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Cullin-RING ligase 4 (CRL4) has attracted enormous attentions because of its extensive regulatory roles in a wide variety of biological and pathological events, especially cancer-associated events. CRL4 exerts pleiotropic effects by targeting various substrates for proteasomal degradation or changes in activity through different internal compositions to regulate diverse events in cancer progression. In this review, we summarize the structure of CRL4 with manifold compositional modes and clarify the emerging functions and molecular mechanisms of CRL4 in a series of cancer-associated events., Competing Interests: Declaration of competing interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2024. Published by Elsevier B.V.)

Autoimmune uveitis is an inflammatory disorder of the eye triggered by the responses of autoreactive T cells to ocular autoantigens. This study aims to understand the role of granulocyte-macrophage-colony-stimulating factor (GM-CSF)-producing T helper (ThGM) cells in the pathophysiology of mouse experimental autoimmune uveitis (EAU). We established an EAU model by immunizing mice with interphotoreceptor retinoid-binding protein (IRBP) 651-670. Splenic or eye-infiltrating ThGM cells were analyzed and enriched by flow cytometry according to the levels of an array of surface markers, transcription factors, and cytokines. Lentiviral transduction was conducted to silence or overexpress the target gene in differentiated ThGM cells. The adoptive transfer was applied to determine the pathogenicity of ThGM cells in vivo. We found that ThGM cells were present in the spleen and the eye after EAU induction. Both splenic and eye-infiltrating ThGM cells were phenotypically CD4 + CCR7 - CXCR3 - CCR6 - CCR10 hi . Eye-infiltrating ThGM cells up-regulated interleukin-1β (IL-1β), interleukin-6 (IL-6), and IL-17 receptor C (IL-17RC) relative to splenic ThGM cells. IL-17RC overexpression enabled interleukin-17A (IL-17A)-induced up-regulation of IL-1β and IL-6 production in ThGM cells. Adoptive transfer of IL-17RC overexpressing ThGM cells exacerbated EAU severity, as evidenced by a higher histology score as well as increased pro-inflammatory cytokines and inflammatory cells in the eye. However, IL-17RC-silenced ThGM cells did not impact EAU. Therefore, for the first time, this study unveils the essential pro-inflammatory role of IL-17RC-expressing ThGM cells in EAU pathophysiology. We discovered a novel mechanism underlying the pathophysiology of autoimmune uveitis., Competing Interests: Declaration of Competing Interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2023 Elsevier Inc. All rights reserved.)

IL-17A is implicated in the pathogenesis of chronic lung allograft dysfunction, which limits survival after lung transplantation. While many cells express the IL-17 receptor A (IL-17RA) which is the main receptor for IL-17A, the cellular targets of IL-17A in development of post-transplant fibrosis are unknown. The purpose of this study was to determine whether IL-17RA expression by donor or recipient structural or bone marrow (BM) cells is required for the development of allograft fibrosis in a mouse intrapulmonary tracheal transplantation (IPTT) model. BM chimeras were generated using C57BL/6 and IL-17RA-knockout mice. After engraftment, allogeneic IPTTs were performed using the chimeric and BALB/c mice as donors or recipients. This allowed us to assess the effect of IL-17RA deficiency in recipient BM, recipient structural, donor BM, or donor structural compartments separately. Tracheal grafts, the surrounding lung, and mediastinal lymph nodes were assessed 28 days after IPTT. Only recipient BM IL-17RA deficiency resulted in attenuation of tracheal graft obliteration. In the setting of recipient BM IL-17RA deficiency, T cells and neutrophils were decreased in mediastinal lymph nodes. Additionally, recipient BM IL-17RA deficiency was associated with increased B220 + PNAd + lymphoid aggregates, consistent with tertiary lymphoid organs, in proximity to the tracheal allograft. In this IPTT model, recipient BM-derived cells appear to be the primary targets of IL-17RA signaling during fibrotic obliteration of the tracheal allograft., (Copyright © 2021 Elsevier B.V. All rights reserved.)

Purpose: Improved prognostication of a patient's outcome could allow for personalized treatment decisions in breast cancer. Homeobox B7 (HOXB7) and interleukin 17 receptor B (IL17RB) are proteins reportedly involved in the development of hormonal therapy resistance. Their prognostic value was previously investigated in tumor tissue but recent mass spectrometric detection of HOXB7 and IL17RB proteins in serum has prompted us to perform the first prognostic evaluation of their serum levels., Patients and Methods: The study included 81 premenopausal breast cancer patients that received adjuvant hormonal therapy. The median follow-up period was 61 months. HOXB7 and IL17RB serum protein levels were measured by quantitative sandwich ELISA and prognostically evaluated by Cox proportional hazards regression analysis., Results: HOXB7 protein was detected in 96.3% and IL17RB in 33.3% of serum samples. Higher levels of serum HOXB7 significantly associated with favorable disease outcome by prognosticating distant (by HR ​= ​0.04; P ​= ​0.001) and local recurrence (by HR ​= ​0.03, P ​= ​0.001). The recurrence rates in the HOXB7 high and HOXB7 low subgroups of patients (cut-off 81.5 ​pg/mL) were 0% and 17%, respectively. Serum IL17RB levels did not significantly associate with either local or distant events. The multivariate analysis highlighted estrogen receptor, histological grade, nodal status and HOXB7 as independent prognostic parameters., Conclusions: Our findings validate the previous mass-spectrometry data by showing that HOXB7 and IL17RB cellular proteins are detectable in serum by a standard ELISA assay. Furthermore, we show that HOXB7 serum levels are the relevant prognosticator of response to hormonal therapy., Competing Interests: Declaration of competing interest The authors declare no conflict of interest., (Copyright © 2021 Medical University of Bialystok. Published by Elsevier B.V. All rights reserved.)

