcerative colitis (positive control). Immunohistochemical staining determined the NLRP3 expression of colonic mucosa and we applied ELISA assay to detact caspase-1 and IL-lbeta levels of the mucosa.
Result:
Caspase-1 and IL-lbeta levels of sigmoid colon mucosa increased in patients with irritable bowel syndrome, but no statistical significance,
In the NLRP3 Immunohistochemistry staining,the positive cells number and the mean density of the colon interstitial mucosa was higher in the IBS group than the normal control group.
IL-lbeta levels and NLRP3 expression of interstitial colon,including positive cells and mean density, had good correlation in the normal control group. IL-1beta levels and NLRP3 expression of interstitial colon had poor correlation in the IBS group.
Conclusions:
NLRP3 expression of the sigmoid colon interstitial mucosa was higher in the IBS group than the normal control group. Caspase-1 and IL-lbeta levels of sigmoid colon mucosa increased iust in some patients with irritable bowel syndrome.
Compared with normal controls,the expression of NLRP3 in colon interstitial didn't match the colon IL-lbeta levels in patients with irritable bowel syndrome. This suggests that NLRP3 expression of monocytes and macrophages was higher in the IBS group,while NLRP3 inflammasome only activated in part of the patients.
Increased expression of NLRP3 in monocytes and macrophages improved the sensitivity to the stimulation of the pathogenic microorganisms. So when the pathogenic microorganisms interact with the intestinal mucosa,the NLRP3 inflammasome mediated synthesis and secretion of IL-lbeta significantly increasd in patients with IBS.
引文
[1]. Saito YA, Schoenfeld P, et al. The epidemiology of irritable bowel Byndrome in North America:a systematic review[J]. Am J Gastroenterol,2002,97(8): 1910-1915.
[2]. Xiong LS, Chen MH, et al. A population-based epidemiologic study of irritable bowel syndrome in South China:stratified randomized study by cluster sampling. Aliment Pharmacol Ther.,2004,19(11):1217-1224.
[3]. Bamngart DC, DiguassAU, et al. Intestinal barrier function. CurtOpin Clin Nutr Metab Care,2002,5(6):685-694.
[4]. Gagnon M, Kheadr EE, Le Blay G, et al. In vitro inhibition of Escherichia coli 0157:H7 by bifidobacterial strains of human origin. Int J Food Microbiol,2004, 92(1):69-78.
[5]. Van der, Waaij D, et al. History of recognition and measurement of colonization resistance of the digestive tract as an introduction to selective gastrointestinal decontamination. Epidemiol Infec,1992,109(3):315-326.
[6]. Si J M, Yu YC, Fan YJ, et al. Intestinal microecology and quality of life in irritable bowel syndrome patients. World J Gastroenterol,2004,10(12): 1802-1805.
[7]. Osipov GA, Parfenov AI, Verkhovtseva NV,et al. Clinical significance of studies of microorganisms of the intestinal mucosaby culture biochemical methods and mass fragmentography Eksp Klin.Gastroenterol,2003, (4): 59-67,115.
[8]. Malinen E, Rinttila T, Kajander K, et al. Analysis of the fecal microbiota of irritable bowel syndrome patients and healthy controls with real-time PCR Am J Gastroenterol,2005,100(2):373-382.
[9]. Neal KR, Hebden J, Spiller R, et al. Prevalence of gastrointeslinal symptoms six months after bacterial gastroenteritis and risk factors for development of the irritable bowel syndrome:postal survey of patients. BMJ,1997,31(4):779-782.
[10]. Marshall JK, Thabane M, et al. Postinfectious irritable bowel syndrome after a food-borne outbreak of acute gastroenteritis attributed to a viral pathogen. Clin Gastroenterol Hepatol,2007,5(4):457-460.
[11]. Giacometti A, Cirioni O, et al. In vitro anticryptosporidial activity of ranalexin alone and in combination with other peptides and with hydrophobic antibiotics,1999,18(11):827-829.
[12]. Spiller RC, Jenkins D, et al. Increased rectal mucosal enteroendocrine cells, T lymphocytes, and increased gut permeability following acute Campylobacter enteritis and in post-dysenteric irritable bowel syndrome. Gut,2000,47 (6):804-811.
[13]. Dunlop SP, Jenkins D, Neal KR, et al. Relative importance of enterochroniaffin cell hyperplasia, anxiety, and depression in postinfectious IBS. Gastroenterology,2003,125(6):1651-1659。
[14]. Spiller RC, Jenkins D, Thornley JP, et al. Increased rectal mucosal enteroendocrine cells, T lymphocytes, and increased gut permeability following acute Campylobacter enteritis and in post-dysenteric irritable bowel syndrome. Gut,2000,47(6):804-811.
[15]. Chadwick VS, Chen W, Shu D, et al. Activation of the mucosal immune system in irritable bowel syndrome. Gastroenterology,2002,122(7): 1778-1783.
[16]. Gronsalkorale W M, Perrey C, Pravica V, et al. Interleukin 10 genotypes in irritable bowel syndrome:evidence for an inflammatory component?Gut, 2003,52(1):91-93.
[17]. Palsson OS, Morteau O.Elevated vasoactive intestinal peptide concentrations in patients with irritable bowel syndrome. Digestive Diseases and Sciences.2004,49(7):1236-1243.
[18]. Gwee KA, Collins SM, et al. Increased rectal mucosal expression of interleukin 1beta in recently acquired post-infectious irritable bowel syndrome. Gut,2003,52(4):523-526.
[19]. Wang LH, Fang XC, Pan GZ. Bacillary dysentery as a causative factor of irritable bowel syndrome and its pathogenesis. Gut,2004,53(8):1096-1101.
[20].宋继中,王巧民等.肠易激综合征患者血清IL-1β、IL-10及皮质醇变化的研究.现代诊断与治疗,2005,16(2)：68-69.
[21].宋继中,王巧民,肠易激综合征患者结肠黏膜神经肽和IL-1β变化及其意义.胃肠病学和肝病学杂志,2007,16(3)：219-222.
[22]. Liebregts T, Adam B.Immune activation in patients with irritable bowel syndrome. Gastroenterology.2007,132(3):913-920.
