IL20Rb aggravates pulmonary fibrosis through enhancing bone marrow derived profibrotic macrophage activation.

Idiopathic pulmonary fibrosis (IPF) is one of the most fatal chronic interstitial lung diseases with unknown pathogenesis, current treatments cannot truly reverse the progression of the disease. Pulmonary macrophages, especially bone marrow derived pro-fibrotic macrophages, secrete multiple kinds of profibrotic mediators (SPP1, CD206, CD163, IL-10, CCL18…), thus further promote myofibroblast activation and fibrosis procession. IL20Rb is a cell-surface receptor that belongs to IL-20 family. The role of IL20Rb in macrophage activation and pulmonary fibrosis remains unclear. In this study, we established a bleomycin-induced pulmonary fibrosis model, used IL4/13-inducing THP1 cells to induce profibrotic macrophage (M2-like phenotype) polarization models. We found that IL20Rb is upregulated in the progression of pulmonary fibrosis, and its absence can alleviate the progression of pulmonary fibrosis. In addition, we demonstrated that IL20Rb promote the activation of bone marrow derived profibrotic macrophages by regulating the Jak2/Stat3 and Pi3k/Akt signaling pathways. In terms of therapeutic strategy, we used IL20Rb neutralizing antibodies for animal administration, which was found to alleviate the progression of IPF. Our results suggest that IL20Rb plays a profibrotic role by promoting profibrotic macrophage polarization, and IL20Rb may become a potential therapeutic target for IPF. Neutralizing antibodies against IL20Rb may become a potential drug for the clinical treatment of IPF.

The effect of interleukin-20 on periodontal tissue destruction in individuals with periodontitis.

BACKGROUND AND OBJECTIVE: Periodontitis is an inflammatory disease that destroys periodontal tissues. Interleukin-20 (IL-20), on the other hand, is known as a potent angiogenic, chemotactic, and pro-inflammatory cytokine associated with various chronic inflammatory disorders. IL-20 has a significant role in the regulation of osteoclastogenesis and osteoblastogenesis. This study aimed to evaluate the effect of IL-20 on periodontal destruction. METHODS: In this study, a total of 60 participants were included, 30 of whom were systemically and periodontally healthy (control group), and 30 were systemically healthy but had periodontitis (periodontitis group). Gingival crevicular fluid (GCF) and serum samples were collected from the participants for biochemical analysis. Enzyme-linked immunosorbent assay was used to determine the levels of IL-20, tumor necrosis factor (TNF)-α, IL1ß/IL-10, RANKL/osteoprotegerin (OPG), and matrix metalloproteinase-8 (MMP8). For statistical analysis, the independent t-test, Pearson correlation coefficients, and the Chi-square test were used. RESULTS: GCF IL-20, RANKL, RANKL/OPG, serum IL-20, RANKL, RANKL/OPG, MMP-8, TNF-α, IL-1B, and IL-1ß/IL-10 values were found to be statistically significantly higher in the periodontitis group than in the control group. GCF OPG and serum IL-10 values were found to be statistically significantly higher in the control group than in the periodontitis group. No statistically significant difference was observed between the groups in serum OPG values. A statistically significantly positive correlation was observed between serum IL-20 value and serum RANKL, RANKL/OPG, MMP-8, TNF-α, IL-1ß values, and periodontal clinical parameters. The ROC curves showed: AUC = 0.788 for GCF IL-20, and AUC = 1.000 for serum IL-20. CONCLUSION: According to the results of the study, IL-20 was found to be associated with periodontitis. The role of IL-20 in periodontal pathogenesis is related to osteoclastogenesis and collagen degradation. It is conceivable that IL-20 may increase bone destruction by both affecting the RANKL/OPG ratio and proinflammatory cytokines.

Spinal interleukin-24 contributes to neuropathic pain after peripheral nerve injury through interleukin-20 receptor2 in mice.

