IFNγ-dependent SOCS3 expression inhibits IL-6-induced STAT3 phosphorylation and differentially affects IL-6 mediated transcriptional responses in endothelial cells

2010 ◽  
Vol 299 (2) ◽  
pp. C354-C362 ◽  
Author(s):  
Hans A. R. Bluyssen ◽  
M. Mehdi Rastmanesh ◽  
Chantal Tilburgs ◽  
Kim Jie ◽  
Sebastiaan Wesseling ◽  
...  
Keyword(s):  
Target Genes ◽  
Interferon Γ ◽  
Cytokine Signaling ◽  
Transcriptional Responses ◽  
Stat3 Phosphorylation ◽  
Socs3 Expression ◽  
Protective Genes ◽  
Inflammatory Phenotype ◽  
Anti Inflammatory ◽  
Interfering Rna

IL-6 has pro- and anti-inflammatory effects and is involved in endothelial cell (EC) dysfunction. The anti-inflammatory effects of IL-6 are mediated by signal transducer and activator of transcription-3 (STAT3), which is importantly controlled by suppressor of cytokine signaling 3 (SOCS3). Therefore, cytokines that modulate SOCS3 expression might inhibit the anti-inflammatory effects of IL-6. We hypothesized that in EC, interferon-γ (IFNγ)-induced SOCS3 expression leads to inhibition of IL-6-induced STAT3 activation and IL-6-dependent expression of anti-, but not pro-inflammatory, target genes. IFNγ activated STAT1 and STAT3 and increased SOCS3 expression in EC. IL-6 only activated STAT3 and induced SOCS3 expression. IFNγ pretreatment of EC inhibited IL-6-induced STAT3 activation accompanied by increased SOCS3 protein. Inhibition of SOCS3 expression, using costimulation, Act-D, and small interfering RNA (siRNA), subsequently implicated the importance of IFNγ-induced SOCS3 in this phenomenon. Pretreatment of EC with IFNγ also affected the transcriptional program induced by IL-6. We identified 1) IL-6 anti-inflammatory target genes that were inhibited by IFNγ, 2) IFNγ-target genes of pro-inflammatory nature that were increased in response to IL-6 in the presence of IFNγ, and 3) a set of target genes that were increased upon IL-6 or IFNγ alone, or combined IFNγ and IL-6. In summary, by increasing SOCS3 expression in EC, IFNγ can selectively inhibit STAT3-dependent IL-6 signaling. This in turn leads to decreased expression of some EC protective genes. In contrast, other genes of pro-inflammatory nature are not inhibited or even increased. This IFNγ-induced shift in IL-6 signaling to a pro-inflammatory phenotype could represent a novel mechanism involved in EC dysfunction.

scholarly journals Genetic Correction of IL-10RB Deficiency Reconstitutes Anti-Inflammatory Regulation in iPSC-Derived Macrophages

2021 ◽  
Vol 11 (3) ◽  
pp. 221
Author(s):  
Dirk Hoffmann ◽  
Johanna Sens ◽  
Sebastian Brennig ◽  
Daniel Brand ◽  
Friederike Philipp ◽  
...  
Keyword(s):  
Disease Modeling ◽  
Integration Site ◽  
Cytokine Secretion ◽  
Cytokine Signaling ◽  
Stat3 Phosphorylation ◽  
Tnf Α ◽  
Socs3 Expression ◽  
Healthy Control ◽  
Anti Inflammatory ◽  
Inflammatory Regulation

Patient material from rare diseases such as very early-onset inflammatory bowel disease (VEO-IBD) is often limited. The use of patient-derived induced pluripotent stem cells (iPSCs) for disease modeling is a promising approach to investigate disease pathomechanisms and therapeutic strategies. We successfully developed VEO-IBD patient-derived iPSC lines harboring a mutation in the IL-10 receptor β-chain (IL-10RB) associated with defective IL-10 signaling. To characterize the disease phenotype, healthy control and VEO-IBD iPSCs were differentiated into macrophages. IL-10 stimulation induced characteristic signal transducer and activator of transcription 3 (STAT3) and suppressor of cytokine signaling 3 (SOCS3) downstream signaling and anti-inflammatory regulation of lipopolysaccharide (LPS)-mediated cytokine secretion in healthy control iPSC-derived macrophages. In contrast, IL-10 stimulation of macrophages derived from patient iPSCs did not result in STAT3 phosphorylation and subsequent SOCS3 expression, recapitulating the phenotype of cells from patients with IL-10RB deficiency. In line with this, LPS-induced cytokine secretion (e.g., IL-6 and tumor necrosis factor-α (TNF-α)) could not be downregulated by exogenous IL-10 stimulation in VEO-IBD iPSC-derived macrophages. Correction of the IL-10RB defect via lentiviral gene therapy or genome editing in the adeno-associated virus integration site 1 (AAVS1) safe harbor locus led to reconstitution of the anti-inflammatory response. Corrected cells showed IL-10RB expression, IL-10-inducible phosphorylation of STAT3, and subsequent SOCS3 expression. Furthermore, LPS-mediated TNF-α secretion could be modulated by IL-10 stimulation in gene-edited VEO-IBD iPSC-derived macrophages. Our established disease models provide the opportunity to identify and validate new curative molecular therapies and to investigate phenotypes and consequences of additional individual IL-10 signaling pathway-dependent VEO-IBD mutations.