[23]. Gross O, Poeck H, et al. Syk kinase signalling couples to the Nlrp3 inflammasome for anti-fungal hostdefence. Nature,2009,459(7245):433-436.
[24]. Jin Y, Mailloux CM, et al.NALP1 in vitiligo-associated multiple autoimmune disease. N Engl J Med,2007,356(12):1216-1225.
[25]. Miao EA, Alpuche-Aranda CM, et al.Cytoplasmic flagellin activates caspase-1 and secretion of interleukin lbeta via Ipaf. Nat Immunol, 2006,7(6):569-575.
[26]. Agostini L, Martinon F, et al. NALP3 forms an IL-lbeta processing inflammasome with increased activity in Muckle-Wells autoinflammatory disorder. Immunity,2004,20(3):319-325.
[27]. Zaiss AK, Vilaysane A, et al.Antiviral antibodies target adenovirus to phagolysosomes and amplify the innate immune response.J Immunol,2009,182(11):7058-7068.
[28]. Mariathasan S,Weiss DS, et al. Cryopyrin activates the inflammasome in response to toxins and ATP. Nature 2006;440(7081):228-232.
[29]. Warren SE, Mao DP, Rodriguez AE, Miao EA, Aderem A. Multiple Nod-like receptors activate caspase 1 during Listeria monocytogenes infection. J Immunol,2008,180(1):7558-7564.
[30]. Duncan JA, Gao X, et al.Neisseria gonorrhoeae activates the proteinase cathepsin B to mediate the signaling activities of the NLRP3 and ASC-containing inflammasome.J Immunol,2009,182(10):6460-6469.
[31]. Willingham SB, Bergstralh DT, et al. Microbial pathogen-induced necrotic cell death mediated by the inflammasome components CIAS1/cryopyrin/NLRP3 and ASC. Cell Host Microbe,2007,2(3):147-159.
[32]. Hise AG, Tomalka J, et al.An Essential Role for the NLRP3 Inflammasome in Host Defense against the Human Fungal Pathogen Candida albicans. Cell Host Microbe,2009,5(5):487-497.
[33]. Craven RR, Gao X, et al.Staphylococcus aureus alpha-hemolysin activates the NLRP3-inflammasome in human and mouse monocytic cells. PLoS One,2009,4(10):e7446.
[34]. Franchi L, Eigenbrod T, et al.The inflammasome:a caspase-1-activation platform that regulates immune responses and disease pathogenesis.Nat Immunol,2009,10(3):241-247.
[35]. Mihai G.N, Claudia A, et al.Differential requirement for the activation of the inflammasome for processing and release of IL-1_ in monocytes and macrophages. Blood,2009,113 (10):2324-2335.
[36]. Nakamura Y, Kambe N,et al. Mast cells mediate neutrophil recruitment and vascular leakage through the NLRP3 inflammasome in histamine-independent urticaria.J Exp Med,2009,206(5):1037-1046.
[37]. Kambe N, Nakamura Y,et al.The Inflammasome, an Innate Immunity Guardian, Participates in Skin Urticarial Reactions and Contact Hypersensitivity.Allergol Int.,2010,59(2). [Epub ahead of print]
[38]. Bauer C, Duewell P,et al. Colitis induced in mice with dextran sulfate sodium (DSS) is mediated by the NLRP3 inflammasome.Gut,2010 May 4. [Epub ahead of print]
[39]. Gross O, Poeck H,et al.Syk kinase signalling couples to the Nlrp3 inflammasome for anti-fungal host defence.Nature,2009,459(7245):433-436
[40]. Hornung V, Bauernfeind F, et al.Silica crystals and aluminum salts activate the NALP3 inflammasome through phagosomal destabilization. Nat Immunol, 2008,9(8):847-856.
[41]. Meissner F, Molawi K, Zychlinsky A.Superoxide dismutase 1 regulates caspase-1 and endotoxic shock. Nat Immunol,2008,9(8):866-872.
[42]. Meng G, Zhang F,et al. A mutation in the Nlrp3 gene causing inflammasome hyperactivation potentiates Th17 cell-dominant immune responses. Immunity, 2009,30(6):860-874.
[43].朱峰,钱家鸣,潘国宗,杨晓鸥.白介素1β和8 mRNA表达等指标监测溃疡性结肠炎活动的应用.中国医学科学学院学报,1999,21(5).
[44]. Thomas PG, Dash P,et al.The intracellular sensor NLRP3 mediates key innate and healing responses to influenza A virus via the regulation of caspase-1.Immunity,2009,30(4):566-575.
[45]. Hebden JM, Erah PO, et al. Increased small bowel but not colonic permeability in post-infectious irritable bowel syndrome. Gastroenterology,114(1):A763.
[1]. Saito YA, Schoenfeld P, et al. The epidemiology of irritable bowel Byndrome in North America:a systematic review[J]. Am J Gastroenterol,2002,97(8): 1910-1915.
[2]. Xiong LS, Chen MH, et al. A population-based epidemiologic study of irritable bowel syndrome in South China:stratified randomized study by cluster sampling. Aliment Pharmacol Ther.,2004,19(11):1217-1224.
[3].中华医学会消化病学分会胃肠动力学组.肠易激综合征诊断和治疗的共识意见[J].中华消化杂志,2008,28：38-40.
[4]. Bamngart DC, DiguassAU, et al. Intestinal barrier function. CurtOpin Clin Nutr Metab Care,2002,5(6):685-694.
[5]. Gagnon M, Kheadr EE, Le Blay G, et al. In vitro inhibition of Escherichia.coli 0157:H7 by bifidobacterial strains of human origin. Int J Food Microbiol,2004, 92(1):69-78.
[6]. Van der, Waaij D, et al.. History of recognition and measurement of colonization resistance of the digestive tract as an introduction to selective gastrointestinal decontamination. Epidemiol Infec,1992,109(3):315-326.
[7]. Si J M, Yu YC, Fan YJ, et al. Intestinal microecology and quality of life in irritable bowel syndrome patients. World J Gastroenterol,2004,10(12): 1802-1805.