Neuroinflammation is critically involved in nerve injury-induced neuropathic pain, characterized by local and systemic increased levels of proinflammatory cytokines. Interleukin-24 (IL-24), a key member of the IL-10 family, has been extensively studied for its therapeutic potential in various diseases, including cancer, autoimmune disorders, and bacterial infections, but whether it is involved in the regulation of neuropathic pain caused by peripheral nerve injury (PNI) has not been well established. In this study, we reported that spared nerve injury (SNI) induced a significant upregulation of IL-24 in fibroblasts, neurons, and oligodendrocyte precursor cells (OPCs, also called NG2-glia) in the affected spinal dorsal horns (SDHs), as well as dorsal root ganglions (DRGs). We also found that tumor necrosis factor α (TNF-α) induced the transcriptional expression of IL-24 in cultured fibroblasts, neurons, and NG2-glia; in addition, astrocytes, microglia, and NG2-glia treated with TNF-α exhibited a prominent increase in interleukin-20 receptor 2 (IL-20R2) expression. Furthermore, we evaluated the ability of IL-24 and IL-20R2 to attenuate pain in preclinical models of neuropathic pain. Intrathecal (i.t.) injection of IL-24 neutralizing antibody or IL-20R2 neutralizing antibody could effectively alleviate mechanical allodynia and thermal hyperalgesia after PNI. Similarly, intrathecal injection of IL-24 siRNA or IL-20R2 siRNA also alleviated mechanical allodynia after SNI. The inhibition of IL-24 reduced SNI-induced proinflammatory cytokine (IL-1ß and TNF-α) production and increased anti-inflammatory cytokine (IL-10) production. Meanwhile, the inhibition of IL-20R2 also decreased IL-1ß mRNA expression after SNI. Collectively, our findings revealed that IL-24/IL-20R might contribute to neuropathic pain through inflammatory response. Therefore, targeting IL-24 could be a promising strategy for treating neuropathic pain induced by PNI.

IL20RB signaling enhances stemness and chemotherapy resistance in pancreatic cancer.

OBJECTIVE: Pancreatic cancer is an aggressive malignancy with high mortality, and cancer cell stemness and related drug resistance are considered important contributors to its poor prognosis. The objective of this study was to identify regulatory targets associated with the maintenance of pancreatic cancer stemness. MATERIALS AND METHODS: Pancreatic tumor samples were collected from patients at Sun Yat-sen University Cancer Center, followed by immunofluorescence analysis. Pancreatic cancer cell lines with Interleukin-20 receptor subunit beta (IL20RB) overexpression and knockdown were established, and clonal formation, spheroid formation and side population cell analysis were conducted. The effects of IL20RB knockdown on the tumor-forming ability of pancreatic cancer cells and chemotherapy resistance in vivo were explored. RESULTS: IL20RB expression was significantly upregulated in pancreatic cancer tissues, and was correlated with unfavorable prognosis. The IL20RB receptor promotes stemness and chemoresistance in both in vitro and in vivo models of pancreatic cancer. Mechanistically, IL20RB enhances the stemness and chemoresistance of pancreatic cancer by promoting STAT3 phosphorylation, an effect that can be counteracted by a STAT3 phosphorylation inhibitors. Additionally, Interleukin-19 derived from the microenvironment is identified as the primary ligand for IL20RB in mediating these effects. CONCLUSION: Our findings demonstrate that IL20RB plays a crucial role in promoting stemness in pancreatic cancer. This discovery provides a potential therapeutic target for this lethal disease.

IL-20 Cytokines Are Involved in the Repair of Airway Epithelial Barrier: Implication in Exposure to Cigarette Smoke and in COPD Pathology.

