scholarly journals Transforming Growth Factor-β Coordinately Induces Suppressor of Cytokine Signaling 3 and Leukemia Inhibitory Factor to Suppress Osteoclast Apoptosis

Endocrinology ◽  
2010 ◽  
Vol 151 (4) ◽  
pp. 1713-1722 ◽  
Author(s):  
Ming Ruan ◽  
Larry Pederson ◽  
Elizabeth W. Bradley ◽  
Ana-Maria Bamberger ◽  
Merry Jo Oursler
Keyword(s):  
Family Member ◽  
Leukemia Inhibitory Factor ◽  
Janus Kinase ◽  
Inhibitory Factor ◽  
Cytokine Signaling ◽  
Suppressor Of Cytokine Signaling ◽  
Socs3 Expression ◽  
Osteoclast Survival ◽  
Osteoclast Apoptosis ◽  
Interacting Domain

Local release of TGF-β during times of high bone turnover leads to elevated levels within the bone microenvironment, and we have shown that TGF-β suppresses osteoclast apoptosis. Therefore, understanding the influences of TGF-β on bone resorbing osteoclasts is critical to the design of therapies to reduce excess bone loss. Here we investigated the mechanisms by which TGF-β sustains suppression of osteoclast apoptosis. We found TGF-β rapidly increased leukemia inhibitory factor (LIF) expression and secretion by phosphorylated mothers against decapentaplegic-dependent and -independent signaling pathways. TGF-β also induced suppressor of cytokine signaling 3 (SOCS3) expression, which was required for TGF-β or LIF to promote osteoclast survival by. Blocking LIF or SOCS3 blocked TGF-β promotion of osteoclast survival, confirming that LIF and SOCS3 expression are necessary for TGF-β-mediated suppression of osteoclast apoptosis. Investigation of the mechanisms by which LIF promotes osteoclast survival revealed that LIF-induced expression of Bcl-XL and repressed Bcl-2 interacting domain expression by activating MAPK kinase, AKT, and nuclear factor-κB pathways. Suppression of Janus kinase/signal transducer and activator of transcription signaling further increased Bcl-XL expression and enhanced osteoclast survival, supporting that this pathway is not involved in prosurvival effects of TGF-β and LIF. These data show that TGF-β coordinately induces LIF and SOCS3 to promote prosurvival signaling. This alters the ratio of prosurvival Bcl2 family member Bcl-XL to proapoptotic family member Bcl-2 interacting domain, leading to prolonged osteoclast survival.

scholarly journals Leukemia-Inhibitory Factor—Neuroimmune Modulator of Endocrine Function*

2000 ◽  
Vol 21 (3) ◽  
pp. 313-345 ◽  
Author(s):  
C. J. Auernhammer ◽  
S. Melmed
Keyword(s):  
Leukemia Inhibitory Factor ◽  
Energy Homeostasis ◽  
Molecular Mechanisms ◽  
Critical Role ◽  
Bone Cell ◽  
Janus Kinase ◽  
Inhibitory Factor ◽  
Endocrine Function ◽  
Cytokine Signaling ◽  
Endocrine Regulation

Abstract Leukemia-inhibitory factor (LIF) is a pleiotropic cytokine expressed by multiple tissue types. The LIF receptor shares a common gp130 receptor subunit with the IL-6 cytokine superfamily. LIF signaling is mediated mainly by JAK-STAT (janus-kinase-signal transducer and activator of transcription) pathways and is abrogated by the SOCS (suppressor-of cytokine signaling) and PIAS (protein inhibitors of activated STAT) proteins. In addition to classic hematopoietic and neuronal actions, LIF plays a critical role in several endocrine functions including the utero-placental unit, the hypothalamo-pituitary-adrenal axis, bone cell metabolism, energy homeostasis, and hormonally responsive tumors. This paper reviews recent advances in our understanding of molecular mechanisms regulating LIF expression and action and also provides a systemic overview of LIF-mediated endocrine regulation. Local and systemic LIF serve to integrate multiple developmental and functional cell signals, culminating in maintaining appropriate hormonal and metabolic homeostasis. LIF thus functions as a critical molecular interface between the neuroimmune and endocrine systems.

scholarly journals Absence of suppressor of cytokine signaling 2 turns cardiomyocytes unresponsive to LIF-dependent increases in Ca2+ levels

2017 ◽  
Vol 312 (4) ◽  
pp. C478-C486 ◽  
Author(s):  
Cibele Rocha-Resende ◽  
Itamar Couto Guedes de Jesus ◽  
Danilo Roman-Campos ◽  
Artur S. Miranda ◽  
Fabiana Alves ◽  
...  
Keyword(s):  
Leukemia Inhibitory Factor ◽  
Inhibitory Factor ◽  
Cytokine Signaling ◽  
Wild Type ◽  
Suppressor Of Cytokine Signaling ◽  
Gp130 Receptor ◽  
Intracellular Ca ◽  
Full Activation

