Increased IL-23 and IL-17 expression by peripheral blood cells of patients with primary biliary cirrhosis

Qian, Cheng; Jiang, Tingwang; Zhang, Weiwei; Ren, Chuanlu; Wang, Qianqian; Qin, Qin; Chen, Jie; Deng, Anmei; Zhong, Ruiqin

doi:10.1016/j.cyto.2013.07.005

Cited by 52 publications

(38 citation statements)

References 22 publications

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“…We did not observe a difference in relative mRNA expression of p35 between the two groups, as was also the case in our previous research (Qian et al 2013). This result might be due to the complexity of IL-12 cytokines.…”

Section: Discussionsupporting

confidence: 64%

Lower Plasma Levels of IL-35 in Patients with Primary Biliary Cirrhosis

Huang

Liu

et al. 2018

Tohoku J. Exp. Med.

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Primary biliary cirrhosis (PBC) is an autoimmune liver disease. Its histological characteristics, such as progressive intrahepatic bile duct destruction, cholestasis, and liver cirrhosis, are caused by the body's autoimmune disorders. Interleukin (IL)-35 has two subunits (p35 and Ebi3) and is a member of the IL-12 family of heterodimeric cytokines. IL-35 has immunosuppressive functions and plays an important role in many autoimmune diseases. In this study, we compared plasma levels of IL-35 and relative mRNA expression levels of p35 and Ebi3 in peripheral blood mononuclear cells (PBMCs) from 70 PBC patients and 70 healthy individuals. The results showed that the relative expression levels of Ebi3 mRNA were lower in PBMCs from PBC patients than in PBMCs from healthy individuals, whereas the levels of p35 mRNA were similar in both groups. Plasma IL-35 concentrations were lower in patients with PBC than in healthy individuals. Plasma levels were higher in PBC patients at an advanced stage compared to patients at an early stage. Variable plasma levels with different stages were also found in transforming growth factor beta (TGF-β), which is mainly produced by regulatory T cells (Tregs). IL-35 and TGF-β levels were positively correlated with each other, and IL-35 was capable of promoting the inhibitory functions of Tregs in PBC patients at both the early and late stages of disease. Lower plasma IL-35 levels were accompanied by higher levels of typical clinical parameters, such as alkaline phosphatase, or of proinflammatory cytokines, such as interferon-gamma (IFN-γ), in PBC patients (P < 0.05 for each). We propose that IL-35 may be involved in the pathogenesis of PBC and could be a potential biomarker for diagnosing this disease.

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Section: Discussionsupporting

confidence: 64%

Lower Plasma Levels of IL-35 in Patients with Primary Biliary Cirrhosis

Huang

Liu

et al. 2018

Tohoku J. Exp. Med.

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“…These results suggest that IL-17A in PBC exerts pro-inflammatory effects in early stage. These results are consistent with the previous results that the expression of IL-17A was increased in PBC patients (Lan et al 2009;Qian et al 2013). We also found the elevated expression of IL-17A receptor in IBECs in PBC patients (Fig.…”

Section: Discussionsupporting

confidence: 83%

“…Thus, IL-17A was elevated in PBC patients compared with healthy controls. Our data confirmed similar findings in previous studies in PBC patients (Lan et al 2009;Qian et al 2013).…”

Section: Elevated Il-17a and Il-17a Receptor In The Livers Of Pbc Patsupporting

confidence: 83%

“…Previous studies showed that frequencies of IL-17A-positive lymphocytic cells were increased in the liver from PBC patients (Lan et al 2009) and IL-17A expression was elevated in peripheral blood of PBC patients (Qian et al 2013). Additionally, IL-17A induced EMT of epithelial cells (Mi et al 2011;Ji et al 2013;Vittal et al 2013).…”

Section: Elevated Il-17a and Il-17a Receptor In The Livers Of Pbc Patmentioning

confidence: 99%

“…Interleukin-17 (IL-17A), a typical pro-inflammatory cytokine, has recently been shown to induce EMT of alveolar epithelial cells (Mi et al 2011) and bronchial epithelial cells (Ji et al 2013;Vittal et al 2013). Interestingly, fre-quencies of IL-17A -positive lymphocytic cells are increased in the liver of PBC patients (Lan et al 2009) and IL-17A expression is elevated in peripheral blood of PBC patients (Qian et al 2013). However, the association between IL-17A and IBECs-EMT and their roles in the pathogenesis of PBC remain unclear.…”

Section: Introductionmentioning

confidence: 99%

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Interleukin-17A-Induced Epithelial-Mesenchymal Transition of Human Intrahepatic Biliary Epithelial Cells: Implications for Primary Biliary Cirrhosis

Huang

Chu

Yin

et al. 2016

Tohoku J. Exp. Med.

