interleukin-8 and Biliary-Atresia

Biliary atresia (BA) is characterized by periductular inflammation and fibrosis and is associated with the progressive obliteration of the bile ducts. The induction and maintenance of systemic and local inflammatory responses plays a pivotal role in this process. Interleukin-8 (IL-8) is an important mediator of inflammation and the immune response in human disease. IL-8 is overexpressed in BA, and its expression positively correlates with inflammation and liver fibrosis. In this review, we focus on the available evidence, recent insights, and future clinical and preclinical possibilities regarding the role of IL-8 in BA.

Topics: Biliary Atresia; Biomarkers; Humans; Inflammation Mediators; Interleukin-8; Liver Cirrhosis; Molecular Targeted Therapy

Biliary atresia (BA) is a progressive fibroinflammatory obstruction of extrahepatic bile ducts that presents as neonatal cholestasis. Due to the overlap in clinical, biochemical, and histological features with other causes of cholestasis, the diagnosis requires an intraoperative cholangiogram. Thus, we determined whether diseased livers express a gene expression signature unique to BA. Applying stringent statistical analysis to a genome-wide liver expression platform of 64 infants with BA at the time of diagnosis, 14 age-appropriate subjects with intrahepatic cholestasis as diseased controls and seven normal controls, we identified 15 genes uniquely expressed in BA with an accuracy of 92.3%. Among these genes, IL8 and LAMC2 were sufficient to classify subjects with BA distinctly from diseased controls with an area under the curve of 0.934 (95% confidence interval [CI]: 0.84-1.03), sensitivity of 96.9%, and specificity of 85.7% using their combined first principal component. Direct measurement of interleukin (IL)8 protein in the serum, however, was not different between the two groups. To investigate whether the liver-restricted increase in IL8 was relevant to disease pathogenesis, we inactivated the signaling of IL8 homologs by genetic targeting of the Cxcr2 receptor in a murine model of experimental BA. Disruption of Cxcr2 shortened the duration of cholestasis, decreased the incidence of bile duct obstruction, and improved survival above wild-type neonatal mice.. The hepatic expression of IL8 and LAMC2 has high sensitivity for BA at diagnosis and may serve as a biomarker of disease, with an important role for the IL8 signaling in experimental BA.

Topics: Animals; Animals, Newborn; Biliary Atresia; Biomarkers; Cholestasis; Diagnosis, Differential; Disease Models, Animal; Female; Genome-Wide Association Study; Humans; Infant; Infant, Newborn; Interleukin-8; Laminin; Male; Mice; Mice, Inbred BALB C; Mice, Knockout; Prospective Studies; Receptors, Interleukin-8B; Sensitivity and Specificity

Inflammation and immune dysregulation persuade biliary duct injury in biliary atresia (BA), a leading cause of pediatric liver transplantation given lack of specific biomarkers. We aimed to determine associations between systemic cytokine profiles and clinical parameters in BA patients and to identify potential BA biomarkers.. Systemic levels of 27 cytokines were measured in 82 BA patients and 25 healthy controls using a multiplex immunoassay. Relative mRNA expressions of candidate cytokines in 20 BA livers and 5 non-BA livers were assessed using quantitative real-time PCR.. Higher levels of 17 cytokines including IL-1β, IL-6, IL-7, IL-8, IL-9, IL-2, IL-15, eotaxin, IP-10, MCP-1, MIP-1α, MIP-1β, G-CSF, IL-1ra, IL-4, IL-5, and IL-10 and lower levels of IFN-α and PDGF were significantly associated with BA. In BA patients, increased levels of IL-7, eotaxin, IP-10, and IL-13 were significantly associated with unfavorable outcomes including jaundice, fibrosis, and portal hypertension. Indeed, systemic levels of those cytokines were significantly correlated with clinical parameters indicating jaundice, fibrosis, and hepatic dysfunction in BA patients. Out of 27 cytokines, 4 (IL-8, IP-10, MCP-1, and PDGF) had potential as sensitive and specific biomarkers of BA. Of these, higher IL-8 levels were significantly associated with reduced survival of BA. In BA livers, relative mRNA expressions of IL-8, IP-10, and MCP-1 were significantly up-regulated.. Higher levels of several cytokines including inflammatory cytokines, immunomodulatory cytokines, chemokines, and anti-inflammatory cytokines and lower levels of growth factors would reflect inflammatory and immune responses related to BA development. Among 27 cytokines, plasma IL-8 might have great potential as a diagnostic and prognostic biomarker for BA.

