The mechanism by which p53 suppresses tumorigenesis remains poorly understood. In the context of aberrant activation of the JAK/STAT5 pathway, SOCS1 is required for p53 activation and the regulation ...of cellular senescence. In order to identify p53 target genes acting during the senescence response to oncogenic STAT5A, we characterized the transcriptome of STAT5A-expressing cells after SOCS1 inhibition. We identified a set of SOCS1-dependent p53 target genes that include several secreted proteins and genes regulating oxidative metabolism and ferroptosis. Exogenous SOCS1 was sufficient to regulate the expression of p53 target genes and sensitized cells to ferroptosis. This effect correlated with the ability of SOCS1 to reduce the expression of the cystine transporter SLC7A11 and the levels of glutathione. SOCS1 and SOCS1-dependent p53 target genes were induced during the senescence response to oncogenic STAT5A, RasV12 or the tumor suppressor PML. However, while SOCS1 sensitized cells to ferroptosis neither RasV12 nor STAT5A mimicked the effect. Intriguingly, PML turned cells highly resistant to ferroptosis. The results indicate different susceptibilities to ferroptosis in senescent cells depending on the trigger and suggest the possibility of killing senescent cells by inhibiting pathways that mediate ferroptosis resistance.
•IL-15 in implicated in various autoimmune diseases.•IL-15 is a potential immunotherapeutic target in autoimmunity.•Biologics targeting IL-15 or its receptors are in clinical or pre-clinical stages.
...Interleukin-15 (IL-15) is a member of the IL-2 family of cytokines, which use receptor complexes containing the common gamma (γc) chain for signaling. IL-15 plays important roles in innate and adaptative immune responses and is implicated in the pathogenesis of several immune diseases. The IL-15 receptor consists of 3 subunits namely, the ligand-binding IL-15Rα chain, the β chain (also used by IL-2) and the γc chain. IL-15 uses a unique signaling pathway whereby IL-15 associates with IL-15Rα during biosynthesis, and this complex is ‘trans-presented’ to responder cells that expresses the IL-2/15Rβγc receptor complex. IL-15 is subject to post-transcriptional and post-translational regulation, and evidence also suggests that IL-15 cis-signaling can occur under certain conditions.
IL-15 has been implicated in the pathology of various autoimmune diseases such as rheumatoid arthritis, autoimmune diabetes, inflammatory bowel disease, coeliac disease and psoriasis. Studies with pre-clinical models have shown the beneficial effects of targeting IL-15 signaling in autoimmunity. Unlike therapies targeting other cytokines, anti-IL-15 therapies have not yet been successful in humans. We discuss the complexities of IL-15 signaling in autoimmunity and explore potential immunotherapeutic approaches to target the IL-15 signaling pathway.
•ADE increases viraemia in DHF and in FCoV infections.•In SARS-CoV infections ADE promotes inflammation.•The underlying cause of hyperinflammation is not clear in Covid-19.
The COVID-19 pandemic has ...rapidly spread around the world with significant morbidity and mortality in a subset of patients including the elderly. The poorer outcomes are associated with ‘cytokine storm-like’ immune responses, otherwise referred to as ‘hyperinflammation’. While most of the infected individuals show minimal or no symptoms and recover spontaneously, a small proportion of the patients exhibit severe symptoms characterized by extreme dyspnea and low tissue oxygen levels, with extensive damage to the lungs referred to as acute respiratory distress symptom (ARDS). The consensus is that the hyperinflammatory response of the host is akin to the cytokine storm observed during sepsis and is the major cause of death. Uncertainties remain on the factors that lead to hyperinflammatory response in some but not all individuals. Hyperinflammation is a common feature in different viral infections such as dengue where existing low-titer antibodies to the virus enhances the infection in immune cells through a process called antibody-dependent enhancement or ADE. ADE has been reported following vaccination or secondary infections with other corona, Ebola and dengue virus. Detailed analysis has shown that antibodies to any viral epitope can induce ADE when present in sub-optimal titers or is of low affinity. In this review we will discuss ADE in the context of dengue and coronavirus infections including Covid-19.
Hepatic stellate cells (HSC) are the key mediators of fibrosis development in non-alcoholic fatty liver disease (NAFLD). Hepatic inflammation induced by high-fat diet activates HSCs, which ...differentiate to myofibroblasts and produce extracellular fibrillar matrix. HSC activation during hepatic fibrogenesis is modulated by cytokines and growth factors produced by stressed hepatocytes and macrophages. SOCS1 is a negative feedback regulator of certain cytokines and growth factors implicated in liver fibrosis.
The goal of this study was to understand the regulatory functions of SOCS1 in HSCs during NAFLD-induced liver fibrosis.