[8]. Osipov GA, Parfenov AI, Verkhovtseva NV,et al. Clinical significance of studies of microorganisms of the intestinal mucosaby culture biochemical methods and mass fragmentography Eksp Klin.Gastroenterol,2003, (4):59-67,115.
[9]. Malinen E, Rinttila T, Kajander K, et al. Analysis of the fecal microbiota of irritable bowel syndrome patients and healthy controls with real-time PCR Am J Gastroenterol,2005,100(2):373-382.
[10]. Carrara M, Desideri S, et al. Small intestine bacterial overgrowth in patients with irritable bowel syndrome. Eur Rev Med Pharmacol Sci, 2008,12(3):197-202.
[11]. Pimentel M, Chow EJ, Lin HC, et al. Normalization of lactulose breath testing correlates with symptom improvement in irritable bowel syndrome:a double-blind, randomized, placebo controlled study. Am J Gastroenterol,2003, 98(2):412-419.
[12]. Neal KR, Hebden J, Spiller R, et al. Prevalence of gastrointeslinal symptoms six months after bacterial gastroenteritis and risk factors for development of the irritable bowel syndrome:postal survey of patients. BMJ, 1997,31(4):779-782.
[13]. Marshall JK, Thabane M, et al. Postinfectious irritable bowel syndrome after a food-borne outbreak of acute gastroenteritis attributed to a viral pathogen. Clin Gastroenterol Hepatol,2007,5(4):457-460.
[14]. Giacometti A, Cirioni O, et al. In vitro anticryptosporidial activity of ranalexin alone and in combination with other peptides and with hydrophobic antibiotics,1999,18(11):827-829.
[15]. Marshall JK, Thabane M, et al.Incidence and epidemiology of irritable bowel syndrome after a large waterborne outbreak of bacterial dysentery. Gastroenterology,2006,131(2):445-450; quiz 660.
[16]. Wang LH, Fang XC, Pan GZ. Bacillary dysentery as a causative factor of irritable bowel syndrome and its pathogenesis. Gut,2004,53(8):1096-1101.
[17]. Coates MD, Mahoney CR,et al. Molecular defects in mucosal serotonin content and decreased serotonin reuptake transporter in ulcerative colitis and irritable bowel syndrome.Gastroenterology,2004,126(7):1657-1664.
[18]. Gwee KA, Leong YL, et al.The role of psychological and biological factors in postinfective gut dysfunction. Gut,1999; 44(3):400-406.
[19]. Dunlop SP, Jenkins D, Neal KR, et al. Relative importance of enterochroniaffin cell hyperplasia, anxiety, and depression in postinfectious IBS. Gastroenterology,2003,125(6):1651-1659。
[20]. Dunlop SP, Jenkins D, Spiller RC. Age-related decline in rectal mucosal lymphocytes and mast cells. Eur J Gastroenterol Hepatol 2004; 16(10):
1011-1015.
[21]. Spiller RC, Jenkins D, Thornley JP, et al. Increased rectal mucosal enteroendocrine cells, T lymphocytes, and increased gut permeability following acute Campylobacter enteritis and in post-dysenteric irritable bowel syndrome. Gut,2000,47(6):804-811.
[22]. Chadwick VS, Chen W, Shu D, et al. Activation of the mucosal immune system in irritable bowel syndrome. Gastroenterology,2002,122(7):1778-1783.
[23]. Spiller RC, Jenkins D, et al. Increased rectal mucosal enteroendocrine cells, T lymphocytes, and increased gut permeability following acute Campylobacter enteritis and in post-dysenteric irritable bowel syndrome. Gut,2000,47 (6):804-811.
[24]. Adam B, Liebregts T, et al. Severity of mucosal inflammation as a predictor for alterations of visceral sensory function in a rat model.Pain.,2006,123(1-2):179-186.
[25]. Gronsalkorale W M, Perrey C, Pravica V, et al. Interleukin 10 genotypes in irritable bowel syndrome:evidence for an inflammatory component?Gut, 2003,52(1):91-93.
[26]. Gwee KA, Collins SM, et al. Increased rectal mucosal expression of interleukin 1beta in recently acquired post-infectious irritable bowel syndrome. Gut,2003,52(4):523-526.
[27]. Gross O, Poeck H, et al. Syk kinase signalling couples to the Nlrp3 inflammasome for anti-fungal hostdefence. Nature,2009,459(7245):433-436.
[28].朱峰,钱家鸣,潘国宗,杨晓鸥.白介素1β和8 mRNA表达等指标监测溃疡性结肠炎活动的应用.中国医学科学学院学报,1999,21(5).
[29]. Abdul-Sater AA, Said-Sadier N, et al. Inflammasomes bridge signaling between pathogen identification and the immune response.Drugs Today (Barc), 2009,45 Suppl B:105-112.
[30]. Martinon F,Tschopp J. NLRs join TLRs as innate sensors of pathogens[J].Trends Immunol,2005,26(8):447-454.
[31]. Da Silva Correia J, Miranda Y,et al.SGT1 is essential for Nod1 activation. Proc Natl Acad Sci USA,2007,104(16):6764-6769.
[32]. Franchi L, Warner N, et al.Function of Nod-like receptors in microbial recognition and host defense. Immunol Rev,227(1):106-128.
[33]. Chamailard M,Philpott D,et al.Gene-environment interaction modulated by allelic heterogeneity in inflammatory diseases.Proc Natl Acad Sci USA,2003,100(6):3455-3460.
[34]. Carneiro LA, Philpott DJ,et al.Innate immune recognition of microbes through Nod1 and Nod2 implications for disease.Microbes Infect,2004,6(6):609-616.
[35]. Girardin SE,Boneca IG, et al.Nodl detects a unique muropeptide from Gram-negative bacterial poptidoglycan. Science,2003,300(5625):1582-1587.
[36]. Boyden ED, Dietrich WF. Nalplb controls mouse macrophage susceptibility to anthrax lethal toxin. Nat Genet,2006,38(2):240-244.
[37]. Hsu LC, Ali SR, et al.A NOD2-NALP1 complex mediates caspase-1-dependent IL-lbetasecretion in responseto Bacillus anthracis infection and muramyl dipeptide. Proc Natl Acad Sci USA,2008,105(22):7803-7808.