Topics: Biliary Atresia; Biomarkers; Chemokine CXCL10; Child; Cytokines; Fibrosis; Humans; Interleukin-7; Interleukin-8; Jaundice; RNA, Messenger

Biliary atresia (BA) is a severe cholestatic liver disease in children featuring cholestasis and liver fibrosis. The early diagnosis of BA is still challenging. This study aimed to evaluate the diagnostic values of matrix metalloprotease-7 (MMP-7), interleukin-8 (IL-8), and gamma-glutamyl transferase (GGT) in BA. Infants diagnosed with BA and non-BA between 2013 and 2018 were retrospectively analyzed. Plasma levels of MMP-7, IL-8, and GGT were measured in these infants. The receiver operating characteristic (ROC) curves and area under the ROC curve (AUC) were used to assess the diagnostic values of MMP-7, IL-8, and GGT. The expression of MMP-7 and IL-8 in the livers was detected by immunofluorescence staining. A total of 229 infants were enrolled in this study: 156 BA infants and 73 non-BA infants including 16 ones with infantile hepatitis syndrome. The plasma levels of MMP-7, IL-8, and GGT in BA infants had a median of 11.8 ng/mL (interquartile range, IQR: 5.3-57.5), 1.5 ng/mL (IQR: 1.0-2.8), and 381.0 U/L (IQR: 197.0-749.0), respectively, which were higher than non-BA subjects [MMP-7, 4.4 ng/mL (IQR: 3.3-6.1); IL-8, 0.7 ng/mL (IQR: 0.5-1.0); GGT, 59.0 U/L (IQR: 26.0-124.0)]. The AUC values of MMP-7, IL-8, and GGT for the diagnosis of BA were 0.8035, 0.8083, and 0.9126, respectively. The AUC values of MMP-7 + IL-8, MMP-7 + GGT, IL-8 + GGT, and MMP-7 + IL-8 + GGT for the diagnosis of BA were 0.8248, 0.9382, 0.9168, and 0.9392, respectively. The AUC values of MMP-7, IL-8, and GGT for differentiating BA infants with cholic stool from non-BA infants with cholic stool were 0.8006, 0.8258, and 0.9141, respectively. The expression of MMP-7 and IL-8 was increased in the cholangiocytes in BA livers.   Conclusion: Plasma MMP-7, IL-8, and GGT alone or a combination of them has good accuracy to differentiate BA from non-BA and may be reliable biomarkers for BA. What is Known: • Biliary atresia (BA) is a severe cholestatic liver disease in children featuring cholestasis and progressive liver fibrosis. • Although early diagnosis of BA is crucial for good outcomes, it remains a clinical challenge. What is New: • Plasma MMP-7, IL-8, and GGT alone or a combination of them has good accuracy to differentiate BA from non-BA. • Plasma MMP-7, IL-8, and GGT have good accuracy for differentiating BA infants with cholic stool from non-BA infants with cholic stool.

