Suppressor of cytokine signaling 2 is induced in Huntington's disease and involved in autophagy.

Suppressor of cytokine signaling (SOCS) proteins are primarily feedback inhibitors of cytokine signaling. The two conserved domains of SOCS proteins have distinct functions. Src homology 2 (SH2) domain inhibits cytokine receptor, while SOCS box acts as an E3 ubiquitin ligase. SOCS2, a cytokine signaling suppressor, has been primarily implicated in regulating inflammatory conditions in neuronal diseases. However, SOCS proteins have been suggested to play diverse roles in healthy and diseased nervous system including neurodegenerative disorders. In this study, SOCS2 was found to be upregulated in Huntington's disease and was substantially induced in extended polyglutamine (polyQ)-expressing striatal cells. The induced level was augmented under aging conditions. In extended polyQ-expressing cells, downregulated SOCS2 improved autophagic dysfunction rather than altered inflammatory conditions. Overall, we suggest that SOCS2 involves in regulating autophagy by functioning as an E3 ligase in extended polyQ conditions, and consequently regulates cell damage and cell death type.

Gene polymorphisms of SOCS1 and SOCS2 and acute lymphoblastic leukemia.

OBJECTIVE: Acute lymphoblastic leukemia (ALL) causes the dysfunction of the systemic blood system and immune system. The etiology and predisposing factors of ALL are unknown. The suppressor of cytokine signaling 1 (SOCS1) and SOCS2 are inhibitors of cytokine signal transduction. Gene polymorphisms of SOCS1 and SOCS2 and their expressions may be related to ALL. PATIENTS AND METHODS: A total of 200 ALL patients in our hospital and 200 healthy people were enrolled in ALL group and control group, respectively. Genomic deoxyribonucleic acids (DNAs) and total RNAs were extracted from the peripheral blood of each subject. Gene polymorphisms of SOCS1 at rs33977706, rs243327, and rs33932899 and those of SOCS2 at rs3816997 were amplified by polymerase chain reaction (PCR) and sequenced. Besides, the expression levels of SOCS1 and SOCS2 in ALL patients were detected by real-time fluorescence quantitative PCR. RESULTS: The frequency of the allele C of SOCS1 rs33977706 in ALL group was lower than that in the control group, displaying a significant difference between the two groups (p=0.015). The frequency of allele A of SOCS2 rs3816997 was notably higher in ALL group than that of the control group (p=0.000). In addition, the frequency of CA genotype of SOCS1 rs33977706 in ALL group was markedly lower than that in the control group, showing a significant difference (p=0.000). ALL group had remarkably higher frequencies of AA genotype of SOCS2 rs3816997 (p=0.000) and ACC haplotype of SOCS gene (p=0.000), and lower frequencies of ATG (p=0.026) and CCC (p=0.006) haplotypes. The two loci, SOCS1 rs33932899 and SOCS1 rs243327, were linked to each other (D'=0.781). Moreover, the expression level of SOCS1 in ALL group was lower than that in the control group, in which the expression of the CT genotype of SOCS1 rs243327 was relatively higher (p=0.021). SOCS2 level was lower in ALL group. Particularly, SOCS2 level in ALL patients carrying AC genotype was lower than those carrying AA and CC genotypes (p=0.000). ALL patients carrying CT genotype of SOCS1 rs243327 had shorter period of agranulocytosis (p=0.000), a lower ratio of bone marrow primitive/immature cells (p=0.001), and a higher hemoglobin (Hb) level in blood (p=0.000). The ratio of bone marrow primordial/immature cells was lower in ALL patients with AC genotype of SOCS2 rs3816997 (p=0.038). CONCLUSIONS: The expression levels of SOCS1 and SOCS2 are prominently related to ALL, and their polymorphisms are associated with the susceptibility to ALL.

Sexual dimorphism in up-regulation of suppressors of cytokine signaling genes in patients with bipolar disorder.

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.

SOCS gene family expression profile in the blood of multiple sclerosis patients.