[38]. Jin Y, Mailloux CM, et al.NALP1 in vitiligo-associated multiple autoimmune disease. N Engl J Med,2007,356(12):1216-1225.
[39]. Sutterwala FS, Mijares LA, et al. Immune recognition of Pseudomonas aeruginosa mediated by the IPAF/NLRC4 inflammasome.J Exp Med, 2007,204(13):3235-3245.
[40]. Miao EA, Alpuche-Aranda CM, et al.Cytoplasmic flagellin activates caspase-1 and secretion of interleukin lbeta via Ipaf. Nat Immunol, 2006,7(6):569-575.
[41]. Suzuki T, Franchi L, et al. Differential regulation of caspase-1 activation, pyroptosis, and autophagy via Ipaf and ASC in Shigella-infected macrophages. PLoS Pathog,2007,3(8):e111
[42]. Lightfield KL, Persson J, et al. Critical function for Naip5 in inflammasome activation by a conserved carboxy-terminal domain of flagellin. Nat
Immunol,2008,9(10):1171-1178.
[43]. Neven B, Prieur AM, et al.Cryopyrinopathies:update on pathogenesis and treatment. Nat Clin Pract Rheumatol,2008,4(9):481-489.
[44]. Aksentijevich I, Nowak M, Mallah M, et al. De novo CIAS1 mutations, cytokine activation, and evidence for genetic heterogeneity in patients with neonatal-onset multisystem inflammatory disease (NOMID):a new member of the expanding family of pyrin-associated autoinflammatory diseases. Arthritis Rheum,2002,46(12):3340-3348.
[45]. Agostini L, Martinon F, et al. NALP3 forms an IL-lbeta processing inflammasome with increased activity in Muckle-Wells autoinflammatory disorder. Immunity,2004,20(3):319-325.
[46]. Hise AG, Tomalka J, et al.An Essential Role for the NLRP3 Inflammasome in Host Defense against the Human Fungal Pathogen Candida albicans. Cell Host Microbe,2009,5(5):487-497.
[47]. Shao W, Yeretssian G, et al.The caspase-1 digestome identifies the glycolysis pathway as a target during infection and septic shock.J Biol Chem, 2007,282 (50):36321-36329.
[48]. Keller M, Ruegg A, et al. Active caspase-1 is a regulator of unconventional protein secretion. Cell,2008,132 (5):818-831.
[49]. Thomas PG, Dash P,et al.The intracellular sensor NLRP3 mediates key innate and healing responses to influenza A virus via the regulation of caspase-1.Immunity,2009,30(4):566-575.
[50]. Zaiss AK, Vilaysane A, et al.Antiviral antibodies target adenovirus to phagolysosomes and amplify the innate immune response.J Immunol,2009,182(11):7058-7068.
[51]. Mariathasan S,Weiss DS, et al. Cryopyrin activates the inflammasome in response to toxins and ATP. Nature 2006;440(7081):228-232.
[52]. Warren SE, Mao DP, Rodriguez AE, Miao EA, Aderem A. Multiple Nod-like receptors activate caspase 1 during Listeria monocytogenes infection. J
Immunol,2008,180(1):7558-7564.
[53]. Duncan JA, Gao X, et al.Neisseria gonorrhoeae activates the proteinase cathepsin B to mediate the signaling activities of the NLRP3 and ASC-containing inflammasome.J Immunol,2009,182(10):6460-6469.
[54]. Willingham SB, Bergstralh DT, et al. Microbial pathogen-induced necrotic cell death mediated by the inflammasome components CIAS1/cryopyrin/NLRP3 and ASC. Cell Host Microbe,2007,2(3):147-159.
[55]. Craven RR, Gao X, et al.Staphylococcus aureus alpha-hemolysin activates the NLRP3-inflammasome in human and mouse monocytic cells. PLoS One,2009,4(10):e7446.
[56]. Martinon F,Petrilli V,et al. Gout-associated uric acid crystals activate the NALP3 inflammasome. Nature,2006,440(7081):237-241.
[57]. Dostert C, Petrilli V, et al. Innate immune activation through Nalp3 inflammasomesensing of asbestos and silica.Science,2008,320(5876):674-677.
[58]. Cassel SL, Eisenbarth SC, et al. The Nalp3 inflammasome is essential for the development of silicosis. Proc Natl Acad Sci USA,2008,105(26):9035-9040.
[59]. Gasse P, Riteau N, et al. Uric acid is a danger signal activating NALP3 inflammasome in lung injury inflammation and fibrosis. Am J Respir Crit Care Med,2009,179(10):903-913.
[60]. Halle A, Hornung V, et al. The NALP3 inflammasome is involved in the innate immuneresponse toamyloid-beta.Nat Immunol,2008,9(8):857-865.
[61]. Franchi L, Eigenbrod T, et al.The inflammasome:a caspase-1-activation platform that regulates immune responses and disease pathogenesis.Nat Immunol,2009,10(3):241-247.
[62]. Stephanie C, Eisenbarth, et al.Crucial role for the Nalp3 inflammasome in the immunostimulatory properties of aluminium adjuvants. Nature,2008, 453(7198):1122-1126.
[63]. Luigi Franchi, Gabriel Nunez. The Nlrp3 inflammasome is critical for aluminium hydroxide-mediated IL-lbeta secretion but dispensable for adjuvant activity.Eur J Immunol,2008,38(8):2085-2089.
[64]. Li H,Stephen B,et al.inflammasome activation by alum and alum's adjuvant effect are mediated by NLRP3.J Immunol,2008,181(1):17-21.
[65]. Kenshi Y, Jun M, et al.NLRP3/cryopyrin is necessary for interleukin-1beta (IL-lbeta) release in response to hyaluronan, an endogenous trigger of inflammation in response to injury.J Biol Chem,2009,284(19):12762-12771.
[66]. Mihai G.N, Claudia A, et al.Differential requirement for the activation of the inflammasome for processing and release of IL-1_ in monocytes and macrophages. Blood,2009,113 (10):2324-2335.
