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

Abstract

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.

The Role of IL-35 in the Pathophysiological Processes of Liver Disease

“…Meanwhile, at different stages of disease, IL-35 was positively correlated with the TGF-β closely, which was related to Treg expression level in LC patients. Interestingly, the change trend of the expression levels of TGF-β and IL-35 in serum was consistent with Th17 Tregs in PBC (Li et al, 2018). Studies shown that the expression level of IL-35 might have relevance to histological grade and the severity of PBC.…”

“…The expression level of IL-35 in serum in PBC patients was lower than that in healthy individuals. The expression level of Ebi3 mRNA was decreased in PBC patients as well, but no statistical difference in the expression level of p35 mRNA level (Li et al, 2018). IL-35 in PBC patients was inversely associated with expression levels of clinical parameters, such as ALP, GGT, AST, ALT, and cytokines produced by CD4+ T cells (IFN-γ, IL-23, IL-17).…”

“…The expression level of IL-35 in serum in patients with stage III or IV was higher than that in patients with stage II. Furthermore, the mRNA and protein expression levels of IL-35 had negative association with LC Child-Pugh classification (Ma et al, 2014;Li et al, 2018). LC patients with portal hypertension were treated with phased joint operation (Cho et al, 2020).…”

Abnormal Expression of ERα in Cholangiocytes of Patients With Primary Biliary Cholangitis Mediated Intrahepatic Bile Duct Inflammation

“…We found that the levels of IL-6, IL-8, and TNF-α in the patients were higher than that in HC (Mann-Whitney test Z = −6.997, P < 0.001; Z = −7.180, P < 0.001; Z = −6.599, P < 0.001, respectively) (Figures 1A–C). Moreover, as Li et al (22) proposed, the serum abnormal cytokines levels may have a linear relationship with the parameters for liver functions (AKP, γ-GT, and TBiL) in PBC patients. As expected, the results from the present study showed that there were a positive correlations between the levels of AKP and IL-6 ( r = 0.430, p = 0.004), IL-8 ( r = 0.389, p = 0.010) and TNF-α ( r = 0.496, p = 0.001) (Figures 1D–F).…”

Kupffer Cells Regulate Natural Killer Cells Via the NK group 2, Member D (NKG2D)/Retinoic Acid Early Inducible-1 (RAE-1) Interaction and Cytokines in a Primary Biliary Cholangitis Mouse Model

“…Patients with PBC exhibit a marked increase in the frequency and absolute number of blood and liver NK cells. The increased presence of scattered NK cells near disrupted small bile ducts was observed at an increased frequency in liver tissues from PBC patients by immunohistochemical observation [ 2 ]. A similar phenomenon was observed in our animal model.…”