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Primary biliary cirrhosis (PBC) is an autoimmune chronic liver disease with worldwide increasing morbidity. However, the etiology of PBC is still unclear. Recently, the epithelial-mesenchymal transition (EMT) and interleukin-17A (IL-17A), a pro-inflammatory cytokine, were proposed to be involved in the pathogenesis of PBC. Therefore, in this study, we aimed to clarify the roles of IL-17A and/or EMT in the onset of PBC. The results showed that the median serum IL-17A level was significantly higher in 29 PBC patients (average course of 40.69 months) than that of 11 healthy controls. The intrahepatic biliary epithelial cells (IBECs), the major target of destruction in PBC, underwent EMT in PBC patients. The immunohistochemical analysis revealed that the protein levels of IL-17A receptor were increased in IBECs and the IL-17A protein was accumulated around the IBECs in the PBC patients. These results imply that the IL-17A-mediated signaling and EMT of intrahepatic biliary epithelial cells (IBEC-EMT) are key pathogenic processes of PBC. To study the association between IL-17A and IBECs-EMT, we then examined if IL-17A induced EMT using a human cell line of IBECs (HIBECs). After the treatment with IL-17A for 48 h, HIBECs changed into bipolar cells with a fibroblastic morphology. Additionally, the results of real-time PCR and Western blot analyses demonstrated that IL-17A up-regulated the expression of a mesenchymal marker vimentin and downregulated the expression of an epithelial marker E-cadherin in HIBECs in the dose-and time-dependent manners. These results suggest that IL-17A may play an important role in the IBECs-EMT.

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IL-12/Th1 and IL-23/Th17 biliary microenvironment in primary biliary cirrhosis: Implications for therapy

et al. 2014

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The interleukin (IL)-12/IL-23 mediated Th1/Th17 signaling pathway has been associated with the etiopathogenesis of primary biliary cirrhosis (PBC). To address the cytokine microenvironment specifically in the liver, we examined the localized expression of cytokine subunits and their corresponding receptors using previously optimized immunohistochemistry with an extensive panel of antibodies directed at IL-12p70, IL-12p35, IFN-γ, IL-12RB2, IL-23p40, IL-23p19, IL-17 and IL-23R using liver from PBC (n=51) and non-PBC (n=80) control liver disease patients. Multiple portal tracts in each patient were blindly evaluated and individually scored. We report herein that although IL-12/Th1 and IL-23/Th17 staining were detected in all of the liver sections, they were primarily localized around the damaged interlobular bile ducts in PBC. Most importantly, Th17 skewing was prominent in advanced PBC patients with intensive secretion of IL-23p19 by inflamed hepatocytes around IL-23R, IL-12RB2, and IFN-γ expressing degenerated cholangiocytes. Our novel finding on the direct association of Th17 skewing and disease severity illustrates the significance of the IL-23/Th17 pathway in the perpetuation of IL-12/Th1-mediated immunopathology in PBC. Furthermore, localized IL-23p19 production by hepatocytes may enhance pro-fibrotic Th17 signaling and pro-inflammatory IFN-γ production that contribute to PBC pathology. In conclusion, our data emphasize the pathogenic relevance of IL-12/Th1 and IL-23/Th17 in the evolution of PBC. Of significance, however, the shift from a Th1 to a Th17 imbalance at advanced stages of the disease suggests the necessity to consider modulation of the IL-23/Th17 pathway as a potential target for therapeutic intervention.

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Increased IL-23 and IL-17 expression by peripheral blood cells of patients with primary biliary cirrhosis

Cited by 52 publications

References 22 publications

Lower Plasma Levels of IL-35 in Patients with Primary Biliary Cirrhosis

Lower Plasma Levels of IL-35 in Patients with Primary Biliary Cirrhosis

Interleukin-17A-Induced Epithelial-Mesenchymal Transition of Human Intrahepatic Biliary Epithelial Cells: Implications for Primary Biliary Cirrhosis

IL-12/Th1 and IL-23/Th17 biliary microenvironment in primary biliary cirrhosis: Implications for therapy

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