Cytokines are necessary to trigger the inflammatory response in kidney ischemia/reperfusion injury. Interleukin-17C (IL-17C), a unique member of the IL-17 family, is a cytokine produced by epithelial cells implicated in host defense and autoimmune diseases. However, little is known about the role of IL-17C in acute kidney injury. We investigated this and found that IL-17C was significantly increased in kidney biopsies of patients and mice with acute kidney injury. Exposure to hypoxia induced upregulation of IL-17C in kidney tubular epithelial cells. To further investigate the role of IL-17C, kidney ischemia/reperfusion injury was induced in mice. Inhibition of IL-17C action with a neutralizing antibody or IL-17 receptor E (IL-17RE) knockout attenuated tubular injury, kidney oxidative stress, and kidney inflammation. Mechanistically, both IL-17C neutralization and IL-17RE knockout attenuated TH17 activation and IL-17A expression in kidneys of mice with acute kidney injury. TNF-α and IL-1β, downstream cytokines of IL-17C, were also reduced in IL-17C antibody pretreated and IL-17RE knockout mice. Additionally, IL-17C knockdown with siRNA decreased hypoxia-induced inflammation in kidney tubular cells and silencing IL-17RE abrogated the effects of IL-17C in kidney tubular cells. Thus, IL-17C may participate in the inflammatory response of acute kidney injury and inhibition of IL-17C or blockade of IL-17 RE may be a novel therapeutic strategy for the treatment of acute kidney injury., (Copyright © 2020 International Society of Nephrology. Published by Elsevier Inc. All rights reserved.)

Systemically delivered targeted biologics have revolutionized the treatment of moderate-to-severe psoriasis. For milder forms of psoriasis, topical therapies, primarily corticosteroids, remain the mainstay of treatment to reduce the risks and off-target side effects associated with systemic therapies. Most newly developed biologics, including monoclonal antibodies, are structurally complex and are unable to penetrate the skin barrier. Recently developed liposomal spherical nucleic acids overcome this barrier and enable topical delivery of antisense oligonucleotides capable of specifically targeting inflammatory pathways underlying psoriasis pathogenesis., (Copyright © 2019 The Authors. Published by Elsevier Inc. All rights reserved.)

Mammary tumorigenesis can be modulated by melatonin, which has oncostatic action mediated by multiple mechanisms, including the inhibition of the activity of transcription factors such as NF-κB and modulation of interleukins (ILs) expression. IL-25 is an active cytokine that induces apoptosis in tumor cells due to differential expression of its receptor (IL-17RB). IL-17B competes with IL-25 for binding to IL-17RB in tumor cells, promoting tumorigenesis. This study purpose is to address the possibility of engaging IL-25/IL-17RB signaling to enhance the effect of melatonin on breast cancer cells. Breast cancer cell lines were cultured monolayers and 3D structures and treated with melatonin, IL-25, siIL-17B, each alone or in combination. Cell viability, gene and protein expression of caspase-3, cleaved caspase-3 and VEGF-A were performed by qPCR and immunofluorescence. In addition, an apoptosis membrane array was performed in metastatic cells. Treatments with melatonin and IL-25 significantly reduced tumor cells viability at 1mM and 1ng/mL, respectively, but did not alter cell viability of a non-tumorigenic epithelial cell line (MCF-10A). All treatments, alone and combined, significantly increased cleaved caspase-3 in tumor cells grown as monolayers and 3D structures (p<0.05). Semi-quantitative analysis of apoptosis pathway proteins showed an increase of CYTO-C, DR6, IGFBP-3, IGFBP-5, IGFPB-6, IGF-1, IGF-1R, Livin, P21, P53, TNFRII, XIAP and hTRA proteins and reduction of caspase-3 (p<0.05) after melatonin treatment. All treatments reduced VEGF-A protein expression in tumor cells (p<0.05). Our results suggest therapeutic potential, with oncostatic effectiveness, pro-apoptotic and anti-angiogenic properties for melatonin and IL-25-driven signaling in breast cancer cells., (Copyright © 2017 Elsevier Inc. All rights reserved.)

