The Distribution and the Fibrotic Role of Elevated Inflammatory Th17 Cells in Patients With Primary Biliary Cirrhosis - PubMed (original) (raw)
The Distribution and the Fibrotic Role of Elevated Inflammatory Th17 Cells in Patients With Primary Biliary Cirrhosis
TianYan Shi et al. Medicine (Baltimore). 2015 Nov.
Abstract
T helper (Th) 17 cells were reported to have the property of proinflammation and profibrosis. We first investigate the levels of Th17 cells in primary biliary cirrhosis (PBC) patients, and then explore their distribution and fibrotic role in the disease.We compared the circulating Th17 and hepatic interleukin (IL)-17-positive cells between patients and healthy controls (HCs) at different disease stages by flow cytometry and immunohistochemistry, respectively. The levels of chemokine (c-c motif) ligand (CCL) 20 were then measured. For exploration of the reason why Th17 cells increased, CD4CD161 populations were sorted and cultured with IL-23 and IL-1β to analyze their proliferation and IL-17 secretions. The serum IL-23 and IL-1β were tested by enzyme-linked immunosorbent assay. The proliferation and expressions of α-smooth muscle actin and IL-8 of hepatic stellate cells (HSCs) were identified after stimulated by different concentrations of IL-17.Circulating and hepatic Th17 cells were elevated in PBC patients compared with HCs. Early PBC patients presented with more Th17 cells in periphery blood and less in the liver than advanced PBC patients. Accordingly, the levels of both serum and hepatic CCL20 for Th17 cells were higher, especially in those with advanced disease. The progenitor of Th17, CD4CD161 cell was increased in PBC. Moreover, the percentage of Th17 cells was positively related with CD4CD161 cell. After stimulation with IL-23 and IL-1β which were improved in PBC patients, CD4CD161 cells from PBC patients expressed more IL-17, although their proliferation were not different between 2 groups. IL-17 can promote the proliferation of HSCs at a dose-dependent method, and also increase the IL-8 expression in a dose/time-dependent way. Anti-IL-17 can neutralize the above reactions.CD4CD161 cells are a source of increased Th17 in PBC patients. With disease progression, Th17 population decreased in the circulation, accompanied by greater accumulation in the liver, which is regulated by CCL20 in advanced patients. IL-17 may be involved in the process of PBC fibrosis.
Conflict of interest statement
The authors have no conflicts of interest to disclose.
Figures
FIGURE 1
Expression of IL-17 in CD4+ T cells in patients with PBC (n = 35), chronic hepatitis B (n = 15), and HCs (n = 35). (A) Frequency of Th17 cells in PBC patients, chronic hepatitis B, and HCs, respectively. (B) Frequency of Th17 cells in E-PBC and A-PBC patient groups, respectively. (C) Representative flow cytometry results for Th17 cells from PBC patients, CHB, and HCs. A-PBC = advanced primary biliary cirrhosis, CHB = chronic hepatitis B, E-PBC = early primary biliary cirrhosis, HCs = healthy controls, IL = interleukin, PBC = primary biliary cirrhosis, Th = T helper.
FIGURE 2
Detection of IL-17+ cells in the liver in patients with PBC (n = 16) and HCs (n = 4). (×100) (Blank arrows indicate the IL-17+ cells, which were stained brown). HCs = healthy controls, IL = interleukin, PBC = primary biliary cirrhosis.
FIGURE 3
The level of CCL20 in serum and liver in PBC patients and HCs. (A) Levels of CCL20 in PBC patients (n = 35) and HCs (n = 35), respectively. (B) Hepatic CCL20 in PBC patients (n = 6) and HCs (n = 4), respectively. CCL20 = chemokine (c-c motif) ligand 20, HCs = healthy controls, PBC = primary biliary cirrhosis.
FIGURE 4
The source for elevated Th17 cells in PBC patients. (A) Frequency of CD161+CD4+ cells in the CD4+ T compartment in PBC patients (n = 20) and HCs (n = 20), respectively. (B) Relationship between Th17 cells and CD161+CD4+ cells (n = 40). (C) IL-17 expression of CD161+CD4+ cells after stimulation in vitro in PBC patients (n = 6) and HCs (n = 6), respectively. (D) Levels of serum IL-23 and IL-1β in PBC patients (n = 35) and HCs (n = 35), respectively. (E) Representative flow cytometry results for CD161+CD4+ cells in the CD4+ T compartment from PBC patients and HCs. HCs = healthy controls, IL = interleukin, PBC = primary biliary cirrhosis, Th = T helper.
FIGURE 5
The influence of IL-17 on HSCs. (A) Proliferation of HSCs after stimulation with IL-17 at different concentrations. (B) Levels of IL-8 in HSCs culture supernatant after stimulation with IL-17 at different concentrations. HSC = hepatic stellate cell, IL = interleukin.
References
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