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1.
J Reprod Immunol ; 77(1): 1-6, 2008 Jan.
Artigo em Inglês | MEDLINE | ID: mdl-17408753

RESUMO

Cytokines are an integral part of the adaptive and innate immune responses. The signalling pathways triggered by receptor engagement translate exposure to cytokine into a coordinated biological response. To contain these responses, the initiation, duration and magnitude of the signal is controlled at multiple levels. Suppressor of cytokine signalling (SOCS) proteins act in a negative feedback loop to inhibit signal transduction. Mice with a deletion of SOCS3 die at midgestion due to placental insufficiency. SOCS3-null placentae have increased numbers of mature trophoblast giant cells, disruption of the labyrinthine layer and a decrease in the spongiotrophoblast layer. Genetic crosses have revealed that the phenotype is due to dysregulation of signalling downstream of the leukaemia inhibitory factor (LIF) receptor alpha (LIFRalpha) and that the ligand responsible for this, LIF, is produced by embryonic tissues and acts in a paracrine fashion. These observations highlight the role of LIF as an extrinsic factor regulating trophoblast differentiation in vivo. The creation of mice with conditional deletion of SOCS3 in different tissues has also uncovered critical roles for SOCS3 in the regulation of IL-6, G-CSF and leptin signalling.


Assuntos
Fator Inibidor de Leucemia/fisiologia , Placenta/fisiologia , Transdução de Sinais/fisiologia , Proteínas Supressoras da Sinalização de Citocina/fisiologia , Animais , Humanos , Camundongos , Proteína 3 Supressora da Sinalização de Citocinas , Proteínas Supressoras da Sinalização de Citocina/genética
2.
Neurotox Res ; 7(1-2): 151-67, 2005.
Artigo em Inglês | MEDLINE | ID: mdl-15639806

RESUMO

The mechanisms determining the fate of Schwann cells during disease and injury of the adult mammalian peripheral nervous system (PNS) are becoming defined by current advances in molecular neurobiology. It is now apparent that the molecular pathways which regulate the production of the mature myelinating Schwann cell during development may also apply to degenerative and regenerative mechanisms following PNS disease. This review outlines neurobiological responses of Schwann cells during development, injury and disease in order to define the molecular pathways which regulate these crucial events. These mechanisms have implications for our attempts to intervene pharmacologically during pathologies of the PNS.


Assuntos
Nervos Periféricos/crescimento & desenvolvimento , Doenças do Sistema Nervoso Periférico/metabolismo , Doenças do Sistema Nervoso Periférico/patologia , Células de Schwann/fisiologia , Animais , Morte Celular/fisiologia , Sobrevivência Celular/fisiologia , Humanos , Traumatismos dos Nervos Periféricos , Nervos Periféricos/citologia , Células de Schwann/citologia , Células de Schwann/patologia
3.
Cell Signal ; 21(3): 394-404, 2009 Mar.
Artigo em Inglês | MEDLINE | ID: mdl-19056487

RESUMO

The mechanism by which Suppressor of Cytokine Signaling-3 (SOCS3) negatively regulates cytokine signaling has been widely investigated using over-expression studies in cell lines and is thought to involve interactions with both the gp130 receptor and JAK1. Here, we compare the endogenous JAK/STAT signaling pathway downstream of Leukemia Inhibitory Factor (LIF) signaling in wild type (WT) Embryonic Stem (ES) cells and in ES cells lacking either the entire Socs3 gene or bearing a truncated form of SOCS3 (SOCS3DeltaSB) lacking the C-terminal SOCS box motif (SOCS3(DeltaSB/DeltaSB)). In SOCS3(DeltaSB/DeltaSB) cells phosphorylated JAK1 accumulated at much higher levels than in WT cells or even cells lacking SOCS3 (SOCS3(-/-)). In contrast enhanced activation of STAT3 and SHP2 was seen in SOCS3(-/-) cells. Size exclusion chromatography of cell extracts showed that in unstimulated cells, JAK1 was exclusively associated with receptors but following cytokine stimulation hyperphosphorylated JAK1 (pJAK1) appeared to dissociate from the receptor complex in a manner independent of SOCS3. In WT and SOCS3(DeltaSB/DeltaSB) cells SOCS3 was associated with pJAK1. The data suggest that dissociation of activated JAK1 from the receptor results in separate targeting of JAK1 for proteasomal degradation through a mechanism dependent on the SOCS3 SOCS box thus preventing further activation of STAT3.