scholarly journals Platelet regulation of myeloid suppressor of cytokine signaling 3 accelerates atherosclerosis

2019 ◽  
Vol 11 (517) ◽  
pp. eaax0481 ◽  
Author(s):  
Tessa J. Barrett ◽  
Martin Schlegel ◽  
Felix Zhou ◽  
Mike Gorenchtein ◽  
Jennifer Bolstorff ◽  
...  
Keyword(s):  
Cardiovascular Disease ◽  
Cytokine Signaling ◽  
Platelet Activity ◽  
Suppressor Of Cytokine Signaling ◽  
Phagocytic Capacity ◽  
Monocyte Migration ◽  
Socs3 Expression ◽  
Platelet Aggregate ◽  
Inflammatory Phenotype

Platelets are best known as mediators of hemostasis and thrombosis; however, their inflammatory effector properties are increasingly recognized. Atherosclerosis, a chronic vascular inflammatory disease, represents the interplay between lipid deposition in the artery wall and unresolved inflammation. Here, we reveal that platelets induce monocyte migration and recruitment into atherosclerotic plaques, resulting in plaque platelet-macrophage aggregates. In Ldlr−/− mice fed a Western diet, platelet depletion decreased plaque size and necrotic area and attenuated macrophage accumulation. Platelets drive atherogenesis by skewing plaque macrophages to an inflammatory phenotype, increasing myeloid suppressor of cytokine signaling 3 (SOCS3) expression and reducing the Socs1:Socs3 ratio. Platelet-induced Socs3 expression regulates plaque macrophage reprogramming by promoting inflammatory cytokine production (Il6, Il1b, and Tnfa) and impairing phagocytic capacity, dysfunctions that contribute to unresolved inflammation and sustained plaque growth. Translating our data to humans with cardiovascular disease, we found that women with, versus without, myocardial infarction have up-regulation of SOCS3, lower SOCS1:SOCS3, and increased monocyte-platelet aggregate. A second cohort of patients with lower extremity atherosclerosis demonstrated that SOCS3 and the SOCS1:SOCS3 ratio correlated with platelet activity and inflammation. Collectively, these data provide a causative link between platelet-mediated myeloid inflammation and dysfunction, SOCS3, and cardiovascular disease. Our findings define an atherogenic role of platelets and highlight how, in the absence of thrombosis, platelets contribute to inflammation.

scholarly journals IκBζ is a key transcriptional regulator of IL-36–driven psoriasis-related gene expression in keratinocytes

2018 ◽  
Vol 115 (40) ◽  
pp. 10088-10093 ◽  
Author(s):  
Anne Müller ◽  
André Hennig ◽  
Sebastian Lorscheid ◽  
Paula Grondona ◽  
Klaus Schulze-Osthoff ◽  
...  
Keyword(s):  
Gene Expression ◽  
Proinflammatory Cytokine ◽  
Target Genes ◽  
Immune Cell ◽  
Transcriptional Regulator ◽  
Inflammatory Cells ◽  
Cytokine Signaling ◽  
Transcriptional Responses ◽  
Psoriasis Therapy ◽  
Proinflammatory Gene

