RANKL/OPG系统及白细胞介素8在炎症性肠病中的表达及作用研究
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摘要
目的探讨炎症性肠病(inflammatory bowel disease, IBD)患者核因子-κB受体活化因子配体(RANKL)和骨保护素(OPG)的肠黏膜表达情况及相关促炎因子白细胞介素-8(IL-8)的血清水平变化,并分析与炎症标志物C-反应蛋白(CRP)、红细胞沉降率(ESR)的相关性。方法收集2016年9月至2018年4月郑州大学第二附属医院38例IBD患者结肠镜活检组织、血清标本及同期检查的CRP、ESR值,其中溃疡性结肠炎(ulcerative colitis, UC)患者28例、克罗恩病(Crhon’s disease, CD)患者10例;同期20名健康体检者血清为对照组,24例同期于我院结肠癌手术切除癌旁正常组织作为癌旁组。应用免疫组织化学染色检测结肠黏膜组织中RANKL及OPG的表达;应用双抗体夹心ELISA法检测外周血中IL-8的水平变化。结果 UC组和CD组结肠黏膜组织中RANKL及OPG的表达高于癌旁组,差异有统计学意义(P<0.05),UC组与CD组比较,差异无统计学意义(P>0.05);UC组和CD组血清中IL-8的水平高于对照组,差异有统计学意义(P<0.05),UC组与CD组比较,差异无统计学意义(P>0.05);IL-8与UC患者CRP、ESR及CD患者ESR呈显著正相关,IL-8与CD患者CRP无显著相关性。结论 RANKL及OPG多在IBD患者的结肠黏膜固有层中表达;相关促炎因子IL-8在IBD患者血清中处于升高状态;IL-8有望成为IBD的新型炎症标志物。
Objective To investigate the expressions of RANKL and OPG in intestinal mucosa and the serum levels of related pro-inflammatory cytokine IL-8 in patients with inflammatory bowel disease(IBD). Methods A total of 38 patients with IBD were collected, including 28 patients with ulcerative colitis(UC) and 10 patients with Crhon's disease(CD). The serum of 20 healthy subjects in the same period were collected as normal control group. Twenty-four cases of paracancerous tissues resected from colon cancer in the Second Affiliated Hospital, Zhengzhou University were used as cancer adjacent group. The expressions of RANKL and OPG in colonic mucosa were detected by routine immunohistochemical staining. The level of IL-8 in peripheral blood was detected by ELISA. Results The expressions of RANKL and OPG in colonic mucosa of UC group and CD group were higher than those in cancer adjacent group, the difference was statistically significant(P<0.05). There was no significant difference between UC group and CD group(P>0.05). The serum levels of IL-8 in UC group and CD group were significantly higher than those in normal control group(P<0.05). There was no significant difference between UC group and CD group(P>0.05). There was a significant positive correlation between IL-8 and CRP and ESR in patients with UC and CD, and no correlation with CRP in CD patients. Conclusion RANKL and OPG are mostly expressed in the lamina propria of the colonic mucosa of patients with IBD, and the pro-inflammatory factor IL-8 is elevated in the serum of patients with IBD. IL-8 is expected to be a new marker of inflammation in IBD.
Objective To investigate the expressions of RANKL and OPG in intestinal mucosa and the serum levels of related pro-inflammatory cytokine IL-8 in patients with inflammatory bowel disease(IBD). Methods A total of 38 patients with IBD were collected, including 28 patients with ulcerative colitis(UC) and 10 patients with Crhon's disease(CD). The serum of 20 healthy subjects in the same period were collected as normal control group. Twenty-four cases of paracancerous tissues resected from colon cancer in the Second Affiliated Hospital, Zhengzhou University were used as cancer adjacent group. The expressions of RANKL and OPG in colonic mucosa were detected by routine immunohistochemical staining. The level of IL-8 in peripheral blood was detected by ELISA. Results The expressions of RANKL and OPG in colonic mucosa of UC group and CD group were higher than those in cancer adjacent group, the difference was statistically significant(P<0.05). There was no significant difference between UC group and CD group(P>0.05). The serum levels of IL-8 in UC group and CD group were significantly higher than those in normal control group(P<0.05). There was no significant difference between UC group and CD group(P>0.05). There was a significant positive correlation between IL-8 and CRP and ESR in patients with UC and CD, and no correlation with CRP in CD patients. Conclusion RANKL and OPG are mostly expressed in the lamina propria of the colonic mucosa of patients with IBD, and the pro-inflammatory factor IL-8 is elevated in the serum of patients with IBD. IL-8 is expected to be a new marker of inflammation in IBD.
引文
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[18]中华医学会消化病学分会炎症性肠病学组.炎症性肠病诊断与治疗的共识意见(2018年,北京)[J].中华消化杂志,2018,38(5):292-311.DOI:10.3760/cma.j.issn.0254-1432.2018.05.002.
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[20]WANG S,LIU Z,WANG L,et al.NF-kappaB signaling pathway,inflammation and colorectal cancer[J].Cell Mol Immunol,2009,6(5):327-334.DOI:10.1038/cmi.2009.43.
[21]ASHCROFT A J,CRUICKSHANK S M,CROUCHER P I,et al.Colonic dendritic cells,intestinal inflammation,and T cell-mediated bone destruction are modulated by recombinant osteoprotegerin[J].Immunity,2003,19(6):849-861.DOI:10.1016/S1074-7613(03)00326-1.