Assuntos
Células-Tronco Embrionárias/metabolismo , Janus Quinase 1/metabolismo , Fator de Transcrição STAT3/metabolismo , Proteínas Supressoras da Sinalização de Citocina/genética , Motivos de Aminoácidos/genética , Animais , Diferenciação Celular/genética , Citocinas/metabolismo , Citocinas/farmacologia , Células-Tronco Embrionárias/citologia , Ativação Enzimática/efeitos dos fármacos , Ativação Enzimática/fisiologia , Regulação da Expressão Gênica no Desenvolvimento/fisiologia , Regulação Enzimológica da Expressão Gênica/fisiologia , Fator Inibidor de Leucemia/metabolismo , Camundongos , Camundongos Knockout , Fosforilação/efeitos dos fármacos , Proteína Tirosina Fosfatase não Receptora Tipo 11/genética , Proteína Tirosina Fosfatase não Receptora Tipo 11/metabolismo , Fator de Transcrição STAT3/genética , Transdução de Sinais/fisiologia , Proteína 3 Supressora da Sinalização de Citocinas , Proteínas Supressoras da Sinalização de Citocina/química , Regulação para Cima/efeitos dos fármacos , Regulação para Cima/fisiologia
4.
Blood ; 110(5): 1466-74, 2007 Sep 01.
Artigo em Inglês | MEDLINE | ID: mdl-17510322

RESUMO

Suppressor of cytokine signaling 3 (SOCS3) is a negative regulator of granulocyte-colony stimulating factor (G-CSF) signaling in vivo. SOCS proteins regulate cytokine signaling by binding, via their SH2 domains, to activated cytokine receptors or their associated Janus kinases. In addition, they bind to the elongin B/C ubiquitin ligase complex via the SOCS box. To ascertain the contribution of the SOCS box of SOCS3 to in vivo regulation of G-CSF signaling, we generated mice expressing a truncated SOCS3 protein lacking the C-terminal SOCS box (SOCS3(Delta SB/Delta SB)). SOCS3(Delta SB/Delta SB) mice were viable, had normal steady-state hematopoiesis, and did not develop inflammatory disease. Despite the mild phenotype, STAT3 activation in response to G-CSF signaling was prolonged in SOCS3(Delta SB/Delta SB) bone marrow. SOCS3(Delta SB/Delta SB) bone marrow contained increased numbers of colony-forming cells responsive to G-CSF and IL-6. Treatment of the mice with pharmacologic doses of G-CSF, which mimics emergency granulopoiesis and therapeutic use of G-CSF, revealed that SOCS3(Delta SB/Delta SB) mice were hyperresponsive to G-CSF. Compared with wild-type mice, SOCS3(Delta SB/Delta SB) mice developed a more florid arthritis when tested using an acute disease model. Overall, the results establish a role for the SOCS box of SOCS3 in the in vivo regulation of G-CSF signaling and the response to inflammatory stimuli.


Assuntos
Artrite/metabolismo , Fator Estimulador de Colônias de Granulócitos/metabolismo , Leucopoese , Transdução de Sinais , Proteínas Supressoras da Sinalização de Citocina/metabolismo , Doença Aguda , Animais , Artrite/genética , Artrite/patologia , Medula Óssea/metabolismo , Medula Óssea/patologia , Modelos Animais de Doenças , Fator Estimulador de Colônias de Granulócitos/genética , Interleucina-6/metabolismo , Leucopoese/genética , Camundongos , Camundongos Mutantes , Receptores de Citocinas/metabolismo , Transdução de Sinais/genética , Proteína 3 Supressora da Sinalização de Citocinas , Proteínas Supressoras da Sinalização de Citocina/genética , Domínios de Homologia de src/genética
5.
Stem Cells ; 24(3): 604-14, 2006 Mar.
Artigo em Inglês | MEDLINE | ID: mdl-16123385