Multiple sclerosis (MS) is a chronic autoimmune disease, and the most common cause of nontraumatic disability in young people. The etiology of this disease is not well defined yet. Cytokines play an important role in differentiation, maturation and survival of a wide range of cells, including cells of the immune system. Suppressor of cytokine signaling (SOCS) proteins are the most important regulators of this cytokine signaling pathway. The aim of present study was to compare the expression levels of SOCS1, SOCS2, SOCS3 and SOCS5 genes in the blood of 50 relapsing-remitting MS (RR-MS) patients and 50 healthy controls by Taqman Quantitative Real-Time PCR in patients and healthy control group. We observed that SOCS1 and SOCS5 expression was significantly down-regulated (P=0.045 and P=0.044, respectively); whereas, no significant difference was observed between MS patients and controls for SOCS2 and SOCS3 gene expression (P=0.747 and P=0.439, respectively). In addition, there was no significant correlation between the expression of SOCS1, SOCS2, SOCS3 and SOCS5 genes and clinical findings, such as the level of physical disability in the MS patients according to the Kurtzke Expanded Disability Status Scale (EDSS) criterion and disease duration. However, a significant positive correlation was observed between expression levels of SOCS genes. This study shows that loss of balance among various members of the SOCS family proteins may contribute to pathophysiology of multiple sclerosis.

Suppressors of cytokine signalling in ankylosing spondylitis and their associations with disease severity, acute-phase reactants and serum cytokines.

OBJECTIVES: To investigate the suppressors of cytokine signalling (SOCS1 and SOCS3) expression in peripheral blood cells in ankylosing spondylitis (AS), and their associations with clinical and laboratory manifestations. METHODS: The levels of SOCS1 and SOCS3 mRNA in peripheral blood mononuclear cells (PBMCs), T cells and monocytes were measured by RT-PCR in 53 AS patients and 31 healthy controls. Patient's serum IL-6, IL-10 and IL-17A levels were determined by ELISA. We evaluated patient's disease activity, functional ability and global assessment, and tested their ESR, CRP and IgA levels. RESULTS: Cellular SOCS1 expression did not show significant differences between AS patients and controls. However, T cells SOCS1 decreased significantly in the AS subgroup with lower ESR than controls (p=0.013). PBMCs (p=0.047) and T cells (p=0.035) SOCS1 decreased significantly in the AS subgroup with lower CRP than controls. Importantly, SOCS3 expression increased significantly in AS patients compared to the controls in PBMCs (p=0.025), T cells (p=0.003) and monocytes (p=0.009). Moreover, PBMCs SOCS3 correlated with ESR (r=0.297, p=0.031) and CRP (r=0.320, p=0.019). T cells SOCS3 correlated with BASFI (r=0.337, p=0.015), ESR (r=0.435, p=0.001) and CRP (r=0.300, p=0.029). Monocytes SOCS3 correlated with ESR (r=0.281, p=0.041) and IgA (r=0.426, p=0.006). Furthermore, T cells SOCS1 (r=-0.454, p=0.023) and T cells SOCS3 (r=-0.405, p=0.045) negatively correlated with serum IL-17A. Monocytes SOCS3 negatively correlated with serum IL-6 (r=-0.584, p=0.002). CONCLUSIONS: The decreased SOCS1 and increased SOCS3 expression in AS PBMCs and T cells, and their correlation with patient's functional ability, acute-phase reactants and serum pro-inflammatory cytokines suggested that SOCS may participate in the pathogenesis of AS.

MicroRNA-155 may be involved in the pathogenesis of atopic dermatitis by modulating the differentiation and function of T helper type 17 (Th17) cells.