Mice lacking SOCS1 specifically in HSCs (
) and control
-floxed (
) mice were fed choline-deficient L-amino acid-defined high-fat diet (CDA-HFD) or normal control diet for 14 weeks. Body weight gain was regularly monitored. Serum alanine aminotransferase levels and liver weight were assessed at the endpoint. Fibrosis development was evaluated by Sirius red staining and hydroxyproline content, and myofibroblast differentiation by immunohistochemistry. Expression of genes encoding pro-fibrogenic factors, cytokines, growth factors and chemokines, and the phenotype and numbers of intrahepatic leukocytes were evaluated.
mice showed increased liver/body weight ratio and displayed increased collagen deposition and myofibroblast differentiation. Induction of
,
,
,
and
genes was significantly elevated in
mice compared to
controls fed CDA-HFD.
gene induction was comparable between the two groups, however,
livers displayed increased SMAD3 phosphorylation. The fibrotic livers of
mice showed increased inflammatory cell infiltration, and flow cytometry analysis revealed elevated numbers of myeloid cells, granulocytes and myeloid-derived dendritic cells.
livers harbored increased numbers of Ly6C
CCR2+ pro-inflammatory macrophages, largely comprised of Ly6C
CCR2+CX3CR1+ cells, suggesting impaired transition to anti-inflammatory macrophages.
Our findings show that SOCS1 exerts non-redundant regulatory functions in HSCs that are critical for attenuating high-fat diet-induced inflammatory response and liver fibrosis development.
Editorial: Cytokines in liver diseases Ilangumaran, Subburaj; Moriggl, Richard; Kalvakolanu, Dhan V
Cytokine (Philadelphia, Pa.),
12/2019, Volume:
124
Journal Article
Peer reviewed
This special issue on 'Cytokines in Liver Diseases' was inspired by many talks and presentations on liver cancer during the 2nd Aegean Conference on Cytokine Signaling in Cancer (ACCSC) held at ...Heraklion, Crete, Greece on May 30-June 04, 2017 (Cytokine 2018, 108: 225-231). The liver is the biggest blood filtration and detoxification unit, and is a vital metabolic organ. Being constantly exposed to potentially harmful dietary chemicals, drugs, alcohol abuse and pathogens, the liver displays an extraordinary capacity to repair tissue damage and to regenerate. Moreover, only a healthy liver can provide the vast majority of plasma proteins, plus serving as a key organ for body homeostasis and metabolic fitness. Occasionally, the liver may have to deal with chronic damage inflicted by hepatotropic infections such as hepatitis viruses and metabolic derangements caused by obesity and the consequent metabolic syndrome. Overwhelming the natural defenses of the liver can compromise its vital functions and this can lead to more severe liver disease such as fibrosis that may progress towards cirrhosis and eventually to hepatocellular carcinoma (HCC). However, in obesity, a worldwide crisis that has been developing during the last few decades, HCC can develop in the fatty liver bypassing the fibrosis and cirrhosis stages. With the availability of effective therapies and vaccination strategies for hepatitis viruses, over nutrition has become the biggest new threat for a healthy liver. Cytokines and chemokines play a key role in the initiation and perpetuation of acute and chronic injury to the liver, and thus they contribute to most liver pathologies. The topic of cytokines in liver diseases is so vast that it cannot be adequately covered in this special issue. However, we have attempted to provide a glimpse of hot topics through comprehensive reviews and a few accompanying original articles on key research areas.
SOCS1-/- mice die prematurely of increased interferon-γ (IFNγ) signaling with severe thymic atrophy and accelerated maturation of T cells. However, it was unclear whether the thymic defects were ...caused by SOCS1 deficiency or by increased IFNγ signaling. UsingSOCS1-/-IFNγ-/- mice, we show in this study that SOCS1 deficiency skews thymocyte development toward CD8 lineage independently of IFNγ. Fetal thymic organ cultures and intrathymic transfer of CD4-CD8- precursors intoRag1-/- mice show that the lineage skewing inSOCS1-/- mice is a T-cell autonomous defect. Interestingly, SOCS1 is not required for attenuating interleukin-7 (IL-7) signaling at the CD4-CD8- stage but is essential for regulating IL-15 and IL-2 signaling in CD8+ thymocytes. IL-15 selectively stimulatesSOCS1-/- CD8+ thymocytes, inducing sustained signal transducer and activator of transcription 5 (STAT5) phosphorylation and massive proliferation. IL-15 also strongly up-regulates Bcl-xL and CD44 in CD8+ thymocytes lacking SOCS1. TheSOCS1 gene is induced in CD4+ thymocytes by γc cytokines, whereas CD8+ thymocytes constitutively express SOCS1 mRNA even in the absence of cytokine stimulation. Because many different cell types express IL-15, our results strongly suggest that SOCS1 functions as an indispensable attenuator of IL-15 receptor signaling in developing CD8+ thymocytes. (Blood. 2003;102:4115-4122)
•There are no cytokines that are consistently associated with obesity in humans.•Unlike in murine models, IL-4 is associated with obesity in humans.•Cellular stress caused by excess energy intake can ...activate signaling pathways that induce inflammation.•Inflammation is a consequence rather than primary cause of insulin resistance.