Topics: Biliary Atresia; Biomarkers; Child; Cholestasis; gamma-Glutamyltransferase; Humans; Infant; Interleukin-8; Liver Cirrhosis; Matrix Metalloproteinase 7; Retrospective Studies

To investigate the expression levels of CD4+ T cells, IL-6, IL-8 and IL-33 in liver tissue of BA, and the relationship with postoperative cholangitis, operative age and early jaundice clearance.. 45 cases of jaundice treated in the hospital from June 2018 to May 2020 were analyzed retrospectively. The expression and distribution of these factors were detected by HE staining and immunohistochemistry, the total bilirubin level and the incidence of cholangitis were recorded, and the relationship between liver inflammation level and the postoperative incidence of cholangitis, age of operation and early jaundice clearance were compared.. Immunohistochemistry showed that the expression of CD4+ T cells, IL-6, IL-8 and IL-33 in the BA group were higher than those in the CBD group. ROC curve analysis showed the AUC of CD4+ T cells, IL-6 and IL-8 were 0.869, 0.886 and 0.838, respectively. The expression level of CD4+ T cells was negatively correlated with the decline rate of TBIL 3 months after operation, and the expressions of IL-8 and IL-33 were negatively correlated with the decline rate of TBIL 1 week after operation.. The high expression of CD4+ T cells, IL-6, IL-8 and IL-33 in the BA liver tissue may lead to cholangitis and can be used as a predictor of early jaundice clearance. The degree of liver inflammation infiltration had nothing to do with the age of operation and is not a risk factor for postoperative cholangitis.

Topics: Biliary Atresia; CD4-Positive T-Lymphocytes; Cholangitis; Humans; Infant; Inflammation; Interleukin-33; Interleukin-6; Interleukin-8; Jaundice; Liver; Portoenterostomy, Hepatic; Prognosis; Retrospective Studies

Biliary atresia (BA) is an immune-related disorder and signal transducer and activator of transcription 3 (STAT3) is a key signalling molecule in inflammation. The present study was designed to clarify the function of STAT3 in BA. STAT3 expression was examined in patients and a mouse BA model in which STAT3 levels were further altered with a specific inhibitor or activator. Neutrophil accumulation and the levels of the neutrophil chemoattractants (C-X-C motif) ligand 1 (CXCL1) and IL-8 were determined. The effects of STAT3 inhibition on IL-8 expression were examined in human biliary epithelial cell (BEC) cultures. Functional changes in liver STAT3+ neutrophils in the mouse model were analysed with 10× single cell RNA-seq methods. Results showed STAT3 and p-STAT3 expression was reduced in BA liver tissue compared with control samples. Administration of a STAT3 inhibitor increased jaundice and mortality and reduced body weight in BA mice. In contrast, the STAT3 activator ameliorated BA symptoms. Extensive neutrophil accumulation together with CXCL1 up-regulation, both of which were suppressed by an anti-CXCL1 antibody, were observed in the STAT3 inhibitor-treated group. Recombinant IL-8 administration increased disease severity in BA mice, and the STAT3 activator had the reverse effect. Inhibiting STAT3 increased apoptosis of human BECs together with up-regulated IL-8 expression. RNA-seq analysis revealed reduced the numbers of STAT3 expressing neutrophil in BA which was accompanied by marked enhanced interferon-related antiviral activities. In conclusion, STAT3 reduction, enhanced IL-8 and CXCL1 expression and promoted the accumulation of interferon-responsive neutrophils resulting in BEC damage in BA.

Topics: Animals; Biliary Atresia; Chemokine CXCL1; Disease Models, Animal; Epithelial Cells; Humans; Infant; Interleukin-8; Liver; Mice, Inbred BALB C; Neutrophil Infiltration; Rotavirus; Rotavirus Infections; STAT3 Transcription Factor

Biliary atresia (BA), the most common cause of pediatric end-stage liver disease, results from fibroinflammatory obstruction of the intrahepatic and extrahepatic bile ducts. The etiology of BA has been extensively studied, and inflammation and imbalanced immune system have been identified as the main pathogenesis of BA. B cells play roles in innate and adaptive immunity, but few studies have investigated the role of B cells in BA. This study aimed to elucidate the role of B cells in the development of BA. The percentage and numbers of total B cells (23.81 ± 11.14%，P < 0.0001, 1.22 ± 0.67 × 10