Our aims were to identify the differential expression of microRNA (miR)-155, as well as to explore the possible regulatory effects of miR-155 on the differentiation and function of T helper type 17 (Th17) cells in atopic dermatitis (AD). The Th17 cell percentage and expression levels of miR-155, retinoic acid-related orphan receptor (ROR)γt, interleukin (IL)-17 and suppressor of cytokine signalling-1 (SOCS1) in peripheral CD4(+) T cells, plasma and skin specimens were detected and compared in AD patients and healthy subjects. A miR-155 mimic and an inhibitor were transfected separately into AD CD4(+) T cells to confirm the in-vivo data. The Th17 cell percentage, miR-155 expression, RORγt mRNA expression, IL-17 mRNA expression and plasma concentration were increased significantly in AD patients compared with healthy subjects. Conversely, SOCS1 mRNA expression and plasma concentration were decreased significantly. Similar results were detected in cultured CD4(+) T cells transfected with the miR-155 mimic compared with a miR-155 inhibitor or a negative control. Additionally, there was a sequential decrease in miR-155 expression, as well as RORγt and IL-17 mRNA expression, but an increase in SOCS1 mRNA expression, from AD lesional skin and perilesional skin to normal skin. Positive correlations were found between miR-155 expression and AD severity, Th17 cell percentage, RORγt mRNA expression and IL-17 mRNA expression and plasma concentration, while negative correlations were observed between miR-155 expression and SOCS1 mRNA expression and plasma concentration in AD peripheral circulation and skin lesions. In conclusion, miR-155 is over-expressed and may be involved in AD pathogenesis by modulating the differentiation and function of Th17 cells.

What is the impact of SOCS3, IL-35 and IL17 in immune pathogenesis of recurrent pregnancy loss?

OBJECTIVE: To investigate the plasma levels of interleukin-4 (IL-4), IL-6, IL-10, tumor necrosis factor-alpha (TNF-alpha), interferon-gamma (IFN-gamma), transforming growth factor-beta (TGF-beta), IL-17, IL-35 and suppressor of cytokine signaling 3 (SOCS3) in the women with history of idiopathic recurrent pregnancy loss (RPL) and in the fertile controls. METHODS: This study was conducted with 60 idiopathic RPL cases and 40 age-matched fertile controls. Mid-follicular plasma levels of IL-17, IFN-gamma, TNF-alpha, TGF-beta, IL-6, IL-4, IL-10, SOCS3 and IL-35 were assayed by an enzyme linked immunosorbent assay. RESULTS: The mean age of RPL and control cases were 31.6 ± 0.6 and 32.1 ± 0.7 years, respectively. While plasma IL-35 and SOCS3 levels of RPL group were significantly lower than that of the control group; IFN-gamma, TNF-alpha, IL-4, IL-6, IL-10, IL-17 and TGF-beta levels of RPL group were significantly higher than that of the control group. The comparison of cytokine ratios between RPL and control groups indicated significantly high TNF-alpha/IL-10, TNF-alpha/IL-4, IFN-gamma/IL-10, IFN-gamma/IL-6 and IFN-gamma/IL-4 ratios in the RPL group. IL-35/IL-17 ratio was significantly low in the RPL group compared to that in the control group. Overstimulation of TNF-alpha presented moderate influence on recurrent miscarriage risk. CONCLUSION: Decreased SOCS3 and IL-35 plasma levels and increased Th1/Th2 cytokine ratios in RPL cases pointed out the supression of anti-inflammatory process and this supression might play an important role in the pathogenesis of idiopathic RPL.

Interleukin-2 and SOCS-1 proteins involvement in the pathophysiology of severe ovarian hyperstimulation syndrome--a preliminary proof of concept.

BACKGROUND: Ovarian hyperstimulation syndrome (OHSS), is characterized by marked ovarian enlargement and acute third space fluid sequestration that almost always develops after hCG administration or in early pregnancy. OHSS is similar to vascular leak syndrome (VLS), which may be attributable to the massive increase in systemic inflammatory cytokines. In the present pilot exploratory case series, we sought to evaluate interleukin (IL)-2 and suppressor of cytokine signaling (SOCS)-1 expressions in the peripheral blood mononuclear cells (PBMCs) of patients suffering from severe ovarian hypertimulation syndrome (OHSS), and to examine whether their expressions differ when compared to PBMCs originated from normal early pregnant women (without OHSS). METHODS: Interleukin-2 and SOCS-1 mRNA expressions were examined in PBMCs of 5 women who were hospitalized due to severe OHSS (OHSS group) and 5 women with early IVF pregnancies and without OHSS (control group). RESULTS: Interleukin-2 mRNA levels in PBMCs were significantly higher in the OHSS as compared to the control groups. Moreover, while SOCS-1 mRNA levels were non-significantly lower, the ratio between IL-2 and SOCS-1 mRNA levels was significantly higher in the OHSS, as compared to the control group. CONCLUSIONS: The inflammatory response to hCG, leading to dysregulation of Il-2 expression and SOCS activation, might be the culprit of OHSS. Additional large prospective studies are required to elucidate the effect of hCG on patients' inherited inflammatory cascades, which may help discriminating those at risk to develop severe OHSS from those who are not.

