Eur J Pediatr Surg 2019; 29(04): 388-393
DOI: 10.1055/s-0038-1660447
Original Article
Georg Thieme Verlag KG Stuttgart · New York

Upregulation of High Mobility Group Box 1 May Contribute to the Pathogenesis of Biliary Atresia

Chun Jing Ye
1   Department of Pediatric Surgery, Children's Hospital of Fudan University, Shanghai Key Laboratory of Birth Defect, Shanghai, China
,
Jiang Wang
1   Department of Pediatric Surgery, Children's Hospital of Fudan University, Shanghai Key Laboratory of Birth Defect, Shanghai, China
,
Yi Fan Yang
1   Department of Pediatric Surgery, Children's Hospital of Fudan University, Shanghai Key Laboratory of Birth Defect, Shanghai, China
,
Zhen Shen
1   Department of Pediatric Surgery, Children's Hospital of Fudan University, Shanghai Key Laboratory of Birth Defect, Shanghai, China
,
Gong Chen
1   Department of Pediatric Surgery, Children's Hospital of Fudan University, Shanghai Key Laboratory of Birth Defect, Shanghai, China
,
Yan Lei Huang
1   Department of Pediatric Surgery, Children's Hospital of Fudan University, Shanghai Key Laboratory of Birth Defect, Shanghai, China
,
Yi Jie Zheng
2   Division of Abbott Diagnostics, Medical Scientific Liaison Asian Pacific, Shanghai, China
,
Rui Dong
1   Department of Pediatric Surgery, Children's Hospital of Fudan University, Shanghai Key Laboratory of Birth Defect, Shanghai, China
,
Shan Zheng
1   Department of Pediatric Surgery, Children's Hospital of Fudan University, Shanghai Key Laboratory of Birth Defect, Shanghai, China
› Author Affiliations
Further Information

Publication History

05 March 2018

25 April 2018

Publication Date:
17 June 2018 (online)

Abstract

Introduction Biliary atresia (BA) is a progressive inflammatory obstructive cholangiopathy in infants. High mobility group box 1 (HMGB1) is known to play an important role as a late mediator of inflammation. However, it is not clear whether HMGB1 levels are of clinical significance in patients with BA. The aim of this study was to determine correlations between serum HMGB1 levels and the clinicopathologic features of BA.

Materials and Methods Serum samples were collected from 19 infants with BA, 7 infants with anicteric choledochal cysts (CC) and normal liver function, and 8 healthy controls. Serum HMGB1 levels were measured with an enzyme-linked immunosorbent assay. Routine liver function tests were performed on serum samples. Quantitative real-time polymerase chain reaction and western blot analyses were used to detect HMGB1 expression in BA liver biopsy tissues. Localization of HMGB1 expression in the hepatic lobule was determined by immunohistochemical analysis.

Results HMGB1 levels in serum collected from BA infants were significantly elevated compared with CC and healthy control patients. Furthermore, elevated serum levels of HMGB1 in BA infants positively correlated with gamma-glutamyl transferase levels. HMGB1 messenger ribonucleic acid and protein expression levels were upregulated in BA liver biopsy tissues compared with CC patients. Immunohistochemical analysis also revealed increased positive immunostaining for HMGB1 in BA liver tissues as compared with CC tissues.

Conclusion HMGB1 may play a crucial role in the pathogenesis of BA. Additionally, the correlation of serum HMGB1 levels with gamma-glutamyl transferase levels may provide a novel marker for the diagnosis of BA.