Topics: B-Lymphocytes; Biliary Atresia; Child; Disease Progression; End Stage Liver Disease; Humans; Interleukin-8; Severity of Illness Index

Although the exact etiology of biliary atresia (BA) is still elusive, inflammation plays a key role. Release of proinflammatory cytokines from activated immune cells perpetuates the injury and causes biliary destruction. We aimed to study interleukin (IL)-2 and IL-8 expression in liver tissue of BA patients compared with other neonatal cholestatic disorders.. The study included 59 infants with neonatal cholestasis in two groups; BA group (n=31) and non-BA group (n=28) with cholestatic disorders other than BA as controls. Demographic, clinical, laboratory, and histopathological parameters were collected. IL-2 and IL-8 immunostaining was performed. Immunostaining in portal cellular infiltrate was scored as positive or negative and expressed as the mean cell count in three portal tracts.. The mean value of IL-2 and IL-8 positive inflammatory cells was significantly higher in BA than in non-BA group (P-values of 0.004 and 0.002 respectively). IL-2 correlated significantly with IL-8 immunostaining in both BA and non-BA group (P<0.0001 for both). Furthermore, both cytokines in both groups correlated significantly with inflammatory activity in liver biopsy while there was no significant correlation with the other studied parameters. Yet, there was a trend of increased expression of IL-2 and IL-8 with increasing stage of fibrosis in BA group. This trend was not observed in non-BA group.. The significantly higher expression of IL-2 and IL-8 in patients with BA compared to non-BA suggests a potential role for these cytokines in the pathogenesis in therapy of this devastating neonatal hepatic disorder.

Topics: Biliary Atresia; Cholestasis; Female; Ferritins; Humans; Infant; Infant, Newborn; Inflammation; Interleukin-2; Interleukin-8; Liver; Liver Diseases; Male; Retrospective Studies

Topics: Animals; Biliary Atresia; Female; Genome-Wide Association Study; Humans; Interleukin-8; Male

Topics: Animals; Biliary Atresia; Female; Genome-Wide Association Study; Humans; Interleukin-8; Male

Viral infection and type I interferon have been implicated in the pathogenesis of biliary atresia (BA), but the expression of toll-like receptors (TLRs) that recognize viruses, as well as of type 1 interferon specific signaling molecules are still unknown in BA. Fresh liver tissues were obtained from patients in early and late stage of BA and from patients with choledochal cyst (CC), as well as from normal controls receiving liver resection for benign lesion other than cholestasis or fibrosis. Archived liver tissues from patients with neonatal hepatitis (NH) were obtained for immunohistochemical studies. TLR2, 3, 4, 7 and 9 that recognized Gram-positive bacteria, double-stranded RNA virus, lipopolysaccharide, single-stranded RNA virus and DNA virus, respectively, were studied. Real-time quantitative reverse transcription polymerase chain reaction (QRT-PCR) was used to quantitate TLR, type I interferon specific molecule MxA, interleukin-6 (IL-6) and IL-8 mRNA expression and immunohistochemistry for TLR 7 and MxA protein staining. These results show that there were significantly higher TLR7 and lower TLR3 and TLR9 mRNA expression in early stage of BA than in CC. MxA mRNA expression was also significantly higher in early stage of BA and in CC than in late stage of BA. Immunoreactive TLR7 and MxA staining was higher in early stage of BA than in late stage of BA, NH and CC, which was associated with significantly higher IL-8 mRNA expression in BA than in CC. The results implicate involvement of TLRs, particularly TLR7, and type 1 specific interferon signaling in the pathogenesis of BA, especially in early stage, which is associated with upregulation of inflammatory cytokines IL-8.

