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Background Proteins encoded by Suppressors of cytokine signaling (SOCS) genes have critical roles in the regulation of immune responses. Meanwhile, several lines of evidence support the presence of immune dysfunction in bipolar disorder (BD) patients. Methods In the present study, we assessed expression levels of SOCS1–3 and SOCS5 genes in peripheral blood of patients with BD and healthy subjects. Results All SOCS genes were up-regulated in patients compared with healthy subjects. However, when comparing patients with sex-matched controls, the significant differences were observed only in the male subjects except for SOCS5 which was up-regulated in both male and female patients compared with the corresponding control subjects. Significant pairwise correlations were found between expression levels of genes in both patients and controls. Based on the area under curve values, SOCS5 had the best performance in the differentiation of disease status in study participants (AUC = 0.92). Combination of four genes increased the specificity of tests and resulted in diagnostic power of 0.93. Conclusion Taken together, these data suggest a role for SOCS genes in the pathogenesis of BD especially in the male subjects. Moreover, peripheral expression levels of SOCS genes might be used as a subsection of a panel of diagnostic biomarkers in BD.

// Dexi Zhou 1, 2, * , Lu Chen 1, 2, * , Kui Yang 1, 2 , Hui Jiang 1, 2 , Wenke Xu 1, 2 and Jiajie Luan 1, 2 1 Department of Pharmacy, Yijishan Hospital, Wannan Medical College, Wuhu, Anhui Province, China 2 Laboratory of Clinical Pharmacy, Wannan Medical College, Wuhu, Anhui Province, China * These authors have contributed equally to this work Correspondence to: Jiajie Luan, email: luanjiajie757@163.com Dexi Zhou, email: zhoudexiahmu@163.com Keywords: macrophage polarization, cytokines signaling, suppressors of cytokine signaling Received: June 22, 2017 Accepted: July 25, 2017 Published: August 04, 2017 ABSTRACT The concept of macrophage polarization is defined in terms of macrophage phenotypic heterogeneity and functional diversity. Cytokines signals are thought to be required for the polarization of macrophage populations toward different phenotypes at different stages in development, homeostasis and disease. The suppressors of cytokine signaling family of proteins contribute to the magnitude and duration of cytokines signaling, which ultimately control the subtle adjustment of the balance between divergent macrophage phenotypes. This review highlights the specific roles and mechanisms of various cytokines family and their negative regulators link to the macrophage polarization programs. Eventually, breakthrough in the identification of these molecules will provide the novel therapeutic approaches for a host of diseases by targeting macrophage phenotypic shift.

Inhibition of immune checkpoint molecules, PD-1 and CTLA4, has been shown to be a promising cancer treatment. PD-1 and CTLA4 inhibit TCR and co-stimulatory signals. The third T cell activation signal represents the signals from the cytokine receptors. The cytokine interferon-γ (IFNγ) plays an important role in anti-tumor immunity by activating cytotoxic T cells (CTLs). Most cytokines use the Janus kinase (JAK)/signal transducer and activator of transcription (STAT) pathway, and the suppressors of cytokine signaling (SOCS) family of proteins are major negative regulators of the JAK/STAT pathway. Among SOCS proteins, CIS, SOCS1, and SOCS3 proteins can be considered the third immunocheckpoint molecules since they regulate cytokine signals that control the polarization of CD4+ T cells and the maturation of CD8+ T cells. This review summarizes recent progress on CIS, SOCS1, and SOCS3 in terms of their anti-tumor immunity and potential applications.

Current treatments for diabetic retinopathy (DR) target late stages when vision has already been significantly a ected. Accumulating evidence suggests that neuroinflammation plays a major role in the pathogenesis of DR, resulting in the disruption of the blood-retinal barrier. Suppressors of cytokine signaling (SOCS) are cytokine-inducible proteins that function as a negative feedback loop regulating cytokine responses. On this basis, the aim of the present study was to evaluate the e ect of a SOCS1-derived peptide administered by eye drops (2 weeks) on retinal neuroinflammation and early microvascular abnormalities in a db/db mouse model. In brief, we found that SOCS1-derived peptide significantly reduced glial activation and neural apoptosis induced by diabetes, as well as retinal levels of proinflammatory cytokines. Moreover, a significant improvement of electroretinogram parameters was observed, thus revealing a clear impact of the histological findings on global retinal function. Finally, SOCS1-derived peptide prevented the disruption of the blood-retinal barrier. Overall, our results suggest that topical administration of SOCS1-derived peptide is e ective in preventing retinal neuroinflammation and early microvascular impairment. These findings could open up a new strategy for the treatment of early stages of DR, This study was supported by grants from the Ministerio de Economía y Competitividad (PI16/00541, SAF2015-63696-R, PI14/00386, PI17/01495 and DTS-2017/00203)