Proinflammatory cytokine signaling in keratinocytes plays a crucial role in the pathogenesis of psoriasis, a skin disease characterized by hyperproliferation and abnormal differentiation of keratinocytes and infiltration of inflammatory cells. Although IL-17A and TNFα are effective therapeutic targets in psoriasis, IL-36 has recently emerged as a proinflammatory cytokine. However, little is known about IL-36 signaling and its downstream transcriptional responses. Here, we found that exposure of keratinocytes to IL-36 induced the expression of IκBζ, an atypical IκB member and a specific transcriptional regulator of selective NF-κB target genes. Induction of IκBζ by IL-36 was mediated by NF-κB and STAT3. In agreement, IL-36–mediated induction of IκBζ was found to be required for the expression of various psoriasis-related genes involved in inflammatory signaling, neutrophil chemotaxis, and leukocyte activation. Importantly, IκBζ-knockout mice were protected against IL-36–mediated dermatitis, accompanied by reduced proinflammatory gene expression, decreased immune cell infiltration, and a lack of keratinocyte hyperproliferation. Moreover, expression of IκBζ mRNA was highly up-regulated in biopsies of psoriasis patients where it coincided withIL36Glevels. Thus our results uncover an important role for IκBζ in IL-36 signaling and validate IκBζ as an attractive target for psoriasis therapy.

Inhibitory Effect of Mechanical Load on IL-1 Induced Cartilage Degradation Is Mediated by Interferon-Gamma and IL-1 Receptor 1

2008 ◽  
Author(s):  
C. T. Chen ◽  
S. Park ◽  
M. Bhargava ◽  
P. A. Torzilli
Keyword(s):  
Mechanical Load ◽  
Interleukin 1 ◽  
Cartilage Degradation ◽  
Inhibitory Effect ◽  
Interferon Γ ◽  
Cytokine Signaling ◽  
Matrix Remodeling ◽  
Inhibitory Protein ◽  
Anti Inflammatory ◽  
Related Proteins

Matrix remodeling in articular cartilage is regulated by the elevation and activation of aggrecanases (ADAMTS-4 and ADAMTS-5) and matrix metalloproteinases (MMPs) [2–4, 7–9, 10]. Several recent studies from our and other groups have shown that mechanical loading can counteract interleukin 1 (IL-1) induced pro-inflammatory and catabolic events by down-regulating aggrecanases, MMPs, and pro-inflammatory genes [1, 3, 5, 6], but the molecular mechanism is not clear. Many previous studies have shown that the regulation of pro-inflammatory effect of IL-1 come from several aspects: anti-inflammatory cytokines (TGF-β, IL-10, IL-6 and interferon γ), IL-1 receptor related proteins (IL-1R1, IL-1R2, and IL-1Ra) as well as a family of intracellular inhibitory protein called Suppressor Of Cytokine Signaling (SOCS.) SOCS1 and SOCS3 are especially important, since they can inhibit both MAPK and NF-κB pathways induced by IL-1 [12]. The objective of this study was to determine whether mechanical load affected anti-inflammatory mediators along with anti-catabolic events.

Effect of IL-6 on the insulin sensitivity in patients with type 2 diabetes

2014 ◽  
Vol 306 (7) ◽  
pp. E769-E778 ◽  
Author(s):  
N. M. Harder-Lauridsen ◽  
R. Krogh-Madsen ◽  
J. J. Holst ◽  
P. Plomgaard ◽  
L. Leick ◽  
...  
Keyword(s):  
Type 2 Diabetes ◽  
Glucose Metabolism ◽  
Glucose Uptake ◽  
Whole Body ◽  
Cytokine Signaling ◽  
Contributing Factors ◽  
Stat3 Phosphorylation ◽  
Socs3 Expression ◽  
Body Energy

Elevated interleukin-6 (IL-6) levels are associated with type 2 diabetes, but its role in glucose metabolism is controversial. We investigated the effect of IL-6 on insulin-stimulated glucose metabolism in type 2 diabetes patients and hypothesized that an acute, moderate IL-6 elevation would increase the insulin-mediated glucose uptake. Men with type 2 diabetes not treated with insulin [ n = 9, age 54.9 ± 9.7 (mean ± SD) yr, body mass index 34.8 ± 6.1 kg/m2, HbA1c7.0 ± 1.0%] received continuous intravenous infusion with either recombinant human IL-6 (rhIL-6) or placebo. After 1 h with placebo or rhIL-6, a 3-h hyperinsulinemic-isoglycemic clamp was initiated. Whole body glucose metabolism was measured using stable isotope-labeled tracers. Signal transducer and activator of transcription 3 (STAT3) phosphorylation and suppressor of cytokine signaling 3 (SOCS3) expression were measured in muscle biopsies. Whole body energy expenditure was measured using indirect calorimetry. In response to the infusion of rhIL-6, circulating levels of IL-6 ( P < 0.001), neutrophils ( P < 0.001), and cortisol ( P < 0.001) increased while lymphocytes decreased ( P < 0.01). However, IL-6 infusion did not change glucose infusion rate, rate of appearance, or rate of disappearance during the clamp. While IL-6 enhanced phosphorylation of STAT3 in skeletal muscle ( P = 0.041), the expression of SOCS3 remained unchanged. Whole body oxygen uptake ( P < 0.01) and expired carbon dioxide ( P < 0.01) increased during rhIL-6 infusion. In summary, although IL-6 induced local and systemic responses, the insulin-stimulated glucose uptake was not affected. While different contributing factors may be involved, our results are in contrast to our hypothesis and previous findings in young, healthy men.