Topics: Adolescent; Adult; Biliary Atresia; Child, Preschool; Choledochal Cyst; Female; GTP-Binding Proteins; Humans; Immunohistochemistry; Infant; Interleukin-6; Interleukin-8; Liver; Male; Matched-Pair Analysis; Myxovirus Resistance Proteins; Polymerase Chain Reaction; Toll-Like Receptor 3; Toll-Like Receptor 7; Toll-Like Receptor 9

Biliary atresia (BA) is a neonatal obliterative cholangiopathy of unknown etiology. Despite the Kasai procedure, hepatic fibrosis and portal hypertension (PH) still occur. Interleukin-8 (IL-8) is an important mediator of inflammation and immune response in human disease. The objective of this study was to investigate the potential role of IL-8 in the pathogenesis of the progressive, sclerosing, inflammatory process and fibrosis in BA. A total of 60 pediatric patients with BA and 15 healthy children were evaluated. The mean ages of BA patients and controls were 6.3 +/- 0.6 and 6.7 +/- 1.1 years, respectively. The patients were classified into two groups according to their clinical outcomes: patients with jaundice (total bilirubin +/- 25.5 micromol/l) and patients without jaundice (total bilirubin < 25.5 micromol/l). The IL-8 levels in serum samples were determined by commercially available enzyme-linked immunosorbent assay. Serum IL-8 levels were higher in the BA patients than in healthy children (236.2 +/- 60.1 vs. 34.5 +/- 12.1 pg/ml, P < 0.001). Patients with jaundice had lower levels of albumin but had greater levels of aspartate aminotransferase, alanine aminotransferase, alkaline phosphatase, and gamma glutamyl transpeptidase compared with patients without jaundice. Serum IL-8 levels in the jaundice group were significantly higher than in those without jaundice (516.5 +/- 130.0 vs. 49.3 +/- 10.4 pg/ml, P < 0.0005). Furthermore, patients with PH had higher IL-8 levels than those without PH (378.1 +/- 102.2 vs. 106.6 +/- 48.4 pg/ml, P < 0.005). In the jaundice-free group, IL-8 levels were elevated in patients with PH compared with those without PH (79.0 +/- 17.4 vs. 19.7 +/- 5.8 pg/ml, P < 0.005). The present study demonstrated elevation of serum IL-8 levels in children with BA. Serum IL-8 levels were also higher in patients with jaundice compared with patients without jaundice. These findings suggest that IL-8 may play a significant role in the pathogenesis of BA.

Topics: Biliary Atresia; Child; Child, Preschool; Disease Progression; Female; Humans; Interleukin-8; Male

Postoperative cholangitis is common after operation for biliary atresia. Empirical pulse therapy with glucocorticoid is effective in reversing some detrimental clinical manifestations, but the rationale for such a therapy still is not substantiated.. Adult male rats were divided into groups according to the treatment: sterile normal saline (NS) or Escherichia coli (EC, 1 mL containing 10(8) cells of ATCC 25922 strain), 1 mL, were infused into the proximal choledochostomy (PC) tube 2 weeks after ligation of the PC tube (bile duct ligation, BDL), then immediate tube-tube choledocho-choledochostomy (biliary drainage, BD) was constructed. A high dose of dexamethasone (DEX, intraperitoneal injection; 2 mg/kg of body weight) was given after BD in treatment groups. Histopathology of the liver, as well as liver chemokine mRNA expression and serum chemokine levels, were studied 24 hours after treatment.. Inflammatory cell infiltration to the liver was retarded with DEX treatment, which was correlated with a significantly lower expression of interleukin-8 (IL-8) and monocyte chemoattractant protein-1 (MCP-1) mRNA in the liver (P =.006). Serum IL-8 and MCP-1 levels were also significantly down-regulated with DEX treatment (P = 0.008).. Glucocorticoid treatment is effective in modulating IL-8 and MCP-1 expression and ameliorating inflammatory cell infiltration in rat liver with bacterial cholangitis and cholestasis.