[67]. Gross O, Poeck H,et al.Syk kinase signalling couples to the Nlrp3 inflammasome for anti-fungal host defence.Nature,2009,459(7245):433-436
[68]. Pelegrin P, Surprenant A.Dynamics of macrophage polarization reveal new mechanism to inhibit IL-lbeta release through pyrophosphates. EMBO J,2009, 28(14):2114-2127.
[69]. Arlehamn CS, Petrilli V, et al.The role of potassium in inflammasome activation by bacteria.J Biol Chem,2010,285(14):10508-10518.
[70]. Meissner F, Molawi K, Zychlinsky A.Superoxide dismutase 1 regulates caspase-1 and endotoxic shock. Nat Immunol,2008,9(8):866-872.
[71]. Hornung V, Bauernfeind F, et al.Silica crystals and aluminum salts activate the NALP3 inflammasome through phagosomal destabilization. Nat Immunol, 2008,9(8):847-856.
[2]. Xiong LS, Chen MH, et al. A population-based epidemiologic study of irritable bowel syndrome in South China:stratified randomized study by cluster sampling. Aliment Pharmacol Ther.,2004,19(11):1217-1224.
[3]. Bamngart DC, DiguassAU, et al. Intestinal barrier function. CurtOpin Clin Nutr Metab Care,2002,5(6):685-694.
[4]. Gagnon M, Kheadr EE, Le Blay G, et al. In vitro inhibition of Escherichia coli 0157:H7 by bifidobacterial strains of human origin. Int J Food Microbiol,2004, 92(1):69-78.
[5]. Van der, Waaij D, et al. History of recognition and measurement of colonization resistance of the digestive tract as an introduction to selective gastrointestinal decontamination. Epidemiol Infec,1992,109(3):315-326.
[6]. Si J M, Yu YC, Fan YJ, et al. Intestinal microecology and quality of life in irritable bowel syndrome patients. World J Gastroenterol,2004,10(12): 1802-1805.
[7]. Osipov GA, Parfenov AI, Verkhovtseva NV,et al. Clinical significance of studies of microorganisms of the intestinal mucosaby culture biochemical methods and mass fragmentography Eksp Klin.Gastroenterol,2003, (4): 59-67,115.
[8]. Malinen E, Rinttila T, Kajander K, et al. Analysis of the fecal microbiota of irritable bowel syndrome patients and healthy controls with real-time PCR Am J Gastroenterol,2005,100(2):373-382.
[9]. Neal KR, Hebden J, Spiller R, et al. Prevalence of gastrointeslinal symptoms six months after bacterial gastroenteritis and risk factors for development of the irritable bowel syndrome:postal survey of patients. BMJ,1997,31(4):779-782.
[10]. Marshall JK, Thabane M, et al. Postinfectious irritable bowel syndrome after a food-borne outbreak of acute gastroenteritis attributed to a viral pathogen. Clin Gastroenterol Hepatol,2007,5(4):457-460.
[11]. Giacometti A, Cirioni O, et al. In vitro anticryptosporidial activity of ranalexin alone and in combination with other peptides and with hydrophobic antibiotics,1999,18(11):827-829.
[12]. Spiller RC, Jenkins D, et al. Increased rectal mucosal enteroendocrine cells, T lymphocytes, and increased gut permeability following acute Campylobacter enteritis and in post-dysenteric irritable bowel syndrome. Gut,2000,47 (6):804-811.
[13]. Dunlop SP, Jenkins D, Neal KR, et al. Relative importance of enterochroniaffin cell hyperplasia, anxiety, and depression in postinfectious IBS. Gastroenterology,2003,125(6):1651-1659。
[14]. Spiller RC, Jenkins D, Thornley JP, et al. Increased rectal mucosal enteroendocrine cells, T lymphocytes, and increased gut permeability following acute Campylobacter enteritis and in post-dysenteric irritable bowel syndrome. Gut,2000,47(6):804-811.
[15]. Chadwick VS, Chen W, Shu D, et al. Activation of the mucosal immune system in irritable bowel syndrome. Gastroenterology,2002,122(7): 1778-1783.
[16]. Gronsalkorale W M, Perrey C, Pravica V, et al. Interleukin 10 genotypes in irritable bowel syndrome:evidence for an inflammatory component?Gut, 2003,52(1):91-93.
[17]. Palsson OS, Morteau O.Elevated vasoactive intestinal peptide concentrations in patients with irritable bowel syndrome. Digestive Diseases and Sciences.2004,49(7):1236-1243.
[18]. Gwee KA, Collins SM, et al. Increased rectal mucosal expression of interleukin 1beta in recently acquired post-infectious irritable bowel syndrome. Gut,2003,52(4):523-526.
[19]. Wang LH, Fang XC, Pan GZ. Bacillary dysentery as a causative factor of irritable bowel syndrome and its pathogenesis. Gut,2004,53(8):1096-1101.
[20].宋继中,王巧民等.肠易激综合征患者血清IL-1β、IL-10及皮质醇变化的研究.现代诊断与治疗,2005,16(2)：68-69.
[21].宋继中,王巧民,肠易激综合征患者结肠黏膜神经肽和IL-1β变化及其意义.胃肠病学和肝病学杂志,2007,16(3)：219-222.
[22]. Liebregts T, Adam B.Immune activation in patients with irritable bowel syndrome. Gastroenterology.2007,132(3):913-920.
[23]. Gross O, Poeck H, et al. Syk kinase signalling couples to the Nlrp3 inflammasome for anti-fungal hostdefence. Nature,2009,459(7245):433-436.
[24]. Jin Y, Mailloux CM, et al.NALP1 in vitiligo-associated multiple autoimmune disease. N Engl J Med,2007,356(12):1216-1225.
[25]. Miao EA, Alpuche-Aranda CM, et al.Cytoplasmic flagellin activates caspase-1 and secretion of interleukin lbeta via Ipaf. Nat Immunol, 2006,7(6):569-575.
[26]. Agostini L, Martinon F, et al. NALP3 forms an IL-lbeta processing inflammasome with increased activity in Muckle-Wells autoinflammatory disorder. Immunity,2004,20(3):319-325.