RESUMO

Leukemia inhibitory factor (LIF) is required to maintain pluripotency and permit self-renewal of murine embryonic stem (ES) cells. LIF binds to a receptor complex of LIFR-beta and gp130 and signals via the Janus kinase-signal transducer and activator of transcription (JAK-STAT) pathway, with signalling attenuated by suppressor of cytokine signalling (SOCS) proteins. Recent in vivo studies have highlighted the role of SOCS-3 in the negative regulation of signalling via gp130. To determine the role of SOCS-3 in ES cell biology, SOCS-3-null ES cell lines were generated. When cultured in LIF levels that sustain self-renewal of wild-type cells, SOCS-3-null ES cell lines exhibited less self-renewal and greater differentiation into primitive endoderm. The absence of SOCS-3 enhanced JAK-STAT and extracellular signal-related kinase 1/2 (ERK-1/2)-mitogen-activated protein kinase (MAPK) signal transduction via gp130, with higher levels of phosphorylated STAT-1, STAT-3, SH-2 domain-containing cytoplasmic protein tyrosine phosphatase 2 (SHP-2), and ERK-1/2 in steady state and in response to LIF stimulation. Attenuation of ERK signalling by the addition of MAPK/ERK kinase (MEK) inhibitors to SOCS-3-null ES cell cultures rescued the differentiation phenotype, but did not restore proliferation to wild-type levels. In summary, SOCS-3 plays a crucial role in the regulation of the LIF signalling pathway in murine ES cells. Its absence perturbs the balance between activation of the JAK-STAT and SHP-2-ERK-1/2-MAPK pathways, resulting in less self-renewal and a greater potential for differentiation into the primitive endoderm lineage.


Assuntos
Diferenciação Celular/genética , Proliferação de Células , Embrião de Mamíferos/metabolismo , Sistema de Sinalização das MAP Quinases/genética , Células-Tronco/metabolismo , Proteínas Supressoras da Sinalização de Citocina/deficiência , Animais , Diferenciação Celular/efeitos dos fármacos , Linhagem da Célula/genética , Proliferação de Células/efeitos dos fármacos , Células Cultivadas , Embrião de Mamíferos/citologia , Endoderma/citologia , Endoderma/metabolismo , Interleucina-6/farmacologia , Fator Inibidor de Leucemia , Sistema de Sinalização das MAP Quinases/efeitos dos fármacos , Camundongos , Camundongos Mutantes , Proteínas Tirosina Quinases/metabolismo , Células-Tronco/citologia , Proteína 3 Supressora da Sinalização de Citocinas , Proteínas Supressoras da Sinalização de Citocina/genética , Proteínas Supressoras da Sinalização de Citocina/metabolismo
6.
Neurobiol Dis ; 20(2): 412-27, 2005 Nov.
Artigo em Inglês | MEDLINE | ID: mdl-15905096

RESUMO

Administration of tumour necrosis factor alpha (TNFalpha) to axotomised mouse neonatal sciatic nerves increased Schwann cell apoptosis in the distal nerve segments, 5-fold greater than axotomy alone. TNFalpha upregulated the low affinity neurotrophin receptor, p75NTR, indicative of phenotype reversion in Schwann cells. Furthermore, re-expression of p75NTR and downregulation of the pro-myelinating transcription factor, Oct 6, in Schwann cells occurred by treatment with TNFalpha, even after the maturation of these cells with brain derived neurotrophic factor (BDNF). TNFalpha treatment of Schwann cells produced only a transient activation of NFkappaB. More importantly, in NFkappaB (p65) mutant mice, axotomy increased Schwann cell apoptosis further than that seen in mice expressing NFkappaB (p65), implicating a survival role for NFkappaB. Collectively, these data suggest that TNFalpha can potentiate Schwann cell death through the modulation of their phenotype. Immature Schwann cells express a high level of p75NTR and as a consequence are susceptible to extracellular death stimuli because of the lack of sustained NFkappaB translocation.


Assuntos
NF-kappa B/metabolismo , Nervos Periféricos/metabolismo , Receptor de Fator de Crescimento Neural/metabolismo , Células de Schwann/metabolismo , Fator de Necrose Tumoral alfa/metabolismo , Animais , Animais Recém-Nascidos , Axotomia , Morte Celular/efeitos dos fármacos , Morte Celular/fisiologia , Diferenciação Celular/efeitos dos fármacos , Diferenciação Celular/fisiologia , Células Cultivadas , Camundongos , Camundongos Endogâmicos C57BL , Camundongos Knockout , NF-kappa B/efeitos dos fármacos , Fator 6 de Transcrição de Octâmero/efeitos dos fármacos , Fator 6 de Transcrição de Octâmero/metabolismo , Nervos Periféricos/efeitos dos fármacos , Nervos Periféricos/fisiopatologia , Doenças do Sistema Nervoso Periférico/metabolismo , Doenças do Sistema Nervoso Periférico/fisiopatologia , Fenótipo , Polirradiculoneuropatia/metabolismo , Polirradiculoneuropatia/fisiopatologia , Ratos , Ratos Wistar , Células de Schwann/efeitos dos fármacos , Células de Schwann/patologia , Nervo Isquiático/efeitos dos fármacos , Nervo Isquiático/metabolismo , Nervo Isquiático/fisiopatologia , Fator de Transcrição RelA/efeitos dos fármacos , Fator de Transcrição RelA/metabolismo , Fator de Necrose Tumoral alfa/farmacologia , Regulação para Cima/efeitos dos fármacos , Regulação para Cima/fisiologia
7.
Proc Natl Acad Sci U S A ; 102(45): 16333-8, 2005 Nov 08.
Artigo em Inglês | MEDLINE | ID: mdl-16258063