Topics: Animals; Bacterial Infections; Biliary Atresia; Chemokine CCL2; Cholangitis; Cholestasis; Dexamethasone; Disease Models, Animal; Down-Regulation; Glucocorticoids; Interleukin-8; Liver; Male; Postoperative Complications; Rats; Rats, Sprague-Dawley

Biliary atresia is a neonatal obstructive cholangiopathy characterized by a destructive, obliterative process affecting both the intrahepatic and extrahepatic ducts of the biliary tree that uniquely presents in the first months of life. The consequence of progressive inflammatory and sclerotic reaction is the development of obstructive jaundice. To determine the proinflammatory cytokine profile in children with biliary atresia, we measured circulating levels of interleukin (IL)-1beta, IL-6, tumor necrosis factor-alpha and IL-8.. Twelve children, five males and seven females, with biliary atresia were studied. In addition, four patients with progressive familial intrahepatic cholestasis and three with Alagille syndrome were also included. Five patients with neonatal hepatitis were studied as controls of a liver disease without portal fibrosis. Serum concentration of total and conjugated bilirubin, gamma-glutamyl transferase and glutamic-pyruvic transaminase were measured by routine methods in all patients at time of sampling for the study. The degree of fibrosis in liver biopsies was scored using the histologic activity index.. In our study IL-8 was detectable in 11 of 12 patients with biliary atresia with a median level of 262 pg/ml and a highly statistically significant difference (P < 0.0001) from controls. In patients with progressive familial intrahepatic cholestasis or with Alagille syndrome serum IL-8 levels were similarly elevated. In patients with neonatal hepatitis, IL-8 levels were marginally increased. Serum IL-8 levels were significantly correlated (Rs = 0.725, P < 0.0001) with the histologic activity index.. Although further studies are needed to determine the role of IL-8 in portal inflammation, our results suggest that increased production of IL-8 may be a mechanism leading to the progressive portal inflammation and fibrosis in patients with chronic liver disease.

Topics: Biliary Atresia; Case-Control Studies; Chronic Disease; Female; Humans; Infant; Interleukin-1; Interleukin-6; Interleukin-8; Liver; Liver Diseases; Male; Tumor Necrosis Factor-alpha

Mutations of human jagged 1 (JAG1) gene are responsible for Alagille Syndrome (AGS), whose 2 main symptoms are intrahepatic bile duct hypoplasia and pulmonary stenosis. We examined the JAG1 mutation in extrahepatic biliary atresia (EHBA), which is similar in phenotype to AGS, although a different pathogenesis is suggested. In 102 cases of EHBA, 9 missense mutations were detected, including 2 intrafamilial expressions in the propositus and an aunt of one family. These mutations were all missense and sporadic except for those of this particular family. The JAG1 gene mutations were generally found in severely ill patients subjected to liver transplantation at less than 5 years of age. None of the 9 cases of EHBA revealed any of the 5 major symptoms of AGS nor any identical pathological findings after 3 years of follow-up. Our cases were clearly separated from AGS by pathological findings and clinical features, and could be diagnosed as EHBA and not as atypical AGS. The increase of interleukin 8 (IL-8) production induced by tumor necrosis factor alpha (TNF-alpha) in Huh 7 cells was suppressed by the coexistence of JAG1 protein. We examined the different influences between wild-type cells and the 3 kinds of mutants detected in EHBA on Huh 7 cells and found that 2 of 3 mutants showed about half of the repressed activity compared with that of wild type. In conclusion, these results suggest that the JAG1 gene abnormality may be an aggravating factor in EHBA.

Topics: Adult; Alagille Syndrome; Bile Ducts; Biliary Atresia; Calcium-Binding Proteins; Child; Child, Preschool; Diagnosis, Differential; DNA Mutational Analysis; Family Health; Female; Humans; Intercellular Signaling Peptides and Proteins; Interleukin-8; Jagged-1 Protein; Male; Membrane Proteins; Mutation, Missense; Pedigree; Phenotype; Proteins; Serrate-Jagged Proteins; Severity of Illness Index; Tumor Necrosis Factor-alpha