[27]. Zaiss AK, Vilaysane A, et al.Antiviral antibodies target adenovirus to phagolysosomes and amplify the innate immune response.J Immunol,2009,182(11):7058-7068.
[28]. Mariathasan S,Weiss DS, et al. Cryopyrin activates the inflammasome in response to toxins and ATP. Nature 2006;440(7081):228-232.
[29]. Warren SE, Mao DP, Rodriguez AE, Miao EA, Aderem A. Multiple Nod-like receptors activate caspase 1 during Listeria monocytogenes infection. J Immunol,2008,180(1):7558-7564.
[30]. Duncan JA, Gao X, et al.Neisseria gonorrhoeae activates the proteinase cathepsin B to mediate the signaling activities of the NLRP3 and ASC-containing inflammasome.J Immunol,2009,182(10):6460-6469.
[31]. Willingham SB, Bergstralh DT, et al. Microbial pathogen-induced necrotic cell death mediated by the inflammasome components CIAS1/cryopyrin/NLRP3 and ASC. Cell Host Microbe,2007,2(3):147-159.
[32]. Hise AG, Tomalka J, et al.An Essential Role for the NLRP3 Inflammasome in Host Defense against the Human Fungal Pathogen Candida albicans. Cell Host Microbe,2009,5(5):487-497.
[33]. Craven RR, Gao X, et al.Staphylococcus aureus alpha-hemolysin activates the NLRP3-inflammasome in human and mouse monocytic cells. PLoS One,2009,4(10):e7446.
[34]. Franchi L, Eigenbrod T, et al.The inflammasome:a caspase-1-activation platform that regulates immune responses and disease pathogenesis.Nat Immunol,2009,10(3):241-247.
[35]. Mihai G.N, Claudia A, et al.Differential requirement for the activation of the inflammasome for processing and release of IL-1_ in monocytes and macrophages. Blood,2009,113 (10):2324-2335.
[36]. Nakamura Y, Kambe N,et al. Mast cells mediate neutrophil recruitment and vascular leakage through the NLRP3 inflammasome in histamine-independent urticaria.J Exp Med,2009,206(5):1037-1046.
[37]. Kambe N, Nakamura Y,et al.The Inflammasome, an Innate Immunity Guardian, Participates in Skin Urticarial Reactions and Contact Hypersensitivity.Allergol Int.,2010,59(2). [Epub ahead of print]
[38]. Bauer C, Duewell P,et al. Colitis induced in mice with dextran sulfate sodium (DSS) is mediated by the NLRP3 inflammasome.Gut,2010 May 4. [Epub ahead of print]
[39]. Gross O, Poeck H,et al.Syk kinase signalling couples to the Nlrp3 inflammasome for anti-fungal host defence.Nature,2009,459(7245):433-436
[40]. Hornung V, Bauernfeind F, et al.Silica crystals and aluminum salts activate the NALP3 inflammasome through phagosomal destabilization. Nat Immunol, 2008,9(8):847-856.
[41]. Meissner F, Molawi K, Zychlinsky A.Superoxide dismutase 1 regulates caspase-1 and endotoxic shock. Nat Immunol,2008,9(8):866-872.
[42]. Meng G, Zhang F,et al. A mutation in the Nlrp3 gene causing inflammasome hyperactivation potentiates Th17 cell-dominant immune responses. Immunity, 2009,30(6):860-874.
[43].朱峰,钱家鸣,潘国宗,杨晓鸥.白介素1β和8 mRNA表达等指标监测溃疡性结肠炎活动的应用.中国医学科学学院学报,1999,21(5).
[44]. Thomas PG, Dash P,et al.The intracellular sensor NLRP3 mediates key innate and healing responses to influenza A virus via the regulation of caspase-1.Immunity,2009,30(4):566-575.
[45]. Hebden JM, Erah PO, et al. Increased small bowel but not colonic permeability in post-infectious irritable bowel syndrome. Gastroenterology,114(1):A763.
[1]. Saito YA, Schoenfeld P, et al. The epidemiology of irritable bowel Byndrome in North America:a systematic review[J]. Am J Gastroenterol,2002,97(8): 1910-1915.
[2]. Xiong LS, Chen MH, et al. A population-based epidemiologic study of irritable bowel syndrome in South China:stratified randomized study by cluster sampling. Aliment Pharmacol Ther.,2004,19(11):1217-1224.
[3].中华医学会消化病学分会胃肠动力学组.肠易激综合征诊断和治疗的共识意见[J].中华消化杂志,2008,28：38-40.
[4]. Bamngart DC, DiguassAU, et al. Intestinal barrier function. CurtOpin Clin Nutr Metab Care,2002,5(6):685-694.
[5]. Gagnon M, Kheadr EE, Le Blay G, et al. In vitro inhibition of Escherichia.coli 0157:H7 by bifidobacterial strains of human origin. Int J Food Microbiol,2004, 92(1):69-78.
[6]. Van der, Waaij D, et al.. History of recognition and measurement of colonization resistance of the digestive tract as an introduction to selective gastrointestinal decontamination. Epidemiol Infec,1992,109(3):315-326.
[7]. Si J M, Yu YC, Fan YJ, et al. Intestinal microecology and quality of life in irritable bowel syndrome patients. World J Gastroenterol,2004,10(12): 1802-1805.
[8]. Osipov GA, Parfenov AI, Verkhovtseva NV,et al. Clinical significance of studies of microorganisms of the intestinal mucosaby culture biochemical methods and mass fragmentography Eksp Klin.Gastroenterol,2003, (4):59-67,115.
[9]. Malinen E, Rinttila T, Kajander K, et al. Analysis of the fecal microbiota of irritable bowel syndrome patients and healthy controls with real-time PCR Am J Gastroenterol,2005,100(2):373-382.
[10]. Carrara M, Desideri S, et al. Small intestine bacterial overgrowth in patients with irritable bowel syndrome. Eur Rev Med Pharmacol Sci, 2008,12(3):197-202.
[11]. Pimentel M, Chow EJ, Lin HC, et al. Normalization of lactulose breath testing correlates with symptom improvement in irritable bowel syndrome:a double-blind, randomized, placebo controlled study. Am J Gastroenterol,2003, 98(2):412-419.