SOCS3 expression correlates with severity of inflammation in mouse hepatitis virus strain 3-induced acute liver failure and HBV-ACLF.

Recently, suppressor of cytokine signaling-3 (SOCS3) has been shown to be an inducible endogenous negative regulator of Janus kinase/signal transducers and activators of transcription (JAK/STAT) pathway which is relevant in inflammatory response, while its functions in acute liver failure and HBV-induced acute-on-chronic liver failure (HBV-ACLF) have not been fully elucidated. In this study, we explored the role of SOCS3 in the development of mouse hepatitis virus strain 3 (MHV-3)-induced acute liver failure and its expression in liver and peripheral blood mononuclear cells (PBMCs) of patients with HBV-ACLF. Inflammation-related gene expression was detected by real-time PCR, immunohistochemistry and Western blotting. The correlation between SOCS3 level and liver injury was studied. Our results showed that the SOCS3 expression was significantly elevated in both the liver tissue and PBMCs from patients with HBV-ACLF compared to mild chronic hepatitis B (CHB). Moreover, a time course study showed that SOCS3 level was increased remarkably in the liver of BALB/cJ mice at 72 h post-infection. Pro-inflammatory cytokines, interleukin (IL)-1ß, IL-6, and tumor necrosis factor (TNF)-α, were also increased significantly at 72 h post-infection. There was a close correlation between hepatic SOCS3 level and IL-6, and the severity of liver injury defined by alanine aminotransferase (ALT) and aspartate aminotransferase (AST) levels, respectively. These data suggested that SOCS3 may play a pivotal role in the pathogenesis of MHV-3-induced acute liver failure and HBV-ACLF.

Impact of STAT/SOCS mRNA expression levels after major injury.

BACKGROUND: Fulminant changes in cytokine receptor signalling might provoke severe pathological alterations after multiple trauma. The aim of this study was to evaluate the posttraumatic imbalance of the innate immune system with a special focus on the STAT/SOCS family. METHODS: 20 polytraumatized patients were included. Blood samples were drawn 0 h-72 h after trauma; mRNA expression profiles of IL-10, STAT 3, SOCS 1, and SOCS 3 were quantified by qPCR. RESULTS: IL-10 mRNA expression increased significantly in the early posttraumatic period. STAT 3 mRNA expressions showed a significant maximum at 6 h after trauma. SOCS 1 levels significantly decreased 6 h-72 h after trauma. SOCS 3 levels were significantly higher in nonsurvivors 6 h after trauma. CONCLUSION: We present a serial, sequential investigation in human neutrophil granulocytes of major trauma patients evaluating mRNA expression profiles of IL-10, STAT 3, SOCS 1, and SOCS 3. Posttraumatically, immune disorder was accompanied by a significant increase of IL-10 and STAT 3 mRNA expression, whereas SOCS 1 mRNA levels decreased after injury. We could demonstrate that death after trauma was associated with higher SOCS 3 mRNA levels already at 6 h after trauma. To support our results, further investigations have to evaluate protein levels of STAT/SOCS family in terms of posttraumatic immune imbalance.

What is the impact of Th1/Th2 ratio, SOCS3, IL17, and IL35 levels in unexplained infertility?

