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Coronavirus disease 2019 (COVID-19) is a contagious disease caused by severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), a highly pathogenic infection responsible for the world pandemic in 2020. COVID-19 is characterized by an increased number of critically ill patients with a high risk of health care system collapse. Therefore, the search for severity biomarkers and potential therapies is crucial. In this study, we evaluated SARS-CoV-2 -induced cytokines, cytokines receptors and growth factors profile, in critical COVID-19 patients admitted in intensive care unit (ICU) aiming to identify potential biomarkers and therapeutic targets. We designed a prospective study enrolling 62 adults with severe COVID-19 during the first two Brazilian COVID-19 waves (from May to July 2020 and December 2020 to May 2021), convenience samples recruitment in first 24 hours and then, every 4 days until day 20 of ICU admission from a tertiary hospital in São Paulo, Brazil. Controls were healthy blood donors. Whole blood was used to evaluate 17 cytokines, cytokines receptors and growth factors. Due to low mortality rate, we used the need of mechanical ventilation as primary endpoint. In our analysis, we found a different pattern in soluble CD137 (sCD137) in critically ill patients with COVID-19, with a direct relationship between increased levels and worse clinical outcome. sCD137 was related with increased risk of mechanical ventilation and World Health Organization (WHO) clinical score for disease severity. CD137 is a tumor necrosis factor receptor (TNF) family member, mainly responsible for T-cell activation. Soluble isoforms of immune checkpoints competitively regulate function of their membrane-bound counterparts. Our study demonstrated the onward increase in sCD137 levels during severe SARS-CoV-2 infection and its correlation with worse outcomes, suggesting sCD137 as a potential reliable severity biomarker.

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CD137 (TNFRSF9, 4-1BB) is a potent co-stimulatory molecule of the tumour necrosis factor receptor superfamily (TNFRSF) that is expressed by activated T cells. CD137/CD137 ligand (CD137L) signalling primarily induces a potent cell-mediated immune response, while signalling of cell surface-expressed CD137L into antigen presenting cells enhances their activation, differentiation and migratory capacity. Studies have shown that bidirectional CD137/CD137L signalling plays an important role in the pathogenesis of autoimmune diseases. This review discusses the mechanisms how CD137/CD137L signalling contributes to immune deviation of helper T cell pathways in various murine models, and the potential of developing immunotherapies targeting CD137/CD137L signalling for the treatment of autoimmune diseases.

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We show here that soluble CD137 (sCD137), the alternately spliced gene product of Tnfsfr9, effectively treats acute type 1 diabetes (T1D) in nonobese diabetic (NOD) mice. sCD137 significantly delayed development of end-stage disease, preserved insulin+ islet beta cells, and prevented progression to end-stage T1D in some mice. We demonstrate that sCD137 induces CD4+ T cell anergy, suppressing antigen-specific T cell proliferation and IL-2/IFN-γ secretion. Exogenous IL-2 reversed the sCD137 anergy effect. sCD137 greatly reduces inflammatory cytokine production by CD8 effector memory T cells, critical mediators of beta cell damage. We demonstrate that human T1D patients have decreased serum sCD137 compared to age-matched controls (as do NOD mice compared to NOD congenic mice expressing a protective Tnfsfr9 allele), that human sCD137 is secreted by regulatory T cells (Tregs; as in mice), and that human sCD137 induces T cell suppression in human T cells. These findings provide a rationale for further investigation of sCD137 as a treatment for T1D and other T cell-mediated autoimmune diseases.

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BACKGROUND: The interaction between CD137 and its ligand (CD137L) plays a major role in the regulation of immune functions and affects cancer immunotherapy. CD137 is a cell surface protein mainly located on activated T cells, and its regulation and functions in immune cells are well established. However, the expression of CD137 and its regulation in cancer cells remain poorly understood. The main purposes of this study were to examine the expression of CD137 in pancreatic cancer cells and to investigate its underlying mechanisms. METHODS: Cells containing inducible K-RasG12V expression vector or with different K-Ras mutational statuses were used as in vitro models to examine the regulation of CD137 expression by K-Ras. Various molecular assays were employed to explore the regulatory mechanisms. Tumor specimens from 15 pancreatic cancer patients and serum samples from 10 patients and 10 healthy donors were used to test if the expression of CD137 could be validated in clinical samples. RESULTS: We found that the CD137 protein was expressed on the cell surface in pancreatic cancer tissues and cancer cell lines. Enzyme-linked immunosorbent assay revealed no difference in the levels of secreted CD137 in the sera of patients and healthy donors. By using the K-Ras inducible cell system, we further showed that oncogenic K-Ras up-regulated CD137 through the activation of MAPK (mitogen-activated protein kinases) and NF-κB (nuclear factor kappa-light-chain-enhancer of activated B cells) pathways, as evidenced by significantly reduced CD137 mRNA expression led by genetic silencing of MAPK1 and p65, the key proteins involved in the respective pathways. Furthermore, we also found that the NF-κB pathway was mainly stimulated by the K-Ras-induced secretion of interleukin-1α (IL-1α) which promoted the transcription of the CD137 gene in pancreatic cancer cell lines. Analysis of the TCGA (the cancer genome atlas) database also revealed a significant correlation between IL-1α and CD137 expression (r = 0.274) in tumor samples from pancreatic cancer patients (P < 0.001). CONCLUSIONS: The present study has demonstrated that the CD137 protein was expressed on pancreatic cancer cell surface, and has identified a novel mechanism by which K-Ras regulates CD137 in pancreatic cancer cells through MAPK and NF-κB pathways stimulated by IL-1α.

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