[12]. Neal KR, Hebden J, Spiller R, et al. Prevalence of gastrointeslinal symptoms six months after bacterial gastroenteritis and risk factors for development of the irritable bowel syndrome:postal survey of patients. BMJ, 1997,31(4):779-782.
[13]. Marshall JK, Thabane M, et al. Postinfectious irritable bowel syndrome after a food-borne outbreak of acute gastroenteritis attributed to a viral pathogen. Clin Gastroenterol Hepatol,2007,5(4):457-460.
[14]. Giacometti A, Cirioni O, et al. In vitro anticryptosporidial activity of ranalexin alone and in combination with other peptides and with hydrophobic antibiotics,1999,18(11):827-829.
[15]. Marshall JK, Thabane M, et al.Incidence and epidemiology of irritable bowel syndrome after a large waterborne outbreak of bacterial dysentery. Gastroenterology,2006,131(2):445-450; quiz 660.
[16]. Wang LH, Fang XC, Pan GZ. Bacillary dysentery as a causative factor of irritable bowel syndrome and its pathogenesis. Gut,2004,53(8):1096-1101.
[17]. Coates MD, Mahoney CR,et al. Molecular defects in mucosal serotonin content and decreased serotonin reuptake transporter in ulcerative colitis and irritable bowel syndrome.Gastroenterology,2004,126(7):1657-1664.
[18]. Gwee KA, Leong YL, et al.The role of psychological and biological factors in postinfective gut dysfunction. Gut,1999; 44(3):400-406.
[19]. Dunlop SP, Jenkins D, Neal KR, et al. Relative importance of enterochroniaffin cell hyperplasia, anxiety, and depression in postinfectious IBS. Gastroenterology,2003,125(6):1651-1659。
[20]. Dunlop SP, Jenkins D, Spiller RC. Age-related decline in rectal mucosal lymphocytes and mast cells. Eur J Gastroenterol Hepatol 2004; 16(10):
1011-1015.
[21]. Spiller RC, Jenkins D, Thornley JP, et al. Increased rectal mucosal enteroendocrine cells, T lymphocytes, and increased gut permeability following acute Campylobacter enteritis and in post-dysenteric irritable bowel syndrome. Gut,2000,47(6):804-811.
[22]. Chadwick VS, Chen W, Shu D, et al. Activation of the mucosal immune system in irritable bowel syndrome. Gastroenterology,2002,122(7):1778-1783.
[23]. Spiller RC, Jenkins D, et al. Increased rectal mucosal enteroendocrine cells, T lymphocytes, and increased gut permeability following acute Campylobacter enteritis and in post-dysenteric irritable bowel syndrome. Gut,2000,47 (6):804-811.
[24]. Adam B, Liebregts T, et al. Severity of mucosal inflammation as a predictor for alterations of visceral sensory function in a rat model.Pain.,2006,123(1-2):179-186.
[25]. Gronsalkorale W M, Perrey C, Pravica V, et al. Interleukin 10 genotypes in irritable bowel syndrome:evidence for an inflammatory component?Gut, 2003,52(1):91-93.
[26]. Gwee KA, Collins SM, et al. Increased rectal mucosal expression of interleukin 1beta in recently acquired post-infectious irritable bowel syndrome. Gut,2003,52(4):523-526.
[27]. Gross O, Poeck H, et al. Syk kinase signalling couples to the Nlrp3 inflammasome for anti-fungal hostdefence. Nature,2009,459(7245):433-436.
[28].朱峰,钱家鸣,潘国宗,杨晓鸥.白介素1β和8 mRNA表达等指标监测溃疡性结肠炎活动的应用.中国医学科学学院学报,1999,21(5).
[29]. Abdul-Sater AA, Said-Sadier N, et al. Inflammasomes bridge signaling between pathogen identification and the immune response.Drugs Today (Barc), 2009,45 Suppl B:105-112.
[30]. Martinon F,Tschopp J. NLRs join TLRs as innate sensors of pathogens[J].Trends Immunol,2005,26(8):447-454.
[31]. Da Silva Correia J, Miranda Y,et al.SGT1 is essential for Nod1 activation. Proc Natl Acad Sci USA,2007,104(16):6764-6769.
[32]. Franchi L, Warner N, et al.Function of Nod-like receptors in microbial recognition and host defense. Immunol Rev,227(1):106-128.
[33]. Chamailard M,Philpott D,et al.Gene-environment interaction modulated by allelic heterogeneity in inflammatory diseases.Proc Natl Acad Sci USA,2003,100(6):3455-3460.
[34]. Carneiro LA, Philpott DJ,et al.Innate immune recognition of microbes through Nod1 and Nod2 implications for disease.Microbes Infect,2004,6(6):609-616.
[35]. Girardin SE,Boneca IG, et al.Nodl detects a unique muropeptide from Gram-negative bacterial poptidoglycan. Science,2003,300(5625):1582-1587.
[36]. Boyden ED, Dietrich WF. Nalplb controls mouse macrophage susceptibility to anthrax lethal toxin. Nat Genet,2006,38(2):240-244.
[37]. Hsu LC, Ali SR, et al.A NOD2-NALP1 complex mediates caspase-1-dependent IL-lbetasecretion in responseto Bacillus anthracis infection and muramyl dipeptide. Proc Natl Acad Sci USA,2008,105(22):7803-7808.
[38]. Jin Y, Mailloux CM, et al.NALP1 in vitiligo-associated multiple autoimmune disease. N Engl J Med,2007,356(12):1216-1225.
[39]. Sutterwala FS, Mijares LA, et al. Immune recognition of Pseudomonas aeruginosa mediated by the IPAF/NLRC4 inflammasome.J Exp Med, 2007,204(13):3235-3245.
[40]. Miao EA, Alpuche-Aranda CM, et al.Cytoplasmic flagellin activates caspase-1 and secretion of interleukin lbeta via Ipaf. Nat Immunol, 2006,7(6):569-575.