BACKGROUND: Dysregulated inflammation as seen in chronic obstructive pulmonary disease (COPD) is associated with impaired wound healing. IL-20 cytokines are known to be involved in wound healing processes. The purpose of this study was to use ex vivo and in vitro approaches mimicking COPD to evaluate the potential modulatory role of interleukin-20 (IL-20) on the inflammatory and healing responses to epithelial wounding. METHODS: The expression of IL-20 cytokines and their receptors was investigated in lung-derived samples collected from non-COPD and COPD patients, from mice chronically exposed to cigarette smoke and from airway epithelial cells from humans and mice exposed in vitro to cigarette smoke. To investigate the role of IL-20 cytokines in wound healing, experiments were performed using a blocking anti-IL-20Rb antibody. RESULTS: Of interest, IL-20 cytokines and their receptors were expressed in bronchial mucosa, especially on airway epithelial cells. Their expression correlated with the disease severity. Blocking these cytokines in a COPD context improved the repair processes after a lesion induced by scratching the epithelial layer. CONCLUSIONS: Collectively, this study highlights the implication of IL-20 cytokines in the repair of the airway epithelium and in the pathology of COPD. IL-20 subfamily cytokines might provide therapeutic benefit for patients with COPD to improve epithelial healing.

The circadian clock circuitry modulates leukemia initiating cell activity in T-cell acute lymphoblastic leukemia.

BACKGROUND: T-cell acute lymphoblastic leukemia (T-ALL) is an aggressive hematological malignancy, characterized by restricted cellular subsets with asymmetrically enriched leukemia initiating cell (LIC) activity. Nonetheless, it is still unclear which signaling programs promote LIC maintenance and progression. METHODS: Here, we evaluated the role of the biological clock in the regulation of the molecular mechanisms and signaling pathways impacting the cellular dynamics in T-ALL through an integrated experimental approach including gene expression profiling of shRNA-modified T-ALL cell lines and Chromatin Immunoprecipitation Sequencing (ChIP-Seq) of leukemic cells. Patient-derived xenograft (PDXs) cell subsets were also genetically manipulated in order to assess the LIC activity modulated by the loss of biological clock in human T-ALL. RESULTS: We report that the disruption of the circadian clock circuitry obtained through shRNA-mediated knockdown of CLOCK and BMAL1 genes negatively impacted the growth in vitro as well as the activity in vivo of LIC derived from PDXs after transplantation into immunodeficient recipient mice. Additionally, gene expression data integrated with ChIP-Seq profiles of leukemic cells revealed that the circadian clock directly promotes the expression of genes, such as IL20RB, crucially involved in JAK/STAT signaling, making the T-ALL cells more responsive to Interleukin 20 (IL20). CONCLUSION: Taken together, our data support the concept that the biological clock drives the expression of IL20R prompting JAK/STAT signaling and promoting LIC activity in T-ALL and suggest that the selective targeting of circadian components could be therapeutically relevant for the treatment of T-ALL patients.

Manipulation of osteogenic and adipogenic differentiation of human degenerative disc and ligamentum flavum derived progenitor cells using IL-1ß, IL-19, and IL-20.

PURPOSE: To elucidate whether pro-inflammatory cytokines might influence the commitment of intervertebral disc (IVD)- and ligamentum flavum (LF)-derived progenitor cells toward either osteogenesis or adipogenesis, specifically Interleukin-1ß (IL-1ß), IL-19, and IL-20. METHODS: Sixty patients with degenerative spondylolisthesis and lumbar or lumbosacral spinal stenosis were included in the study. Injuries to the spine, infections, and benign or malignant tumors were excluded. From nine patient samples, IVD- and LF-derived cells were isolated after primary culture, and two clinical samples were excluded due to mycoplasma infection. The effects of IL-1ß, IL-19, as well as IL-20 in regulating osteogenic and adipogenic differentiation in vitro were investigated. RESULTS: Primary IVD- and LF-derived cells were found to have a similar cell morphology and profile of surface markers (CD44, CD90, and CD105) as placenta-derived mesenchymal stem cells (MSCs). Primary IVD/LF cells have a high capacity to differentiate into osteocytes and adipocytes. IL-19 had a tendency to promote adipogenesis. IL-20 inhibited osteogenesis and promoted adipogenesis; IL-1ß promoted osteogenesis but inhibited adipogenesis. CONCLUSION: IL-1ß, IL-19, and IL-20 impact the adipogenic and osteogenic differentiation of IVD-derived and LF-derived cells. Modulating the expression of IL-1ß, IL-19, and IL-20 provides a potential avenue for controlling cell differentiation of IVD- and LF-derived cells, which might have beneficial effect for degenerative spondylolisthesis and spinal stenosis.

