Dataset Information

The Interleukin-20 Cytokine Family in Liver Disease.

ABSTRACT: The three main causes of inflammation and chronic injury in the liver are viral hepatitis, alcohol consumption, and non-alcoholic steatohepatitis, all of which can lead to liver fibrosis, cirrhosis, and hepatocellular carcinoma, which in turn may prompt the need for liver transplant. The interleukin (IL)-20 is a subfamily part of the IL-10 family of cytokines that helps the liver respond to damage and disease, they participate in the control of tissue homeostasis, and in the immunological responses developed in this organ. The best-studied member of the family in inflammatory balance of the liver is the IL-22 cytokine, which on the one hand may have a protective role in fibrosis progression but on the other may induce liver tissue susceptibility in hepatocellular carcinoma development. Other members of the family might also carry out this dual function, as some of them share IL receptor subunits and signal through common intracellular pathways. Investigators are starting to consider the potential for targeting IL-20 subfamily members in liver disease. The recently explored role of miRNA in the transcriptional regulation of IL-22 and IL-24 opens the door to promising new approaches for controlling the local immune response and limiting organ injury. The IL-20RA cytokine receptor has also been classified as being under miRNA control in non-alcoholic steatohepatitis. Moreover, researchers have proposed combining anti-inflammatory drugs with IL-22 as a hepatoprotective IL for alcoholic liver disease (ALD) treatment, and clinical trials of ILs for managing severe alcoholic-derived liver degeneration are ongoing. In this review, we focus on exploring the role of the IL-20 subfamily of cytokines in viral hepatitis, ALD, non-alcoholic steatohepatitis, and hepatocellular carcinoma, as well as delineating the main strategies explored so far in terms of therapeutic possibilities of the IL-20 subfamily of cytokines in liver disease.

SUBMITTER: Caparros E

PROVIDER: S-EPMC5985367 | biostudies-literature | 2018

REPOSITORIES: biostudies-literature

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The Interleukin-20 Cytokine Family in Liver Disease.

Caparrós Esther E Francés Rubén R

Frontiers in immunology 20180528

The three main causes of inflammation and chronic injury in the liver are viral hepatitis, alcohol consumption, and non-alcoholic steatohepatitis, all of which can lead to liver fibrosis, cirrhosis, and hepatocellular carcinoma, which in turn may prompt the need for liver transplant. The interleukin (IL)-20 is a subfamily part of the IL-10 family of cytokines that helps the liver respond to damage and disease, they participate in the control of tissue homeostasis, and in the immunological respon ...[more]

PMID: 29892294

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Project description:Nontuberculous mycobacteria (NTM) cause pulmonary disease in individuals without obvious immunodeficiency. This study was initiated to gain insight into the immunological factors that predispose persons to NTM pulmonary disease (NTMPD). Blood was obtained from 15 pairs of NTMPD patients and their healthy household contacts. Peripheral blood mononuclear cells (PBMCs) were stimulated with the Mycobacterium avium complex (MAC). A total of 34 cytokines and chemokines were evaluated in plasma and PBMC culture supernatants using multiplex immunoassays, and gene expression in the PBMCs was determined using real-time PCR. PBMCs from NTMPD patients produced significantly less interleukin-1β (IL-1β), IL-18, IL-1α, and IL-10 than PBMCs from their healthy household contacts in response to MAC. Although plasma RANTES levels were high in NTMPD patients, they had no effect on IL-1β production by macrophages infected with MAC. Toll-like receptor 2 (TLR2) and TWIK2 (a two-pore domain K+ channel) were impaired in response to MAC in PBMCs of NTMPD patients. A TLR2 inhibitor decreased all four cytokines, whereas a two-pore domain K+ channel inhibitor decreased the production of IL-1β, IL-18, and IL-1α, but not IL-10, by MAC-stimulated PBMCs and monocytes. The ratio of monocytes was reduced in whole blood of NTMPD patients compared with that of healthy household contacts. A reduced monocyte ratio might contribute to the attenuated production of IL-1 family cytokines by PBMCs of NTMPD patients in response to MAC stimulations. Collectively, our findings suggest that the attenuated IL-1 response may increase susceptibility to NTM pulmonary infection through multiple factors, including impaired expression of the TLR2 and TWIK2 and reduced monocyte ratio. IMPORTANCE Upon MAC stimulation, the production of IL-1 family cytokines and IL-10 by PBMCs of NTMPD patients was attenuated compared with that of healthy household contacts. Upon MAC stimulation, the expression of TLR2 and TWIK2 (one of the two-pore domain K+ channels) was attenuated in PBMCs of NTMPD patients compared with that of healthy household contacts. The production of IL-1 family cytokines by MAC-stimulated PBMCs and MAC-infected monocytes of healthy donors was reduced by a TLR2 inhibitor and two-pore domain K+ channel inhibitor. The ratio of monocytes was reduced in whole blood of NTMPD patients compared with that of healthy household contacts. Collectively, our data suggest that defects in the expression of TLR2 and TWIK2 in human PBMCs or monocytes and reduced monocyte ratio are involved in the reduced production of IL-1 family cytokines, and it may increase susceptibility to NTM pulmonary infection.