Little is known regarding the role of suppressor of cytokine signaling (SOCS) in the control of cytokine signaling in cardiomyocytes. We investigated the consequences of SOCS2 ablation for leukemia inhibitory factor (LIF)-induced enhancement of intracellular Ca2+ ([Ca2+]i) transient by performing experiments with cardiomyocytes from SOCS2-knockout (ko) mice. Similar levels of SOCS3 transcripts were seen in cardiomyocytes from wild-type and SOCS2-ko mice, while SOCS1 mRNA was reduced in SOCS2-ko. Immunoprecipitation experiments showed increased SOCS3 association with gp130 receptor in SOCS2-ko myocytes. Measurements of Ca2+ in wild-type myocytes exposed to LIF showed a significant increase in the magnitude of the Ca2+ transient. This change was absent in LIF-treated SOCS2-ko cells. LIF activation of ERK and STAT3 was observed in both wild-type and SOCS2-ko cells, indicating that in SOCS2-ko, LIF receptors were functional, despite the lack of effect in the Ca2+ transient. In wild-type cells, LIF-induced increase in [Ca2+]i and phospholamban Thr17 [PLN(Thr17)] phosphorylation was inhibited by KN-93, indicating a role for CaMKII in LIF-induced Ca2+ raise. LIF-induced phosphorylation of PLN(Thr17) was abrogated in SOCS2-ko myocytes. In wild-type cardiomyocytes, LIF treatment increased L-type Ca2+ current ( ICa,L), a key activator of CaMKII in response to LIF. Conversely, SOCS2-ko myocytes failed to activate ICa,L in response to LIF, providing a rationale for the lack of LIF effect on Ca2+ transient. Our data show that absence of SOCS2 turns cardiomyocytes unresponsive to LIF-induced [Ca2+] raise, indicating that endogenous levels of SOCS2 are crucial for full activation of LIF signaling in the heart.

scholarly journals Sox2 controls neural stem cell self-renewal through a Fos-centered gene regulatory network

2020 ◽  
Author(s):  
Miriam Pagin ◽  
Simone Giubbolini ◽  
Cristiana Barone ◽  
Gaia Sambruni ◽  
Yanfen Zhu ◽  
...  
Keyword(s):  
Molecular Mechanisms ◽  
Cytokine Signaling ◽  
Normal Brain ◽  
Suppressor Of Cytokine Signaling ◽  
Self Renewal ◽  
Upstream Regulator ◽  
Socs3 Expression ◽  
Pharmacological Manipulations

AbstractThe Sox2 transcription factor is necessary for the long-term self-renewal of neural stem cells (NSC). Its mechanism of action is still poorly defined. To identify molecules regulated by Sox2, and acting in mouse NSC maintenance, we transduced, individually or in combination, into Sox2-deleted NSC, genes whose expression is strongly downregulated following Sox2 loss (Fos, Jun, Egr2). Fos alone rescued long-term proliferation, as shown by in vitro cell growth and clonal analysis. Further, Fos requirement for efficient long-term proliferation was demonstrated by the strong reduction of NSC clones capable of long-term expansion following CRISPR/Cas9-mediated Fos inactivation. Previous work showed that the Suppressor of cytokine signaling 3 (Socs3) gene is strongly downregulated following Sox2 deletion, and its reexpression by lentiviral transduction rescues long-term NSC proliferation. Fos appears to be an upstream regulator of Socs3, possibly together with Jun and Egr2; indeed, Sox2 reexpression in Sox2-deleted NSC progressively activates both Fos and Socs3 expression; in turn, Fos transduction activates Socs3 expression. Based on available SOX2 ChIPseq and ChIA-PET data, as well as results from the literature, we propose a model whereby Sox2 is a direct activator of both Socs3 and Fos, as well as possibly Jun and Egr2; in turn, Fos, Jun and Egr2 may activate Socs3. These results provide the basis for developing a model of a network of interactions, regulating critical effectors of NSC proliferation and long-term maintenance.Significance statementProliferation and maintenance of NSC are essential during normal brain development, and, postnatally, for the maintenance of hippocampal function and memory until advanced age. Little is known about the molecular mechanisms that maintain the critical aspects of NSC biology (quiescence and proliferation) in postnatal age. Our work provides a methodology, transduction of genes deregulated following Sox2 deletion, that allows to test many candidate genes for their ability to sustain NSC proliferation. In principle, this may have interesting implications for identifying targets for pharmacological manipulations.

scholarly journals A Role of Suppressor of Cytokine Signaling 3 (SOCS3/CIS3/SSI3) in CD28-mediated Interleukin 2 Production

2003 ◽  
Vol 197 (4) ◽  
pp. 425-436 ◽  
Author(s):  
Akira Matsumoto ◽  
Yoh-ichi Seki ◽  
Ryosuke Watanabe ◽  
Katsuhiko Hayashi ◽  
James A. Johnston ◽  
...  
Keyword(s):  
T Cells ◽  
T Cell ◽  
T Cell Activation ◽  
Interleukin 2 ◽  
Sh2 Domain ◽  
Janus Kinase ◽  
Expression Level ◽  
Cytokine Signaling ◽  
Suppressor Of Cytokine Signaling ◽  
Cd28 Costimulation