Grass carp IL-20 binds to IL-20R2 but induces STAT3 phosphorylation via IL-20R1.

IL-20 is a pleiotropic cytokine that belongs to the IL-10 family and has a variety of biological functions in tissue homeostasis and regulation of host immune defenses. It signals through a heterodimeric receptor composed of a subunit with a long intracellular domain (R1 type receptor) and a subunit with a short intracellular domain (R2 type receptor). In this study, the R1 type receptor (CiIL-20R1/CRFB8) and the R2 type receptor (CiIL-20R2/CRFB16) were identified in grass carp Ctenopharyngodon idella. Expression analysis revealed that IL-20R2 was highly expressed in the gills and skin in healthy fish. Infection with Flavobacterium columnare resulted in the downregulation of both receptors in the gill at 48 and 72 h, whilst infection with grass carp reovirus induced their expression in the head kidney and spleen at 72 h. In the primary head kidney leucocytes, the expression levels of IL-20R1 and IL-20R2 were decreased after stimulation with 250 ng/mL IL-1ß but not affected by IFN-γ. Co-immunoprecipitation analysis showed that CiIL-20R2/CRFB16 but not CiIL-20R1/CRFB8 bound to CiIL-20L. Furthermore, it was shown that CiIL-20R1/CRFB8 was responsible for activating the phosphorylation of STAT3, whilst CiIL-20R2/CRFB16 was not involved. Structural modeling analysis showed that key residues involved in the interaction between IL-20 and receptors were highly conserved between grass carp and humans, suggesting that the signal transduction and functions of IL-20/IL-20R axis are evolutionarily conserved.

Overexpression of interleukin-20 correlates with favourable prognosis in diffuse large B-cell lymphoma.

Diffuse large B-cell lymphoma (DLBCL) is the most common type of lymphoma worldwide, accounting for about 40% of cases. The role of cytokines in the pathogenesis of lymphomas has been rarely addressed, although cytokines have a close immunological relationship with lymphocytes. We observed overexpression of interleukin (IL)-20 in reactive germinal centres (GCs) leading us to hypothesise that IL-20 may play a role in lymphomagenesis. In this study, we surveyed for IL-20 expression in various types of lymphoma and found that IL-20 was expressed most frequently in follicular lymphoma (94%), but also in Burkitt lymphoma (81%), mantle cell lymphoma (57%), nodal marginal zone lymphoma (56%), Hodgkin lymphomas (50%), small lymphocytic lymphoma (50%) and diffuse large B-cell lymphoma (DLBCL, 48%). IL-20 was not expressed in extranodal marginal zone lymphoma of mucosa-associated lymphoid tissue (MALT lymphoma), lymphoplasmacytic lymphoma, and plasmacytoma. T-cell lymphomas were largely negative for IL-20 expression, except for anaplastic large cell lymphoma (ALCL, 61%), which frequently expressed IL-20, especially in cutaneous ALCL, and showed an inverse association with ALK expression (p=0.024). We further tested IL-20 expression in another large cohort of DLBCL and found IL-20 expression more frequently in germinal centre B-cell (GCB) than in non-GCB subtype [16/26 (62%) versus 24/64 (38%), p=0.038]. In this cohort, IL-20 was associated with a lower rate of extranodal involvement (p=0.009), bone marrow involvement (p=0.040), and better overall survival (p=0.020). Mechanistically, IL-20 overexpression promoted G1 cell cycle arrest and subsequent apoptosis of DLBCL cells and vice versa in vitro. We conclude that IL-20 may be involved in lymphomagenesis and may be useful as a prognostic marker in patients with DLBCL. In addition, IL-20 plays an inhibitory role in DLBCL growth, probably through cell cycle regulation.

Systemic lupus erythematosus variants modulate the function of an enhancer upstream of TNFAIP3.