Project description:Mycetoma is a neglected tropical disease, endemic in many tropical and subtropical regions, characterised by massive deformity and disability and can be fatal if untreated early and appropriately. Interleukins (IL) -35 and IL-37 are newly discovered cytokines that play an important role in suppressing the immune system. However, the expression of these interleukins in patients with Madurella mycetomatis (M. mycetomatis) induced eumycetoma has not yet been explored. The aim of this study is to determine the levels of IL-1 family (IL-1β, IL-37) and IL-12 family (IL-12, IL-35) in a group of these patients and the association between these cytokines levels and the patients' demographic characteristics. The present, case-control study was conducted at the Mycetoma Research Centre, Soba University Hospital, University of Khartoum, Sudan and it included 140 individuals. They were divided into two groups; group I: healthy controls [n = 70; median age 25 years (range 12 to 70 years)]. Group II: mycetoma patients [n = 70 patients; median age 25 (range 13 to 70 years)]. Cytokines levels were measured in sera using enzyme linked immunosorbent assay (ELISA). There was a significant negative correlation between IL-1β and IL-12 levels and lesion size and disease duration, while IL-37 and IL-35 levels were significantly positively correlated with both lesion size and disease duration. The analysis of the risk factors of higher circulatory levels of IL-37 in patients of mycetoma showed a negative significant association with IL-1β cytokine, where a unit increment in IL-1β will decrease the levels of IL-37 by 35.28 pg/ml. The levels of IL-37 among the patients with a duration of mycetoma infection ≤ 1 year were significantly low by an average of 18.45 pg/ml compared to patients with a mycetoma infection's duration of ≥ 5years (reference group). Furthermore, the risk factors of higher levels of IL-35 in mycetoma patients revealed a negative significant association with IL-12, as a unit increment in IL-12 decreases the levels of IL-35 by 8.99 pg/ml (p < 0.001). Levels of IL-35 among the patients with duration of mycetoma infection ≤ one year were significantly low on average by 41.82 pg/ml (p value = 0.002) compared to patients with a duration of mycetoma infection ≥ 5 years (reference group). In conclusion, this study indicates that both IL-35 and IL-37 are negatively associated with the levels of IL-1β and IL-12 in eumycetoma mycetoma infection; and high levels of IL-37 and IL-35 may have a negative impact on disease progression.

Project description:PurposeInflammatory responses may be involved in the glaucomatous process. Our previous studies mapped a T104M mutation in interleukin-20 receptor beta (IL-20RB) in a family with primary open angle glaucoma (POAG). IL-20RB can heterodimerize with IL-20RA to propagate signals from IL-20 family cytokines, IL-19, IL-20, and IL-24 (the type I receptor complex), or it can heterodimerize with IL-22RA to propagate signals from IL-20 and IL-24 (type II receptor complex). In this study, we investigated IL-20 heterodimeric receptor complexes in the trabecular meshwork (TM) compared to dermal fibroblast cell cultures, and examined the phosphorylation of signal transducer and activator of transcription (STAT)-1, -3, and -5 following exposure to IL-20 family cytokines. Additionally, we determined the effects of IL-20 family cytokines on outflow rates in anterior segment perfusion culture, an in vitro model of intraocular pressure (IOP) regulation.MethodsPrimary human TM (HTM) cells were grown from dissected TM tissue, and IL-20 receptor expression was investigated with PCR. A Duolink assay was performed to investigate in situ IL-20 receptor protein interactions in HTM or dermal fibroblasts, and Imaris software was used to quantitate the association of the heterodimeric complexes. Phosphorylation of STAT-1, -3, and -5 were evaluated in HTM or dermal fibroblasts using Western immunoblotting after exposure to IL-10, IL-19, IL-20, IL-22, or IL-24. Anterior segment perfusion culture was performed in human cadaver and porcine eyes treated with IL-20, IL-19, or IL-24.ResultsAll of the IL-20 receptors, IL-20RA, IL-20RB, and IL-22RA1 were expressed in HTM cells. Two isoforms of IL-20RA were expressed: The V1 variant, which is the longest, is the predominant isoform, while the V3 isoform, which lacks exon 3, was also expressed. The Duolink assay demonstrated that the type I (IL-20RA-IL-20RB) and type II (IL-22RA1-IL-20RB) receptors were expressed in HTM cells and dermal fibroblasts. However, in the HTM cells, the type I receptor was present at significantly higher levels, while the type II receptor was preferentially used in the dermal fibroblasts. The HTM cells and the dermal fibroblasts predominantly phosphorylate the Ser727 site in STAT-3. The dermal fibroblasts had higher induction of phosphorylated STAT-1 compared to the HTM cells, while neither cell type had phosphorylated STAT-5 in the cell lysates. The outflow rates in the human anterior segment cultures were increased 2.3-fold by IL-20. However, IL-19 and IL-24 showed differential responses. For IL-19 and IL-24, 50% of the eyes responded with a 1.7- or 1.5-fold increase, respectively, while the other half did not respond. Similarly, perfused porcine anterior segments showed "responders" and "non-responders": IL-20 responders (2.3-fold increase in outflow, n=12) and non-responders (n=11); IL-19 responders (2.1-fold increase, n=7) and non-responders (n=5); and IL-24 responders (1.8-fold increase, n=12) and non-responders (n=5).ConclusionsType I and type II IL-20 receptor complexes are expressed in human TM cells with predominant expression of the type I receptor (IL-20RA and IL-20RB), which propagates signals from all three IL-20 family cytokines. However, there was a variable response in the outflow rates following perfusion of cytokines in two different species. This may explain why some people are more susceptible to developing elevated IOP in response to inflammation.

Dataset Information

The Interleukin-20 Cytokine Family in Liver Disease.

Publications

The Interleukin-20 Cytokine Family in Liver Disease.

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