Implantation necessitates complex interactions among the developing embryo, decidualizing endometrium, and developing maternal immune tolerance and/or alterations in cellular and humoral immune responses. Overstimulation of T helper 1 (Th1) or Th2 cytokines in systemic and local environments, alterations of the prevalence of IL17 and regulatory T cell (Treg) cytokines have also been suggested to contribute to the pathogenesis of implantation failure. We aimed to investigate the plasma levels of IL4, IL6, IL10, TNFα, IFNγ, TGFß, IL17, IL35, and SOCS3 in infertile and fertile women. This case-control study was conducted with 80 women suffering from unexplained infertility and 40 fertile women. Peripheral venous blood samples were drawn on day 21 of the menstrual cycle. The extracted plasma samples were assayed by an enzyme linked immunosorbent assay. Statistical analysis was performed using SPSS version 16.0. Our main findings were as follows: despite the significantly high IL17 and IL35 plasma levels of infertile women, IL35/IL17 ratio was significantly lower in the infertile group compared with that in the fertile group; SOCS3 plasma levels showed an inverse relation with plasma levels of all cytokines except IL35; increased plasma IL17 levels (>3.42 pg/mL) have a negative impact on fertility; TNFα/IL10, IFNγ/IL10, IFNγ/IL6, and IFNγ/IL4 ratios were significantly higher in infertile group compared with those in the fertile group. It is not possible to show the major immunological factor(s) of unexplained infertility, but our findings point out that the decreased suppressor activity of the immune system may play a role in implantation failure.

Plasma IL-17, IL-35, interferon-γ, SOCS3 and TGF-ß levels in pregnant women with preeclampsia, and their relation with severity of disease.

UNLABELLED: Abstract Objective: To research the hypothesis of preeclampsia (PE) is associated with increased systemic inflammatory responses of Th1-type as well as decreased Th2-type responses; we evaluated the maternal plasma levels of IFN-gamma, TNF-alpha, TGF-beta, IL-4, IL-6, IL-10, IL-17, IL-35 and SOCS3 in preeclamptic and healthy pregnants. METHODS: This study was conducted with 40 preeclamptic (study group) and 40 normotensive pregnant (control) women in third trimester when they were admitted to the labor and delivery unit. The extracted maternal plasma samples were assayed by an enzyme-linked immunosorbent assay. Statistical analysis was performed by SPSS 16.0 version. RESULTS: While IFN-gamma and TGF-beta levels of preeclamptic women were significantly higher (p < 0.01), IL-35 and IL-17 levels of preeclamptic women were significantly lower (p < 0.01) than those of controls. The ratios of IFN-gamma/IL-10, IFN-gamma/IL-6, IFN-gamma/IL-4 were significantly high and ratio of IL-35/IL-17 was significantly low in the PE group compared to those in the control group. Maternal plasma SOCS3 levels showed negative correlation with blood pressure and proteinuria severity, but none of the cytokines showed influence on blood pressure and proteinuria after adjusting for maternal and gestational age. CONCLUSIONS: Increased IFN-gamma/TGF-beta production and reduced IL-35/IL-17/SOCS3 production in preeclamptic women may lead to less cytokine inhibitory activity in PE, which may account for the increased proteinuria and blood pressure in PE.

Decreased interferon-α and interferon-ß production in obesity and expression of suppressor of cytokine signaling.