// Sung-Hoon Jung 1 , Su-Min Kim 1 , Choong-Eun Lee 1 1 Department of Biological Science, College of Science, Sungkyunkwan University, Suwon 440-746, Korea Correspondence to: Choong-Eun Lee, email: celee@skku.edu Keywords: suppressors of cytokine signaling, reactive oxygen species, Src, thioredoxin, EMT signaling Received: February 26, 2016 Accepted: August 09, 2016 Published: August 23, 2016 ABSTRACT Reactive oxygen species (ROS) participate in malignant progression of cancers including epithelial-mesenchymal transition (EMT). We have investigated the role of suppressors of cytokine signaling (SOCS)1 as an inhibitor of ROS-induced EMT using colon cancer cell lines transduced with SOCS1 and shSOCS1. Hydrogen peroxide treatment induced EMT features such as elevation of vimentin and Snail with a corresponding reduction of E-cadherin. The EMT markers are significantly decreased upon SOCS1 over-expression while increased under SOCS1 knock-down. SOCS1 inhibited ROS signaling pathways associated with EMT such as Src, Jak, and p65. Of note, strong up-regulation of Src activity in SOCS1-ablated cells was responsible for the elevated signaling leading to EMT, as shSrc or Src inhibitor abolished the shSOCS1-induced promotion of EMT response. Suppression of ROS-inducible EMT markers and invasion in SOCS1 over-expressing cells correlated with significantly low intracellular ROS levels in these cells. Analysis of antioxidant enzymes in SOCS1-transduced cells revealed a selective up-regulation of thioredoxin (Trx1), while thioredoxin ablation restored ROS levels and the associated EMT markers. As a mechanism of thioredoxin up-regulation by SOCS1, inhibition of Src activity promoting nuclear translocation of Nrf-2 is proposed. Taken together, our data strongly indicate that SOCS1 antagonizes EMT by suppressing Src activity, leading to thioredoxin expression and down-regulation of ROS levels in colon cancer cells.

Suppressors of cytokine signaling (SOCS) are a family of eight proteins that negatively regulate Janus kinase and signal transducers and activators of transcription signaling in cells that utilize this pathway to respond to extracellular stimuli. SOCS are best known for attenuating cytokine signaling in the immune system. However, they are also expressed in many other cell types, including pancreatic β-cells, where there is considerable interest in harnessing SOCS molecules to prevent cytokine-mediated apoptosis during diabetes and allogeneic transplantation. Apart from their potential as therapeutic targets, SOCS molecules play a central role for regulating important functions in β-cells, including growth, glucose sensing, and insulin secretion. This review will discuss SOCS proteins as central regulators for diverse cellular processes important for normal β-cell function as well as their protective anti-apoptotic effects during β-cell stress.

Skeletal muscle, cytokines, and oxidative stress in end-stage renal disease.BackgroundEnd-stage renal disease (ESRD) is a state of microinflammation, with increased activation of cytokines and augmented oxidative stress. While peripheral blood mononuclear cells are an established source of reactive oxygen species and inflammatory cytokines during hemodialysis (HD), skeletal muscle is also capable of generating these biomolecules.MethodsFemoral arterio-venous (A-V) balance of interleukin-1 (IL-1), IL-6, IL-10, tumor necrosis factor-α (TNF-α), malonyldialdehyde (MDA), and carbonyl protein (CP) were measured in 17 ESRD patients and 9 healthy volunteers. ESRD patients were studied before (pre-HD) and during HD. mRNA levels of cytokines, heme oxygenase-1 (HO-1), and suppressors of cytokine signaling-2 (SOCS-2) were quantitated in the skeletal muscle by real-time polymerase chain reaction (PCR).ResultsArterial concentration of MDA (pmol/mL) was higher pre-HD (325.5 ± 19.6) compared to controls (267.7 ± 14.7), but decreased intradialysis (248.8 ± 16.1) (P < 0.01). Dialysis clearance of MDA was 16.9 ± 3.1mL/min. CP concentration (nmol/mg protein) in the artery was significantly higher pre-HD (2.29 ± 0.09) than in controls (1.92 ± 0.05), and remained stable during HD (2.23 ± 0.07). Plasma cytokines increased to a variable degree in the artery and vein during HD. A-V balance studies demonstrated that the MDA (17.8%) and CP (5.1%) concentrations increased significantly in the vein intradialysis. Venous concentration of IL-6 was higher than that in the artery during dialysis (16.27 ± 2.42 vs. 11.29 ± 2.17 pg/dL, P < 0.01). mRNA levels of IL-6 (0.028 ± 0.02 vs. 6.69 ± 0.21), HO-1 (0.96 ± 0.01 vs. 5.08 ± 1.11), and SOCS-2 (0.63 ± 0.12 vs. 0.82 ± 0.14) in the muscle increased during HD (P < 0.01). Immunohistochemical studies confirmed the increase in IL-6 protein in the skeletal muscle during HD. The intradialytic increase in IL-1, IL-10, and TNF-α gene expression was not significant.ConclusionSkeletal muscle may also contribute to the circulating plasma IL-6 and increased oxidative stress during HD.