TNFAIP3/A20 is a prominent autoimmune disease risk locus that is correlated with hypomorphic TNFAIP3 expression and exhibits complex chromatin architecture with over 30 predicted enhancers. This study aimed to functionally characterize an enhancer ∼55 kb upstream of the TNFAIP3 promoter marked by the systemic lupus erythematosus (SLE) risk haplotype index SNP, rs10499197. Allele effects of rs10499197, rs58905141, and rs9494868 were tested by EMSA and/or luciferase reporter assays in immune cell types. Co-immunoprecipitation, ChIP-qPCR, and 3C-qPCR were performed on patient-derived EBV B cells homozygous for the non-risk or SLE risk TNFAIP3 haplotype to assess haplotype-specific effects on transcription factor binding and chromatin regulation at the TNFAIP3 locus. This study found that the TNFAIP3 locus has a complex chromatin regulatory network that spans ∼1M bp from the promoter region of IL20RA to the 3' untranslated region of TNFAIP3. Functional dissection of the enhancer demonstrated co-dependency of the RelA/p65 and CEBPB binding motifs that, together, increase IL20RA and IFNGR1 expression and decreased TNFAIP3 expression in the context of the TNFAIP3 SLE risk haplotype through dynamic long-range interactions up- and downstream. Examination of SNPs in linkage disequilibrium (D' = 1.0) with rs10499197 identified rs9494868 as a functional SNP with risk allele-specific increase in nuclear factor binding and enhancer activation in vitro. In summary, this study demonstrates that SNPs carried on the ∼109 kb SLE risk haplotype facilitate hypermorphic IL20RA and IFNGR1 expression, while suppressing TNFAIP3 expression, adding to the mechanistic potency of this critically important locus in autoimmune disease pathology.

The IL-20RB receptor and the IL-20 signaling pathway in regulating host defense in oral mucosal candidiasis.

Pseudomembranous candidiasis (thrush), erythematous candidiasis, and fungal esophagitis are infections of the barrier mucosa of the upper gastrointestinal tract. The majority of these infections are caused by Candida albicans, an opportunistic fungal pathogen that frequently exists as a harmless commensal on mucosal surfaces lining the gastrointestinal tract. Oral infections are initiated in the superficial stratified squamous epithelium, in which keratinocytes are the most abundant host cells and are the initial points of contact with C. albicans present in saliva. Intrinsic features of oral keratinocytes are likely to play important roles in host defense and tissue homeostasis in oral candidiasis. One understudied pathway that may be important for modulating oral candidiasis is the IL-20 cytokine signaling pathway that employs keratinocyte IL-20RB receptors as ligands for IL-19, IL-20, and IL-24. We report that production of human oral keratinocyte il24 mRNA and protein are stimulated during co-culture with C. albicans. To test the role of the IL-20 family signaling pathway in oral candidiasis, Il20rb-/- mice (lacking the IL-20RB receptor) were compared to wild-type mice in a murine model of oropharyngeal candidiasis. Fungal burdens and percent loss in body weight were determined. Despite comparable fungal burdens, the Il20rb-/- mice exhibited less weight loss over the course of their infection compared to the B6 mice, suggestive of reduced overall disease consequences in the mutant mice. Interference with IL-20 family cytokine signaling may be useful for augmenting the ability of the host to defend itself against pathogens.

Interleukin 20 receptor subunit beta (IL20RB) predicts poor prognosis and regulates immune cell infiltration in clear cell renal cell carcinoma.