[2]ZEISSIG S,BRGEL N,GNZEL D,et al.Changes in expression and distribution of claudin 2,5 and 8 lead to discontinuous tight junctions and barrier dysfunction in active Crohn’s disease[J].Gut,2007,56(1):61-72.DOI:10.1136/gut.2006.094375.
[3]EDELBLUM K L,TURNER J R.The tight junction in inflammatory disease:communication breakdown[J].Curr Opin Pharmacol,2009,9(6):715-720.DOI:10.1016/j.coph.2009.06.022.
[4]ARSENESCU R,ARSENESCU V,DE VILLIERS W J.TNF-αand the development of the neonatal immune system:implications for inhibitor use in pregnancy[J].Am J Gastroenterol,2011,106(4):559-562.DOI:10.1038/ajg.2011.5.
[5]S'LEBIODA T J,KMIE C'Z.Tumour necrosis factor superfamily members in the pathogenesis of inflammatory bowel disease[J].Mediators Inflamm,2014,2014(5):325129.DOI:10.1155/2014/325129.
[6]NAHIDI L,LEACH S T,SIDLER M A,et al.Osteoprotegerin in pediatric Crohn’s disease and the effects of exclusive enteral nutrition[J].Inflamm Bowel Dis,2011,17(2):516-523.DOI:10.1002/ibd.21361.
[7]VIDAL K,SERRANT P,SCHLOSSER B,et al.Osteoprotegerin production by human intestinal cells:a potential regulator of mucosal immune responses[J].Am J Physiol Gastrointest Liver Physiol,2004,287(4):G836-G844.DOI:10.1152/ajpgi.00428.2003
[8]MOSCHEN A R,KASER A,ENRICH B,et al.The RANKL/OPGsystem is activated in inflammatory bowel disease and relates to the state of bone loss[J].2005,54(4):479-487.DOI:10.1136/gut.2004.044370.
[9]MIHELLER P,MUZES G,RCZ K,et al.Changes of OPG and RANKLconcentrations in Crohn’s disease after infliximab therapy[J].Inflamm Bowel Dis,2007,13(11):1379-1384.DOI:10.1002/ibd.20234.
[10]NAHIDI L,LEACH S T,LEMBERG D A,et al.Osteoprotegerin exerts its pro-inflammatory effects through nuclear factor-κB activation[J].Dig Dis Sci,2013,58(11):3144-3155.DOI:10.1007/s10620-013-2851-2.
[11]SCHOTTELIUS A J,BALDWIN A S.A role for transcription factor NF-kappa B in intestinal inflammation[J].Int J Colorectal Dis,1999,14(1):18-28.DOI:10.1007/s003840050178.
[12]SCHREIBER S,NIKOLAUS S,HAMPE J.Activation of nuclear factor kappa B inflammatory bowel disease[J].Gut,1998,42(4):477-484.DOI:10.1136/gut.42.4.477.
[13]OECKINGHAUS A,GHOSH S.The NF-kappaB family of transcription factors and its regulation[J].Cold Spring Harb Perspect Biol,2009,1(4):a000034.DOI:10.1101/cshperspect.a000034.
[14]WALANA W,YE Y,LI M,et al.IL-8 antagonist,CXCL8(3-72)K11R/G31P coupled with probiotic exhibit variably enhanced therapeutic potential in ameliorating ulcerative colitis[J].Biomed Pharmacother,2018,103:253-261.DOI:10.1016/j.biopha.2018.04.008.
[15]INA K,KUSUGAMI K,YAMAGUCHI T,et al.Mucosal interleukin-8 is involved in neutrophil migration and binding to extracellular matrix in inflammatory bowel disease[J].Am J Gastroenterol,1997,92(8):1342-1346.
[16]KABBANI T A,KOUTROUBAKIS I E,SCHOEN R E,et al.Association of Vitamin D level with clinical status in inflammatory bowel disease:a 5-year longitudinal study[J].Am J Gastroenterol,2016,111(5):712-719.DOI:10.1038/ajg.2016.53.
[17]SU J,XIE C,FAN Y,et al.Interleukin-25 enhances the capacity of mesenchymal stem cells to induce intestinal epithelial cell regeneration[J].Am J Transl Res,2017,9(12):5320-5331.
[18]中华医学会消化病学分会炎症性肠病学组.炎症性肠病诊断与治疗的共识意见(2018年,北京)[J].中华消化杂志,2018,38(5):292-311.DOI:10.3760/cma.j.issn.0254-1432.2018.05.002.
[19]MATTERN J,KOOMGI R,VOLM M.Biological characterization of subgroups of squamous cell lung carcinomas[J].Clin Cancer Res,1999,5(6):1459-1463.
[20]WANG S,LIU Z,WANG L,et al.NF-kappaB signaling pathway,inflammation and colorectal cancer[J].Cell Mol Immunol,2009,6(5):327-334.DOI:10.1038/cmi.2009.43.
[21]ASHCROFT A J,CRUICKSHANK S M,CROUCHER P I,et al.Colonic dendritic cells,intestinal inflammation,and T cell-mediated bone destruction are modulated by recombinant osteoprotegerin[J].Immunity,2003,19(6):849-861.DOI:10.1016/S1074-7613(03)00326-1.
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