[41]. Suzuki T, Franchi L, et al. Differential regulation of caspase-1 activation, pyroptosis, and autophagy via Ipaf and ASC in Shigella-infected macrophages. PLoS Pathog,2007,3(8):e111
[42]. Lightfield KL, Persson J, et al. Critical function for Naip5 in inflammasome activation by a conserved carboxy-terminal domain of flagellin. Nat
Immunol,2008,9(10):1171-1178.
[43]. Neven B, Prieur AM, et al.Cryopyrinopathies:update on pathogenesis and treatment. Nat Clin Pract Rheumatol,2008,4(9):481-489.
[44]. Aksentijevich I, Nowak M, Mallah M, et al. De novo CIAS1 mutations, cytokine activation, and evidence for genetic heterogeneity in patients with neonatal-onset multisystem inflammatory disease (NOMID):a new member of the expanding family of pyrin-associated autoinflammatory diseases. Arthritis Rheum,2002,46(12):3340-3348.
[45]. Agostini L, Martinon F, et al. NALP3 forms an IL-lbeta processing inflammasome with increased activity in Muckle-Wells autoinflammatory disorder. Immunity,2004,20(3):319-325.
[46]. Hise AG, Tomalka J, et al.An Essential Role for the NLRP3 Inflammasome in Host Defense against the Human Fungal Pathogen Candida albicans. Cell Host Microbe,2009,5(5):487-497.
[47]. Shao W, Yeretssian G, et al.The caspase-1 digestome identifies the glycolysis pathway as a target during infection and septic shock.J Biol Chem, 2007,282 (50):36321-36329.
[48]. Keller M, Ruegg A, et al. Active caspase-1 is a regulator of unconventional protein secretion. Cell,2008,132 (5):818-831.
[49]. Thomas PG, Dash P,et al.The intracellular sensor NLRP3 mediates key innate and healing responses to influenza A virus via the regulation of caspase-1.Immunity,2009,30(4):566-575.
[50]. Zaiss AK, Vilaysane A, et al.Antiviral antibodies target adenovirus to phagolysosomes and amplify the innate immune response.J Immunol,2009,182(11):7058-7068.
[51]. Mariathasan S,Weiss DS, et al. Cryopyrin activates the inflammasome in response to toxins and ATP. Nature 2006;440(7081):228-232.
[52]. Warren SE, Mao DP, Rodriguez AE, Miao EA, Aderem A. Multiple Nod-like receptors activate caspase 1 during Listeria monocytogenes infection. J
Immunol,2008,180(1):7558-7564.
[53]. Duncan JA, Gao X, et al.Neisseria gonorrhoeae activates the proteinase cathepsin B to mediate the signaling activities of the NLRP3 and ASC-containing inflammasome.J Immunol,2009,182(10):6460-6469.
[54]. Willingham SB, Bergstralh DT, et al. Microbial pathogen-induced necrotic cell death mediated by the inflammasome components CIAS1/cryopyrin/NLRP3 and ASC. Cell Host Microbe,2007,2(3):147-159.
[55]. Craven RR, Gao X, et al.Staphylococcus aureus alpha-hemolysin activates the NLRP3-inflammasome in human and mouse monocytic cells. PLoS One,2009,4(10):e7446.
[56]. Martinon F,Petrilli V,et al. Gout-associated uric acid crystals activate the NALP3 inflammasome. Nature,2006,440(7081):237-241.
[57]. Dostert C, Petrilli V, et al. Innate immune activation through Nalp3 inflammasomesensing of asbestos and silica.Science,2008,320(5876):674-677.
[58]. Cassel SL, Eisenbarth SC, et al. The Nalp3 inflammasome is essential for the development of silicosis. Proc Natl Acad Sci USA,2008,105(26):9035-9040.
[59]. Gasse P, Riteau N, et al. Uric acid is a danger signal activating NALP3 inflammasome in lung injury inflammation and fibrosis. Am J Respir Crit Care Med,2009,179(10):903-913.
[60]. Halle A, Hornung V, et al. The NALP3 inflammasome is involved in the innate immuneresponse toamyloid-beta.Nat Immunol,2008,9(8):857-865.
[61]. Franchi L, Eigenbrod T, et al.The inflammasome:a caspase-1-activation platform that regulates immune responses and disease pathogenesis.Nat Immunol,2009,10(3):241-247.
[62]. Stephanie C, Eisenbarth, et al.Crucial role for the Nalp3 inflammasome in the immunostimulatory properties of aluminium adjuvants. Nature,2008, 453(7198):1122-1126.
[63]. Luigi Franchi, Gabriel Nunez. The Nlrp3 inflammasome is critical for aluminium hydroxide-mediated IL-lbeta secretion but dispensable for adjuvant activity.Eur J Immunol,2008,38(8):2085-2089.
[64]. Li H,Stephen B,et al.inflammasome activation by alum and alum's adjuvant effect are mediated by NLRP3.J Immunol,2008,181(1):17-21.
[65]. Kenshi Y, Jun M, et al.NLRP3/cryopyrin is necessary for interleukin-1beta (IL-lbeta) release in response to hyaluronan, an endogenous trigger of inflammation in response to injury.J Biol Chem,2009,284(19):12762-12771.
[66]. Mihai G.N, Claudia A, et al.Differential requirement for the activation of the inflammasome for processing and release of IL-1_ in monocytes and macrophages. Blood,2009,113 (10):2324-2335.
[67]. Gross O, Poeck H,et al.Syk kinase signalling couples to the Nlrp3 inflammasome for anti-fungal host defence.Nature,2009,459(7245):433-436
[68]. Pelegrin P, Surprenant A.Dynamics of macrophage polarization reveal new mechanism to inhibit IL-lbeta release through pyrophosphates. EMBO J,2009, 28(14):2114-2127.
[69]. Arlehamn CS, Petrilli V, et al.The role of potassium in inflammasome activation by bacteria.J Biol Chem,2010,285(14):10508-10518.
[70]. Meissner F, Molawi K, Zychlinsky A.Superoxide dismutase 1 regulates caspase-1 and endotoxic shock. Nat Immunol,2008,9(8):866-872.
[71]. Hornung V, Bauernfeind F, et al.Silica crystals and aluminum salts activate the NALP3 inflammasome through phagosomal destabilization. Nat Immunol, 2008,9(8):847-856.