OBJECTIVE: We analyzed the interferon-α (IFN-α), IFN-ß, and proinflammatory responses induced by Toll-like receptor (TLR) ligands in peripheral blood mononuclear cells (PBMCs) from obese subjects and their association with suppressor of cytokine signaling-1 (SOCS1) and SOCS3 expression. METHODS: The IFN responses were measured by real-time quantitative reverse transcription polymerase chain reaction (qRT-PCR) and enzyme-linked immunosorbent assay in PBMCs stimulated with TLR-3 and TLR-7 ligands from 30 non-obese (body mass index ≤ 25 kg/m(2)) and 30 obese (body mass index ≥ 30 kg/m(2)) volunteers. The mRNA expression of nuclear factor-κB, SOCS1, and SOCS3 also was evaluated by qRT-PCR. Proinflammatory cytokine responses were measured by enzyme-linked immunosorbent assay. RESULTS: Obese subjects showed a decreased ability to produce IFN-α and IFN-ß in response to TLR ligands; this response was associated with increased basal levels of SOCS3 but not SOCS1. However, after stimulation, the expression of SOCS3 and SOCS1 mRNA was significantly lower in PBMCs from obese compared with non-obese subjects. The PBMCs from obese subjects also showed higher basal levels of interleukin-6 and a decreased response of proinflammatory cytokines interleukin-6 and interleukin-1ß after stimulation with the TLR-3 ligand compared with PBMCs from non-obese participants. CONCLUSION: These data suggest that obesity is related to impaired IFN-α and IFN-ß responses and increased SOCS3 basal mRNA expression and that a signaling pathway by TLR-3 may be involved. These results could explain, at least in part, the inadequate response of obese people against viral infections, such as influenza.

Novel link between inflammation and impaired glucose transport during equine insulin resistance.

Although insulin resistance (IR) has been increasingly recognized in horses, a clear understanding of its pathophysiology is lacking. The purpose of the present study was to determine the early pathologic changes in IR horses by characterizing alterations in proteins that play key roles in innate immunological responses and inflammatory pathways, and by identifying potential links with glucose transport and insulin signaling. Visceral (VIS) and subcutaneous (SC) adipose tissue and skeletal muscle (SM) biopsies were collected from horses, which were classified as insulin-sensitive (IS) or IR based on the results of an insulin-modified frequently sampled intravenous glucose tolerance test. Protein expression of Toll-like receptor 4 (TLR-4), suppressor of cytokine signaling 3 (SOCS-3) and tumor necrosis factor alpha (TNF-α) were quantified by Western blotting in VIS and SC adipose depots and SM, as well as insulin receptor substrate 1 (IRS-1). To better characterize the potential relationship between inflammation, IR and impaired glucose transport, we correlated active cell surface glucose transporter 4 (GLUT-4) content (measured by a cell surface biotinylated assay) with individual- and tissue-specific data related to inflammation. IR was associated with a significantly increased expression of TLR-4 and SOCS-3 in SM and VIS tissue, without a significant change in SC site. We also observed a significant increase in TNF-α in VIS, but not in SC, tissue of IR vs. IS horses. There was no difference in total content or serine phosphorylation of IRS-1 for any sampling site in IR compared to IS horses. We further observed a significant positive correlation between TLR-4 content and SOCS-3, as well as a significant negative correlation between SOCS-3 content and GLUT-4 trafficking. Taken together, the data suggested a pro-inflammatory state in SM and VIS, but not SC, adipose depot during compensated IR. In addition, SOCS-3 appears to be a novel link between inflammation and dysregulated glucose metabolism and insulin sensitivity during the early pathogenesis of insulin resistance.

A pivotal role for antigen-presenting cells overexpressing SOCS3 in controlling invariant NKT cell responses during collagen-induced arthritis.

OBJECTIVE: Suppressor of cytokine signalling (SOCS) proteins constitute a class of intracellular proteins that are key physiological regulators of immune cell function. It has previously been shown that antigen-presenting cells (APCs) overexpressing SOCS3 steer T helper immune responses and protect against experimental arthritis. A study was undertaken to investigate the contribution of SOCS3 in regulating invariant natural killer T (iNKT) cell responses during collagen-induced arthritis (CIA). METHODS: DBA/1 mice were immunised with type II collagen and adenoviruses encoding SOCS3 were administered intravenously before the clinical onset of arthritis. Murine APCs overexpressing SOCS3 were co-cultured with an iNKT cell hybridoma and interleukin 2 (IL-2) release was measured by Luminex multi-analyte technology. The frequency and activation of primary iNKT cells was assessed by flow cytometry. Murine APCs were analysed for cytokine and CD1d expression following viral SOCS3 gene transfer. RESULTS: Viral overexpression of SOCS3 in APCs resulted in reduced activation of the iNKT cell hybridoma. Importantly, during initiation of CIA, adenovirus-mediated overexpression of SOCS3 in hepatic and splenic APCs inhibited iNKT cell expansion in both organs. The iNKT cell population from SOCS3-treated mice showed low expression of the early activation marker CD69 and primary liver iNKT cells produced less interferon γ and IL-4 upon α-galactosylceramide stimulation. No differences in CD1d surface expression were observed, but SOCS3-transduced APCs produced decreased levels of proinflammatory cytokines and increased levels of IL-10. CONCLUSION: These results demonstrate a critical role for SOCS3 in controlling the immunostimulatory capacities of APCs, which has direct implications for the effector function of iNKT cells during arthritis.