BACKGROUND AND OBJECTIVE: Emerging evidence has proven the robust role of tumor mutation burden (TMB) and immune cell infiltration (ICI) in cancer immunotherapy. However, the precise effect of TMB and ICI on clear cell renal cell carcinoma (ccRCC) remains elusive and merits further investigation. Therefore, we aim to identify the TMB-related genes in predicting prognosis and to explore the potential mechanisms of the identified Interleukin 20 receptor subunit beta (IL20RB) in ICI in ccRCC. METHOD: The relative information of patients with ccRCC was obtained from The Cancer Genome Atlas database (TCGA). Immune-related genes were downloaded from the Immunology Database and Analysis Portal database. Cox regression analysis was used to identify prognosis-related immune genes for ccRCC. The relationship of IL20RB expression levels with clinicopathological parameters was analyzed using the "limma" and "survival" packages. Gene Expression Omnibus (GEO) and International Cancer Genome Consortium (ICGC) databases were used as external validation. Quantitative Real-time PCR (qRT-PCR) and western blots were used to validate the expression levels of IL20RB in tumor cells. Cell counting kit-8 (CCK-8) assay and colony formation assay were used to examine the effect of IL20RB on the viability of ccRCC cells. Gene set enrichment analysis (GSEA) was introduced for the analysis of IL20RB-related signaling pathways. Tumor Immune Estimation Resource (TIMER) and Tumor and Immune System Interaction Database (TISIDB) were utilized to determine the correlation of IL20RB expression levels with tumor-infiltrating immune cells (TIICs). RESULTS: IL20RB was significantly overexpressed in different ccRCC tissues and cells. High IL20RB expression in ccRCC patients was associated with short overall survival, high tumor grade, and advanced TNM stage. After knockdown of IL20RB with small interfering RNA (siRNA) technology, ccRCC cells' proliferation was significantly attenuated. Moreover, overexpression of IL20RB could increase the infiltration level of several immune cells, especially T follicular helper cells (Tfh), and overexpressed Tfh cells were correlated with poor prognosis in ccRCC. CONCLUSIONS: IL20RB may function as an immune-associated therapeutic target for it determines cancer progression and regulates immune cell infiltration in ccRCC.

Interleukin-20 is involved in dry eye disease and is a potential therapeutic target.

BACKGROUND: Dry eye disease (DED) is a common disease in ophthalmology, affecting millions of people worldwide. Recent studies have shown that inflammation is the core mechanism of DED. IL-20 is a proinflammatory cytokine involved in various inflammatory diseases. Therefore, we aimed to explore the role of this cytokine in the pathogenesis of DED and evaluate the therapeutic potential of the anti-IL-20 monoclonal antibody (mAb) 7E for DED treatment. METHODS: Clinical tear samples from patients with DED and non-DED controls were collected and their IL-20 protein levels were determined. We established three DED animal models to explore the role of IL-20 and the efficacy of IL-20 antibody in DED. Benzalkonium chloride (BAC)-induced over-evaporative DED, extra-orbital lacrimal gland excision (LGE)-induced aqueous tear-deficient DED, and desiccating stress (DS)-induced combined over-evaporative and aqueous tear-deficient DED animal models were established to investigate the role of IL-20. The anti-IL-20 antibody 7E was established to neutralize IL-20 activity. The effects of IL-20 or 7E on human corneal epithelial cells and macrophages under hyperosmotic stress were analyzed. 7E was topically applied to eyes to evaluate the therapeutic effects in the DED animal models. RESULTS: IL-20 was significantly upregulated in the tears of patients with DED and in the tears and corneas of DED animal models. Under hyperosmotic stress, IL-20 expression was induced via NFAT5 activation in corneal epithelial cells. 7E suppressed hyperosmotic stress-induced activation of macrophages. IL-20 induced cell death in corneal epithelial cells and 7E protected cells from hyperosmotic stress-induced cell death. Blocking IL-20 signaling with 7E protected mice from BAC-induced, LGE-induced, and DS-induced DED by reducing DED symptoms and inhibiting inflammatory responses, macrophage infiltration, apoptosis, and Th17 populations in the conjunctiva and draining lymph nodes. CONCLUSIONS: Our results demonstrated the functions of IL-20 in DED and presented a potential therapeutic option for this condition.

IL-20 promotes cutaneous inflammation and peripheral itch sensation in atopic dermatitis.