Suppressor of cytokine signaling (SOCS)3 has been characterized as a negative feedback regulator in cytokine-mediated Janus kinase signal transducer and activator of transcription signaling. However, this study shows that T cells from transgenic mice expressing SOCS3 exhibit a significant reduction in interleukin (IL)-2 production induced by T cell receptor cross-linking when T cells are costimulated with CD28. Decreased protein expression in SOCS3+/− mice enhanced CD28-mediated IL-2 production, clearly indicating the correlation between expression level of SOCS3 and IL-2 production ability. The SOCS3 protein interacted with phosphorylated CD28 through its SH2 domain but not the kinase inhibitory region. In addition, a point mutation in the SOCS3 SH2 domain attenuated the inhibition of CD28 function in IL-2 promoter activation. Committed T helper (Th)2 cells exclusively expressed SOCS3 and production of Th2 cytokines, such as IL-4 and IL-5, was much less dependent on CD28 costimulation compared with interferon γ and IL-2 production in Th1 cells. Consistent with this notion, the expression level of SOCS3 in early T cell activation influenced the ability of IL-2 production induced by CD28 costimulation. Therefore, the SOCS3 may play an alternative role in prohibiting excessive progression of CD28-mediated IL-2 production.

Suppressor of cytokine signaling 2 (SOCS2) deletion protects against multiple low dose streptozotocin-induced type 1 diabetes in adult male mice

2016 ◽  
Vol 26 (1) ◽  
Author(s):  
Amira Alkharusi ◽  
Mercedes Mirecki-Garrido ◽  
Zuheng Ma ◽  
Fahad Zadjali ◽  
Amilcar Flores-Morales ◽  
...  
Keyword(s):  
Type I Diabetes ◽  
Janus Kinase ◽  
Cytokine Signaling ◽  
Type I ◽  
Suppressor Of Cytokine Signaling ◽  
Β Cell ◽  
Diabetes In Mice ◽  
Socs Proteins ◽  
Stat Pathway

AbstractDiabetes type 1 is characterized by the failure of beta cells to produce insulin. Suppressor of cytokine signaling (SOCS) proteins are important regulators of the Janus kinase/signal transducer and activator of transcription (JAK-STAT) pathway. Previous studies have shown that GH can prevent the development of type I diabetes in mice and that SOCS2 deficiency mimics a state of increased GH sensitivity.The elevated sensitivity of SOCS2We show that 6-month-old SOCS2Knockdown of SOCS2 makes mice less sensitive to MLDSTZ. These results are consistent with the proposal that elimination of SOCS2 in pancreatic islets creates a state of β-cell hypersensitivity to GH/PRL that mimics events in pregnancy, and which is protective against MLDSTZ-induced type I diabetes in mice. SOCS2-dependent control of β-cell survival may be of relevance to islet regeneration and survival in transplantation.

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 Suppressor of Cytokine Signaling 3 Is Induced by Angiotensin II in Heart and Isolated Cardiomyocytes, and Participates in Desensitization

Endocrinology ◽  
2003 ◽  
Vol 144 (10) ◽  
pp. 4586-4596 ◽  
Author(s):  
Vivian C. Calegari ◽  
Rosangela M. N. Bezerra ◽  
Márcio A. Torsoni ◽  
Adriana S. Torsoni ◽  
Kleber G. Franchini ◽  
...  
Keyword(s):  
Angiotensin Ii ◽  
Rat Heart ◽  
Ventricular Myocytes ◽  
Janus Kinase ◽  
Neonatal Rat ◽  
Cytokine Signaling ◽  
Ang Ii ◽  
Suppressor Of Cytokine Signaling ◽  
Rat Ventricular Myocytes ◽  
Neonatal Rat Ventricular Myocytes

Angiotensin II (Ang II) exerts a potent growth stimulus on the heart and vascular wall. Activation of the Janus kinase/signal transducer and activator of transcription (JAK/STAT) intracellular signaling pathway by Ang II mediates at least some of the mitogenic responses to this hormone. In other signaling systems that use the JAK/STAT pathway, proteins of the suppressor of cytokine signaling (SOCS) family participate in signal regulation. In the present study it is demonstrated that SOCS3 is constitutively expressed at a low level in rat heart and neonatal rat ventricular myocytes. Ang II at a physiological concentration enhances the expression of SOCS3 mRNA and protein, mainly via AT1 receptors. After induction, SOCS3 associates with JAK2 and impairs further activation of the JAK2/STAT1 pathway. Pretreatment of rats with a specific phosphorthioate antisense oligonucleotide to SOCS3, reverses the desensitization to angiotensin signaling, as detected by a fall in c-Jun expression after repetitive infusions of the hormone. Thus, SOCS3 is induced by Ang II in rat heart and neonatal rat ventricular myocytes and participates in the modulation of the signal generated by this hormone.

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