Clinical significance of suppressor of cytokines signalling-3 mRNA expression from patients with non-Hodgkin lymphoma under chemotherapy.

INTRODUCTION: To date, little is known about blood immune marker changes that may be related to the development of Non Hodgkin Lymphoma (NHL) and treatment response with few serum biomarkers that could be useful in follow- up of the patients. OBJECTIVE: To quantify the expression of suppressor of cytokine signalling-3-(SOCS-3) gene at the mRNA level in the peripheral blood of patients with NHL and correlate with clinical pathological features and response to treatment. METHODS: Thirty patients with NHL and 20 healthy controls were enrolled in the study. The SOCS-3 mRNA level in peripheral blood (PB) was detected by semi-quantitative real-time polymerase chain reaction. Quantification of cytokines such as interleukin 6 and tumour necrosis factor alpha (IL-6 & TNF-α) were performed using sandwich enzyme-linked immunosorbent assays (ELISA). RESULTS: Increased expression of SOCS-3 mRNA in peripheral blood plus increased serum levels of IL-6 and TNF alpha from NHL cases with no complete remission after therapy. Higher levels of expression of SOCS-3 are associated with advanced disease, bone marrow involvement, extranodal involvement, poor performance status, B cell symptoms (fever, night sweats and weight loss) and high serum lactate dehydrogenase level which are evaluated by international prognostic index (IPI). Complete responses occur in 60% of patients with normal expression of SOCS-3 gene. Increased expression of SOCS-3 is common in diffuse large B cell lymphoma, CLL/small lymphocytic B cell lymphoma and follicular lymphoma. CONCLUSIONS: Over-expression of SOCS-3 mRNA from peripheral blood of NHL patients correlates with advanced disease and poor response to treatment. SOCS-3 mRNA expression in peripheral blood from NHL patients might be used to monitor response during treatment.

SOCS3 and SOCS5 mRNA expressions may predict initial steroid response in nephrotic syndrome children.

Suppressors of Cytokine Signaling (SOCS) inhibit Signal Transducers and Activators of Transcription (STATs) phosphorylation by binding and inhibiting Janus Kinases (JaKs). The aim of the present study was to evaluate the influence of glucocorticosteroids on the JaK/STAT signaling pathway in the leukocytes of nephrotic syndrome (NS) patients. The study group was composed of 34 steroid sensitive NS (SSNS) children and 20 steroid resistant NS (SRNS) subjects. Gene expression was assessed by real-time PCR using pre-designed human JaK/STAT PCR array. Protein expression was evaluated using ELISA assay (plasma concentration) and immunofluorescence (in situ protein expression). In SSNS children, the initial increased expression of JaK1, JaK2, JaK3, STAT1, STAT2, STAT6, TYK2, SOCS1, SOCS2, SOCS3, SOCS4 and SOCS5 was reduced back to the control limits. Similarly, in SRNS patients the increased levels of almost all mRNA expressions for the abovementioned genes were decreased, with the exceptions of SOCS3 and SOCS5 expressions. These mRNA expressions were still significantly increased and correlated with early unfavorable course of nephrotic syndrome in children. Plasma levels of SOCS3, SOCS5, IL-6 and IL-20 were significantly increased in SRNS subjects after six weeks of steroids medication compared to SSNS and control participants. We conclude that SOCS3 and SOCS5 increased mRNA expressions might predict initial resistance to steroids in NS patients.