MyD88 plays a key role in LPS-induced Stat3 activation in the hypothalamus

2010 ◽  
Vol 298 (2) ◽  
pp. R403-R410 ◽  
Author(s):  
Yosuke Yamawaki ◽  
Hitomi Kimura ◽  
Toru Hosoi ◽  
Koichiro Ozawa
Keyword(s):  
Time Course ◽  
Molecular Mechanisms ◽  
Intraperitoneal Administration ◽  
Primary Response ◽  
Janus Kinase ◽  
Negative Regulator ◽  
Cytokine Signaling ◽  
Stat3 Phosphorylation ◽  
Socs3 Expression ◽  
Hypothalamic Function

Infection causes the production of proinflammatory cytokines, which act on the central nervous system (CNS) and can result in fever, sleep disorders, depression-like behavior, and even anorexia, although precisely how cytokines regulate the functions of the CNS remain unclear. In the present study, we investigated the regulatory-molecular mechanisms by which cytokines affect hypothalamic function in a state of infection. The intraperitoneal administration of lipopolysaccharide (LPS), a ligand of Toll-like receptor 4 (TLR4), time-dependently (2–24 h) increased signal transducer and activator of transcription 3 (STAT3) phosphorylation in the hypothalamus and liver, which corresponded with anorexia observed within 24 h. Interestingly, the pattern of phosphorylation in response to LPS differed between the hypothalamus and liver. In the hypothalamus, LPS increased STAT3 phosphorylation from 2 h, with a peak at 4 h and a decline thereafter, whereas, in the liver, the peak activation of STAT3 persisted from 2 to 8 h. The time course of the LPS-induced expression of suppressor of cytokine signaling 3 (SOCS3), a STAT3-induced negative regulator of the Janus kinase-STAT pathway, was similar to that of STAT3 phosphorylation. Using mice deficient in myeloid differentiation primary-response protein 88 (MyD88), an adapter protein of TLR4, we found that LPS-induced STAT3 phosphorylation and SOCS3 expression in the hypothalamus and liver were predominantly mediated through MyD88. Moreover, we observed that MyD88-deficient mice were resistant to LPS-induced anorexia. Taken together, our findings reveal a novel mechanism, i.e., MyD88 plays a key role in mediating STAT3 phosphorylation and anorexia in the CNS in a state of infection and inflammation.

Abstract 130: Il-10 Regulates the Immunoregulatory Response in the Regression of Atherosclerosis

2012 ◽  
Vol 111 (suppl_1) ◽  
Author(s):  
Cathal McCarthy ◽  
Michelle Duffy ◽  
Declan Mooney ◽  
William James ◽  
Desmond J Fitzgerald ◽  
...  
Keyword(s):  
Inflammatory Cytokine ◽  
Immune Cell ◽  
Receptor Expression ◽  
Cytokine Signaling ◽  
Aortic Tissue ◽  
Cholesterol Diet ◽  
Stat3 Phosphorylation ◽  
Anti Inflammatory ◽  
Anti Inflammatory Cytokine ◽  
M2 Phenotype