 
  • References

  • 1 Bessho K, Bezerra JA. Biliary atresia: will blocking inflammation tame the disease?. Annu Rev Med 2011; 62: 171-185
  • 2 Hartley J, Harnden A, Kelly D. Biliary atresia. BMJ 2010; 340: c2383
  • 3 Petersen C, Davenport M. Aetiology of biliary atresia: what is actually known?. Orphanet J Rare Dis 2013; 8: 128
  • 4 Bezerra JA, Tiao G, Ryckman FC. , et al. Genetic induction of proinflammatory immunity in children with biliary atresia. Lancet 2002; 360 (9346): 1653-1659
  • 5 Hartley JL, Davenport M, Kelly DA. Biliary atresia. Lancet 2009; 374 (9702): 1704-1713
  • 6 Bezerra JA. Biliary atresia--translational research on key molecular processes regulating biliary injury and obstruction. Chang Gung Med J 2006; 29 (03) 222-230
  • 7 Mack CL. The pathogenesis of biliary atresia: evidence for a virus-induced autoimmune disease. Semin Liver Dis 2007; 27 (03) 233-242
  • 8 Baumann U, Ure B. Biliary atresia. Clin Res Hepatol Gastroenterol 2012; 36 (03) 257-259
  • 9 Feldman AG, Mack CL. Biliary atresia: cellular dynamics and immune dysregulation. Semin Pediatr Surg 2012; 21 (03) 192-200
  • 10 de Oliveira FdosS, Kieling CO, dos Santos JL. , et al. Serum and tissue transforming [corrected] growth factor β1 in children with biliary atresia. J Pediatr Surg 2010; 45 (09) 1784-1790
  • 11 Okamura A, Harada K, Nio M, Nakanuma Y. Interleukin-32 production associated with biliary innate immunity and proinflammatory cytokines contributes to the pathogenesis of cholangitis in biliary atresia. Clin Exp Immunol 2013; 173 (02) 268-275
  • 12 Bessho K, Mourya R, Shivakumar P. , et al. Gene expression signature for biliary atresia and a role for interleukin-8 in pathogenesis of experimental disease. Hepatology 2014; 60 (01) 211-223
  • 13 Mack CL, Tucker RM, Sokol RJ. , et al. Biliary atresia is associated with CD4+ Th1 cell-mediated portal tract inflammation. Pediatr Res 2004; 56 (01) 79-87
  • 14 Shivakumar P, Campbell KM, Sabla GE. , et al. Obstruction of extrahepatic bile ducts by lymphocytes is regulated by IFN-gamma in experimental biliary atresia. J Clin Invest 2004; 114 (03) 322-329
  • 15 Dong R, Dong K, Wang X, Chen G, Shen C, Zheng S. Interleukin-33 overexpression is associated with gamma-glutamyl transferase in biliary atresia. Cytokine 2013; 61 (02) 433-437
  • 16 Li J, Razumilava N, Gores GJ. , et al. Biliary repair and carcinogenesis are mediated by IL-33-dependent cholangiocyte proliferation. J Clin Invest 2014; 124 (07) 3241-3251
  • 17 Dong R, Deng P, Huang Y, Shen C, Xue P, Zheng S. Identification of HSP90 as potential biomarker of biliary atresia using two-dimensional electrophoresis and mass spectrometry. PLoS One 2013; 8 (07) e68602
  • 18 Dong R, Zheng S. Interleukin-8: a critical chemokine in biliary atresia. J Gastroenterol Hepatol 2015; 30 (06) 970-976
  • 19 Goodwin GH, Sanders C, Johns EW. A new group of chromatin-associated proteins with a high content of acidic and basic amino acids. Eur J Biochem 1973; 38 (01) 14-19
  • 20 Chen R, Hou W, Zhang Q, Kang R, Fan XG, Tang D. Emerging role of high-mobility group box 1 (HMGB1) in liver diseases. Mol Med 2013; 19: 357-366
  • 21 Venereau E, Casalgrandi M, Schiraldi M. , et al. Mutually exclusive redox forms of HMGB1 promote cell recruitment or proinflammatory cytokine release. J Exp Med 2012; 209 (09) 1519-1528
  • 22 Harris HE, Andersson U, Pisetsky DS. HMGB1: a multifunctional alarmin driving autoimmune and inflammatory disease. Nat Rev Rheumatol 2012; 8 (04) 195-202
  • 23 Alvarez F. Is biliary atresia an immune mediated disease?. J Hepatol 2013; 59 (04) 648-650
  • 24 Nakamura K, Tanoue A. Etiology of biliary atresia as a developmental anomaly: recent advances. J Hepatobiliary Pancreat Sci 2013; 20 (05) 459-464
  • 25 Lages CS, Simmons J, Chougnet CA, Miethke AG. Regulatory T cells control the CD8 adaptive immune response at the time of ductal obstruction in experimental biliary atresia. Hepatology 2012; 56 (01) 219-227
  • 26 Mieli-Vergani G, Vergani D. Biliary atresia. Semin Immunopathol 2009; 31 (03) 371-381
  • 27 Mack CL, Feldman AG, Sokol RJ. Clues to the etiology of bile duct injury in biliary atresia. Semin Liver Dis 2012; 32 (04) 307-316
  • 28 Schreiber RA, Kleinman RE. Genetics, immunology, and biliary atresia: an opening or a diversion?. J Pediatr Gastroenterol Nutr 1993; 16 (02) 111-113
  • 29 Jafri M, Donnelly B, Bondoc A, Allen S, Tiao G. Cholangiocyte secretion of chemokines in experimental biliary atresia. J Pediatr Surg 2009; 44 (03) 500-507
  • 30 Andersson U, Tracey KJ. HMGB1 is a therapeutic target for sterile inflammation and infection. Annu Rev Immunol 2011; 29: 139-162
  • 31 Hori O, Brett J, Slattery T. , et al. The receptor for advanced glycation end products (RAGE) is a cellular binding site for amphoterin. Mediation of neurite outgrowth and co-expression of rage and amphoterin in the developing nervous system. J Biol Chem 1995; 270 (43) 25752-25761
  • 32 Park JS, Svetkauskaite D, He Q. , et al. Involvement of toll-like receptors 2 and 4 in cellular activation by high mobility group box 1 protein. J Biol Chem 2004; 279 (09) 7370-7377
  • 33 Dumitriu IE, Baruah P, Bianchi ME, Manfredi AA, Rovere-Querini P. Requirement of HMGB1 and RAGE for the maturation of human plasmacytoid dendritic cells. Eur J Immunol 2005; 35 (07) 2184-2190
  • 34 Ivanov S, Dragoi AM, Wang X. , et al. A novel role for HMGB1 in TLR9-mediated inflammatory responses to CpG-DNA. Blood 2007; 110 (06) 1970-1981
  • 35 Qiu Y, Yang J, Wang W. , et al. HMGB1-promoted and TLR2/4-dependent NK cell maturation and activation take part in rotavirus-induced murine biliary atresia. PLoS Pathog 2014; 10 (03) e1004011