Chronic inflammation in adipose tissues has been associated with obesity and metabolic syndrome over the years. Various studies using animal models have contributed to our knowledge on the pro- and anti- inflammatory mediators that regulate obesity. Analyses of cytokine profiles in humans have not revealed a clear scenario. Likewise, treatments targeting inflammation to control obesity and insulin resistance has not yielded promising results. In this review we summarize the data available in human obesity and discuss the possible reasons that could explain the difficulties in treating obesity and insulin resistance by targeting pro-inflammatory cytokines.
•SOCS1 plays non-redundant roles in hepatocytes and macrophages to control fibrosis.•Loss of SOCS1 in hepatocytes or macrophages reduces Mmp2 but increases Timp1.•Hepatic Ifng expression requires ...SOCS1 in hepatocytes and macrophages.•SOCS1 deficiency in hepatocytes or macrophages enhances Pdgfb expression.
The hepatic fibrogenic response is a protective mechanism activated by hepatocyte damage and is resolved upon elimination of the cause. However, persistent injuries cause liver fibrosis (LF) to evolve into cirrhosis, which promotes the development of hepatocellular carcinoma (HCC). Development of efficient treatments for LF requires better understanding the underlying molecular pathogenic mechanisms. The loss of suppressor of cytokine signaling 1 (SOCS1) expression promotes LF and HCC in human and mice, but the underlying mechanisms remain unclear. SOCS1 is a key regulator of immune cell activation. To investigate the anti-fibrogenic functions of SOCS1 in hepatocytes and macrophages, we generated mice lacking SOCS1 in hepatocytes (Socs1fl/flAlbCre) or macrophages (Socs1fl/flLysMCre) and evaluated hepatic fibrogenic response to carbon tetrachloride (CCl4). Socs1fl/flAlbCre and Socs1fl/flLysMCre mice showed severe LF characterized by increased collagen deposition, hydroxyproline content, myofibroblast accumulation along with elevated expression of Acta2 and Col1a1 genes. CCl4 treatment triggered significant damage to hepatocytes in Socs1fl/flAlbCre mice but not in Socs1fl/flLysMCre mice. In both mice CCl4 treatment reduced the expression of Mmp2 and increased the expression of Timp1. SOCS1 deficiency in hepatocytes or macrophages did not affect Il6, Tnfa or Tgfb, but diminished Infg and augmented Pdgfb expression. Both Socs1fl/flAlbCre and Socs1fl/flLysMCre livers showed increased mononuclear cell infiltration accompanied by elevated Ccl2 expression. Our findings show that SOCS1 exerts non-redundant functions in hepatocytes and macrophages to regulate the hepatic fibrogenic response possibly through limiting hepatocyte damage and the inflammatory response of macrophages, and support the idea of exploiting SOCS1 in LF treatment.
SOCS1 is a negative feedback regulator of cytokine and growth factor receptor signaling, and plays an indispensable role in attenuating interferon gamma signaling. Studies on SOCS1-deficient mice ...have established a crucial role for SOCS1 in regulating CD8
T cell homeostasis. In the thymus, SOCS1 prevents thymocytes that had failed positive selection from surviving and expanding, ensures negative selection and prevents inappropriate developmental skewing toward the CD8 lineage. In the periphery, SOCS1 not only controls production of T cell stimulatory cytokines but also attenuates the sensitivity of CD8
T cells to synergistic cytokine stimulation and antigen non-specific activation. As cytokine stimulation of CD8
T lymphocytes increases their sensitivity to low affinity TCR ligands, SOCS1 likely contributes to peripheral T cell tolerance by putting brakes on aberrant T cell activation driven by inflammatory cytokines. In addition, SOCS1 is critical to maintain the stability of T regulatory cells and control their plasticity to become pathogenic Th17 and Th1 cells under the harmful influence of inflammatory cytokines. SOCS1 also regulates T cell activation by dendritic cells via modulating their generation, maturation, antigen presentation, costimulatory signaling, and cytokine production. The above control mechanisms of SOCS1 on T cells, T regulatory cells and dendritic cells collectively contribute to immunological tolerance and prevent autoimmune manifestation. On other hand, silencing SOCS1 in dendritic cells or CD8
T cells stimulates efficient antitumor immunity. Thus, even though SOCS1 is not a cell surface checkpoint inhibitor, its regulatory functions on T cell responses qualify SOCS1as a "non-classical" checkpoint blocker. SOCS1 also functions as a tumor suppressor in cancer cells by regulating oncogenic signal transduction pathways. The loss of SOCS1 expression observed in many tumors may have an impact on classical checkpoint pathways. The potential to exploit SOCS1 to treat inflammatory/autoimmune diseases and elicit antitumor immunity is discussed.
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