We have previously shown that dietary administration of conjugated linoleic acid (CLA) induces regression of pre-established atherosclerosis in the apoE -/- mouse, via modification of inflammatory cell function. However, the exact mechanism through which this occurs has not been elucidated. Here we describe a functional role for signaling of the anti-inflammatory cytokine, IL-10, in atherosclerosis regression and investigate the consequence of enhanced IL-10 generation on the immune cell population in vivo . Our initial aim was todelineate the atheroprotective mechanisms modulated by CLA. Transcriptomic analysis of aortic tissue in the CLA-induced regression model identified an enrichment of the IL-10 signaling pathway. Further analysis of the network identified increased IL-10 receptor expression (localized to the macrophage cells) and STAT3 phosphorylation; and increased expression of downstream target genes such as the anti-inflammatory cytokine IL-1Ra (by 3.45 ± 0.83 p<0.05 fold) and suppressor of cytokine signaling (SOCS3) (by 2.24± 0.44 p<0.01 fold). Moreover, there was increased circulating IL-10 serum levels in apoE -/- mice fed a CLA supplemented 1% cholesterol diet compared with apoE -/- mice fed a 1% cholesterol diet alone (41.9 ± 8.9 vs 79.8 pg/ml ± 22.4 p<0.01). Interestingly, both IL-10 production and STAT3 phosphorylation was significantly increased in bone marrow derived macrophages from CLA fed mice. We next employed flow cytometry to delineate the phenotype of single cell suspensions of aortae. CLA supplementation regulated immune cell infiltration of the aorta with increased number of the anti-inflammatory Ly6C lo monocytes evident during regression (29±8 vs 77±14cells/mg aorta p<0.05). In addition, CLA-induced regression was associated with increased polarization towards an anti-inflammatory M2 phenotype, confirmed by an enrichment of M2 genes in the aorta, which occurred as a consequence of increased aortic IL-10 production. In summary CLA mediated induction of IL-10 signaling alters the immunoinflammatory response to atherosclerosis, with increased volume of Ly6C lo monocytes infiltrating the regressing lesions and directed polarization of macrophages towards an M2 phenotype in the plaque microenvironment.

scholarly journals p-Cymene and Rosmarinic Acid Ameliorate TNBS-Induced Intestinal Inflammation Upkeeping ZO-1 and MUC-2: Role of Antioxidant System and Immunomodulation

2020 ◽  
Vol 21 (16) ◽  
pp. 5870 ◽  
Author(s):  
Rodrigo de Oliveira Formiga ◽  
Edvaldo Balbino Alves Júnior ◽  
Roseane Carvalho Vasconcelos ◽  
Gerlane Coelho Bernardo Guerra ◽  
Aurigena Antunes de Araújo ◽  
...  
Keyword(s):  
Rosmarinic Acid ◽  
Intestinal Inflammation ◽  
Intestinal Barrier ◽  
Inflammatory Activity ◽  
Cytokine Signaling ◽  
Mesenteric Lymph Nodes ◽  
Communicating Junctions ◽  
Socs3 Expression ◽  
Anti Inflammatory ◽  
Cluster Of Differentiation

p-Cymene (p-C) and rosmarinic acid (RA) are secondary metabolites that are present in medicinal herbs and Mediterranean spices that have promising anti-inflammatory properties. This study aimed to evaluate their intestinal anti-inflammatory activity in the trinitrobenzene sulphonic acid (TNBS)-induced colitis model in rats. p-C and RA (25–200 mg/kg) oral administration reduced the macroscopic lesion score, ulcerative area, intestinal weight/length ratio, and diarrheal index in TNBS-treated animals. Both compounds (200 mg/kg) decreased malondialdehyde (MDA) and myeloperoxidase (MPO), restored glutathione (GSH) levels, and enhanced fluorescence intensity of superoxide dismutase (SOD). They also decreased interleukin (IL)-1β and tumor necrosis factor (TNF)-α, and maintained IL-10 basal levels. Furthermore, they modulated T cell populations (cluster of differentiation (CD)4+, CD8+, or CD3+CD4+CD25+) analyzed from the spleen, mesenteric lymph nodes, and colon samples, and also decreased cyclooxigenase 2 (COX-2), interferon (IFN)-γ, inducible nitric oxide synthase (iNOS), and nuclear transcription factor kappa B subunit p65 (NFκB-p65) mRNA transcription, but only p-C interfered in the suppressor of cytokine signaling 3 (SOCS3) expression in inflamed colons. An increase in gene expression and positive cells immunostained for mucin type 2 (MUC-2) and zonula occludens 1 (ZO-1) was observed. Altogether, these results indicate intestinal anti-inflammatory activity of p-C and RA involving the cytoprotection of the intestinal barrier, maintaining the mucus layer, and preserving communicating junctions, as well as through modulation of the antioxidant and immunomodulatory systems.

scholarly journals SOCS1 cooperates with FLT3-ITD in the development of myeloproliferative disease by promoting the escape from external cytokine control