Atopic dermatitis (AD) is a chronic skin disease, which is associated with intense itch, skin barrier dysfunction and eczematous lesions. Aberrant IL-20 expression has been implicated in numerous inflammatory diseases, including psoriasis. However, the role of IL-20 in AD remains unknown. Here, RNA-seq, Q-PCR, and immunocytochemistry were utilized to examine disease-driven changes of IL-20 and its cognate receptor subunits in skin from healthy human subjects, AD patients and murine AD-models. Calcium imaging, knockdown and cytokine array were used to investigate IL-20-evoked responses in keratinocytes and sensory neurons. The murine cheek model and behavioral scoring were employed to evaluate IL-20-elicited sensations in vivo. We found that transcripts and protein of IL-20 were upregulated in skin from human AD and murine AD-like models. Topical MC903 treatment in mice ear enhanced IL-20R1 expression in the trigeminal sensory ganglia, suggesting a lesion-associated and epidermal-driven mechanism for sensitization of sensory IL-20 signaling. IL-20 triggered calcium influx in both keratinocytes and sensory neurons, and promoted their AD-related molecule release and transcription of itch-related genes. In sensory neurons, IL-20 application increased TLR2 transcripts, implicating a link between innate immune response and IL-20. In a murine cheek model of acute itch, intradermal injection IL-20 and IL-13 elicited significant itch-like behavior, though only when co-injected. Our findings provide novel insights into IL-20 function in peripheral (skin-derived) itch and clinically relevant intercellular neuron-epidermal communication, highlighting a role of IL-20 signaling in the pathophysiology of AD, thus forming a new basis for the development of a novel antipruritic strategy via interrupting IL-20 epidermal pathways.

γ-Secretase inhibitors suppress IL-20-mediated osteoclastogenesis via Notch signalling and are affected by Notch2 in vitro.

Rheumatoid arthritis (RA) is a chronic immune disease involving the small joints, which often causes irreversible damage. In recent years, elevated interleukin 20 (IL-20) has been observed in synovial fluid, while IL-20 receptor overexpression has been observed in synovial cells. IL-20 is a pleiotropic cytokine that participates in various immune diseases. Further understanding of the relationship between IL-20 and RA can help to identify a potential clinical treatment for RA. This study demonstrated that IL-20 can regulate osteoclast differentiation and function in a dose-dependent manner, while influencing the expression of Notch signalling. Quantitative reverse transcription polymerase chain reaction and western blotting showed that γ-secretase-inhibiting drugs can reverse the effects of IL-20. The effects of Notch2 on IL-20-induced osteoclastogenesis were investigated by immunofluorescence and Notch2 gene silencing via transfection of small interfering RNA; the results showed that Notch2 obviously affected the expression levels of the key protein NFATc1 and downstream osteoclastic proteins. In conclusion, we found that IL-20 regulated the osteoclastogenesis in a dose-dependent manner via Notch signalling, primarily by means of Notch2 activity. This study may help to find new targets for RA treatment.

IL-20 Activates ERK1/2 and Suppresses Splicing of X-Box Protein-1 in Intestinal Epithelial Cells but Does Not Improve Pathology in Acute or Chronic Models of Colitis.

The cytokine Interleukin (IL)-20 belongs to the IL-10 superfamily. IL-20 levels are reported to increase in the intestines of Ulcerative Colitis (UC) patients, however not much is known about its effects on intestinal epithelial cells. Here, we investigated the influence of IL-20 on intestinal epithelial cell lines and primary intestinal organoid cultures. By using chemical-induced (dextran sodium sulphate; DSS) colitis and a spontaneous model of colitis (Winnie mice), we assess whether recombinant IL-20 treatment is beneficial in reducing/improving pathology. Following stimulation with IL-20, intestinal primary organoids from wild-type and Winnie mice increased the expression of ERK1/2. However, this was lost when cells were differentiated into secretory goblet cells. Importantly, IL-20 treatment significantly reduced endoplasmic reticulum (ER) stress, as measured by spliced-XBP1 in epithelial cells, and this effect was lost in the goblet cells. IL-20 treatment in vivo in the DSS and Winnie models had minimal effects on pathology, but a decrease in macrophage activation was noted. Taken together, these data suggest a possible, but subtle role of IL-20 on epithelial cells in vivo. The therapeutic potential of IL-20 could be harnessed by the development of a targeted therapy or combination therapy to improve the healing of the mucosal barrier.