Background: Targeting the IL-17 pathway represents a highly effective strategy for the treatment of psoriasis, using antibodies against IL-17A and IL-17 receptor, suggesting that Th17 cells essentially contribute to development of psoriasis. Th17 differentiation depends on the key transcription factor, RORγt., Objective: To develop a novel RORγt antagonist which is effective on psoriasis via oral administration., Methods: A chemical library was screened using cell-based high-throughput methods, luciferase reporter assay, competitive binding assay, and T cell differentiation assay. To evaluate in vivo effects of a novel RORγt antagonist, A213, we orally administrated it to two independent mouse models of psoriasis; IL-23-injection model and K5.Stat3C transgenic mouse., Results: Oral administration of A213 resulted in attenuation of skin inflammation in the both mouse models. At the same time, increased levels of IL-17A expression were significantly reduced in the skin lesions and skin-draining lymph nodes., Conclusion: These results implicate a new therapeutic application of RORγt antagonist for the treatment of psoriasis., (Copyright © 2016 Japanese Society for Investigative Dermatology. Published by Elsevier Ireland Ltd. All rights reserved.)

IL17RB is the receptor for IL17E, the only member of IL17 family promoting Th2 reactions. The mechanism of IL17BR regulation is poorly understood. We previously demonstrated that expression of IL17RB is induced on human macrophages by IL4 and enhanced by TGFβ. In the present study we investigated the immediate signaling targets of IL17RB. Using Yeast Two Hybrid screening we identified DAZAP2 as a binding partner of IL17RB. We established that 2 SH2-binding domains of DAZAP2 are essential for its binding to IL17RB. Deletion of these domains or substitution of tyrosines to alanines abrogates the binding. In IL17RB DAZAP2-binding domain was mapped to the region between aa 329 and 347 within its cytoplasmic part. Confocal microscopy revealed that in primary human macrophages that do not express IL17RB DAZAP2 is predominantly localized in the nucleus, while in IL17RB positive macrophages a portion of DAZAP2 is visualized in the cytoplasm. Stimulation of IL17RB with its ligand IL17E induces accumulation of DAZAP2 in the cytoplasm. Further we established that DAZAP2 interacts with Smurf2 an E3 ubiquitin ligase which induces proteasome-dependent degradation of the protein. In summary we established a new mechanism of IL17RB regulation-Smurf2 dependent degradation of its adaptor protein DAZAP2., (Copyright © 2011 Elsevier GmbH. All rights reserved.)

Churg-Strauss syndrome (CSS) is characterized by systemic vasculitis and blood and tissue eosinophilia. Blood eosinophilia correlates with disease activity, and activated T cells from CSS patients are predominantly T helper 2 (Th2). Interleukin (IL)-25 has been shown to link innate and adaptive immunity by enhancing Th2 cytokine production. We sought to determine the involvement of IL-25 and its receptor IL-17RB in the pathogenesis of CSS. We found increased levels of IL-25 in the serum of active CSS patients (952 ± 697 vs 75 ± 49 pg/mL in inactive patients and 47 ± 6 pg/mL in healthy donors). IL-25 was correlated with disease activity and eosinophil level. Eosinophils were the main source of IL-25, whereas activated CD4(+) memory T cells were the IL-17RB-expressing cells in CSS. IL-25 enhanced the production of IL-4, IL-5, and IL-13 by activated peripheral blood mononuclear cells. IL-25 and IL-17RB were observed within the vasculitic lesions of patients with CSS, and IL-17RB colocalized with T cells. Increased expression of IL-17RB, tumor necrosis factor receptor-associated factor 6, and JunB in vasculitic lesions of CSS underscored the IL-25-mediated activation, whereas up-regulation of GATA3 and IL-10 supported Th2 differentiation. Our findings suggest that eosinophils, through the production of IL-25, exert a critical role in promoting Th2 responses in target tissues of CSS.

Interleukin-17 is a T-cell-derived pro-inflammatory cytokine, exhibiting multiple biological activities in a variety of cells and believed to fine tune all general phases of hematopoietic response. However, the signaling mechanism of this novel cytokine remains unknown. Here, we report for the first time that the early signaling events triggered by interleukin-17 involve tyrosine phosphorylation of several members of the JAK and STAT proteins in human U937 monocytic leukemia cells. Immunoprecipitation with specific antibodies followed by Western blot analysis with antiphosphotyrosine antibody has shown that in U937 cells, interleukin-17 induces time-dependent stimulation of tyrosine phosphorylation of JAK 1, 2 and 3, Tyk 2 and STAT 1, 2, 3 and 4 within 0.5 to 30 min. Interleukin-17-mediated tyrosine phosphorylation of these proteins strongly suggests that the JAK/STAT signaling pathway may play a major role in transducing signals from interleukin-17 receptors to the nucleus., (Copyright 1999 Academic Press.)