Blood ◽  
2012 ◽  
Vol 120 (8) ◽  
pp. 1691-1702 ◽  
Author(s):  
Pavankumar N. G. Reddy ◽  
Bülent Sargin ◽  
Chunaram Choudhary ◽  
Stefan Stein ◽  
Manuel Grez ◽  
...  
Keyword(s):  
Bone Marrow ◽  
Target Genes ◽  
Colony Growth ◽  
Interferon Γ ◽  
Myelogenous Leukemia ◽  
Cytokine Signaling ◽  
Interferon Α ◽  
Myeloproliferative Disease ◽  
Clinical Prognosis ◽  
Murine Bone Marrow

Abstract Activating mutations in the receptor tyrosine kinase FLT3 are frequently found in acute myelogenous leukemia patients and confer poor clinical prognosis. It is unclear how leukemic blasts escape cytokine control that regulates normal hematopoiesis. We have recently demonstrated that FLT3-internal tandem duplication (ITD), when localized to the biosynthetic compartment, aberrantly activates STAT5. Here, we show that one of the target genes induced by STAT5 is suppressor of cytokine signaling (SOCS)1—a surprising finding for a known tumor suppressor. Although SOCS1 expression in murine bone marrow severely impaired cytokine-induced colony growth, it failed to inhibit FLT3-ITD–supported colony growth, indicating resistance of FLT3-ITD to SOCS1. In addition, SOCS1 coexpression did not affect FLT3-ITD–mediated signaling or proliferation. Importantly, SOCS1 coexpression inhibited interferon-α and interferon-γ signaling and protected FLT3-ITD hematopoietic cells from interferon-mediated growth inhibitory effects. In a murine bone marrow transplantation model, the coexpression of SOCS1 and FLT3-ITD significantly shortened the latency of a myeloproliferative disease compared with FLT3-ITD alone (P < .01). Mechanistically, SOCS proteins shield FLT3-ITD from external cytokine control, thereby promoting leukemogenesis. The data demonstrate that SOCS1 acts as a conditional oncogene, providing novel molecular insights into cytokine resistance in oncogenic transformation. Restoring cytokine control may provide a new way of therapeutic intervention.

SOCS1 Cooperates with FLT3-ITD In the Development of Myeloproliferative Disease by Promoting the Escape From External Cytokine Control.

Blood ◽  
2010 ◽  
Vol 116 (21) ◽  
pp. 1054-1054
Author(s):  
Christian H. Brandts ◽  
Pavankumar Reddy ◽  
Bülent Sargin ◽  
Chunaram Choudhary ◽  
Carsten Muller-Tidow ◽  
...  
Keyword(s):  
Bone Marrow ◽  
Target Genes ◽  
Conflicts Of Interest ◽  
Colony Growth ◽  
Interferon Γ ◽  
Negative Regulator ◽  
Cytokine Signaling ◽  
Myeloproliferative Disease ◽  
Clinical Prognosis ◽  
Murine Bone Marrow

Abstract Abstract 1054 Activating mutations of FLT3 such as FLT3-ITD are frequently found in AML patients and confer poor clinical prognosis. It is unclear how leukemic blasts escape cytokine control, which regulates normal hematopoiesis. We have recently demonstrated that FLT3-ITD, when localized to the endoplasmic reticulum, aberrantly activates STAT5. Here we show that one of the target genes induced by STAT5 is SOCS1, a potent negative regulator of cytokine signaling and known tumor suppressor gene. Importantly, a significantly increased SOCS1 expression was found in FLT3-ITD+ AML. While SOCS1 expression in murine bone marrow severely impaired cytokineinduced colony growth, it failed to inhibit FLT3-ITD supported colony growth, indicating resistance of FLT3-ITD to SOCS1. Furthermore, SOCS1 co-expression inhibited interferon-γ signaling and protected FLT3-ITD hematopoietic cells from interferon-γ mediated growth inhibitory effects. In a murine bone marrow transplantation model, the co-expression of SOCS1 and FLT3-ITD significantly shortened the latency of a myeloproliferative disease compared to FLT3-ITD alone (p<0.01). Mechanistically, SOCS proteins shield FLT3-ITD from external cytokine control, thereby promoting malignant transformation. The data demonstrate that SOCS1 acts as a conditional oncogene, providing novel molecular insights into cytokine resistance in oncogenic transformation. Restoring cytokine control may provide a new way of therapeutic intervention. Disclosures: No relevant conflicts of interest to declare.

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