IL-20 Cytokines Are Involved in Epithelial Lesions Associated with Virus-Induced COPD Exacerbation in Mice.

(1) Background: viral infections are a frequent cause of chronic obstructive pulmonary disease (COPD) exacerbations, which are responsible for disease progression and mortality. Previous reports showed that IL-20 cytokines facilitate bacterial lung infection, but their production and their role in COPD and viral infection has not yet been investigated. (2) Methods: C57BL/6 WT and IL-20 Rb KO mice were chronically exposed to air or cigarette smoke (CS) to mimic COPD. Cytokine production, antiviral response, inflammation and tissue damages were analyzed after PVM infection. (3) Results: CS exposure was associated with an increase in viral burden and antiviral response. PVM infection in CS mice enhanced IFN-γ, inflammation and tissue damage compared to Air mice. PVM infection and CS exposure induced, in an additive manner, IL-20 cytokines expression and the deletion of IL-20 Rb subunit decreased the expression of interferon-stimulated genes and the production of IFN-λ2/3, without an impact on PVM replication. Epithelial cell damages and inflammation were also reduced in IL-20 Rb-/- mice, and this was associated with reduced lung permeability and the maintenance of intercellular junctions. (4) Conclusions: PVM infection and CS exposure additively upregulates the IL-20 pathway, leading to the promotion of epithelial damages. Our data in our model of viral exacerbation of COPD identify IL-20 cytokine as a potential therapeutic target.

Interleukin 20 receptor A expression in colorectal cancer and its clinical significance.

BACKGROUND: Interleukin 20 receptor A (IL20RA) has been shown to play a role in the establishment and progression of multiple tumors. However, the expression of this protein in colorectal cancer (CRC) and its correlation with the clinicopathological parameters of CRC have remained unclear. METHODS: A total of 323 paraffin sections including CRC tissues and adjacent normal tissues after surgery were collected. IL20RA protein expression was detected by immunohistochemical staining. The difference expression of IL20RA mRNA between CRC and normal tissues was also explored in the Oncomine and GEO databases. In addition, the IL20RA-related differentially expressed genes were analyzed in TCGA database and enrichment analysis was conducted to explore the cell functions and pathways related to IL20RA expression. RESULTS: There was increased IL20RA expression in CRC compared with that in normal tissues. High IL20RA expression was associated with greater tumor diameter, lymph node metastasis, and poor TNM stage in CRC, while also being suggestive of poor prognosis. The main pathways of IL20RA-related differentially expressed genes in TCGA were protein heterodimerization activity, oxygen binding, oxygen transporter activity, hormone activity, and lipid transporter activity. Meanwhile, IL20RA-related differentially expressed genes were mainly enriched in peroxidase, nucleotide stimulant repair, fatty acid metabolism, basal transcription factor, and RNA degradation. CONCLUSIONS: IL20RA might have a role as a biomarker for CRC. Its upregulation might contribute to an aggressive phenotype in CRC. IL20RA's involvement in the development and progression of CRC might occur through it affecting fatty acid metabolism, oxygen binding, oxygen transport, and hormone activity.

Increased expression of IL-20 is associated with ischemic cardiomyopathy and acute myocardial infarction.

Background: The expression and clinical significance of IL-20 in coronary artery diseases needs to be analyzed. Methods: IL-20 and its receptors were analyzed in coronary artery tissues. In a separate study, plasma IL-20 was also evaluated. Results: IL-20 and its receptors were significantly higher in coronary artery stenosis tissues from ischemic cardiomyopathy patients than that from controls. T lymphocytes and macrophages were the main source of IL-20 and expressed its receptors abundantly. Plasma IL-20 was significantly higher in acute myocardial infarction patients than that in controls. Conclusion: IL-20 was closely associated with the presence of acute myocardial infarction. IL-20 may participate in the progression of coronary artery stenosis and plaque vulnerability via regulating T lymphocytes and macrophages.