RESUMO

The suppressor of cytokine-signaling (SOCS) proteins act as negative-feedback inhibitors of cytokine and growth-factor-induced signal transduction. In vivo studies have implicated SOCS3 as a negative regulator of signaling downstream of gp130, the receptor subunit shared by IL-6-like cytokines. Mice lacking SOCS3 die at midgestation because of placental failure, and SOCS3 ablation in a cell-type-specific manner results in changes in the functional outcome of gp130 signaling in response to IL-6. In this study, we show that genetic reduction of leukemia-inhibitory factor (LIF) production by embryo-derived tissues is sufficient to prevent the placental defect. This establishes LIF signaling as a major physiological regulator of trophoblast differentiation in vivo. Mice deficient in both SOCS3 and LIF are born in predicted numbers and appear normal at birth but exhibit failure to thrive and high neonatal mortality. Adult SOCS3-null mice on a LIF-null background succumb to a spontaneous fatal inflammatory disease characterized by neutrophilia and inflammatory-cell tissue infiltrates. The disease spectrum mimics that seen in mice with a conditional deletion of SOCS3 in hematopoietic and endothelial cells, extending the evidence for a major role for SOCS3 in the homeostatic regulation of the inflammatory response and indicates that LIF is not required for this process.


Assuntos
Inflamação/etiologia , Interleucina-6/fisiologia , Placentação/fisiologia , Proteínas Supressoras da Sinalização de Citocina/fisiologia , Animais , Células da Medula Óssea/fisiologia , Feminino , Fator Estimulador de Colônias de Granulócitos/farmacologia , Inflamação/prevenção & controle , Interleucina-6/genética , Fator Inibidor de Leucemia , Masculino , Camundongos , Camundongos Endogâmicos C57BL , Gravidez , Proteína 3 Supressora da Sinalização de Citocinas , Proteínas Supressoras da Sinalização de Citocina/genética
8.
Neurobiol Dis ; 15(3): 415-36, 2004 Apr.
Artigo em Inglês | MEDLINE | ID: mdl-15056450

RESUMO

Spinal cord injury (SCI) is a major cause of disability, and at present, there is no universally accepted treatment. The functional decline following SCI is contributed to both direct mechanical injury and secondary pathophysiological mechanisms that are induced by the initial trauma. These mechanisms initially involve widespread haemorrhage at the site of injury and necrosis of central nervous system (CNS) cellular components. At later stages of injury, the cord is observed to display reactive gliosis. The actions of astrocytes as well as numerous other cells in this response create an environment that is highly nonpermissive to axonal regrowth. Also manifesting important effects is the immune system. The early recruitment of neutrophils and at later stages, macrophages to the site of insult cause exacerbation of injury. However, at more chronic stages, macrophages and recruited T helper cells may potentially be helpful by providing trophic support for neuronal and non-neuronal components of the injured CNS. Within this sea of injurious mechanisms, the oligodendrocytes appear to be highly vulnerable. At chronic stages of SCI, a large number of oligodendrocytes undergo apoptosis at sites that are distant to the vicinity of primary injury. This leads to denudement of axons and deterioration of their conductive abilities, which adds significantly to functional decline. By indulging into the molecular mechanisms that cause oligodendrocyte apoptosis and identifying potential targets for therapeutic intervention, the prevention of this apoptotic wave will be of tremendous value to individuals living with SCI.


Assuntos
Apoptose/fisiologia , Regeneração Nervosa/fisiologia , Oligodendroglia/patologia , Traumatismos da Medula Espinal/patologia , Traumatismos da Medula Espinal/fisiopatologia , Animais , Humanos , Degeneração Neural/patologia , Transdução de Sinais/fisiologia
9.
Glia ; 48(1): 64-75, 2004 Oct.
Artigo em Inglês | MEDLINE | ID: mdl-15326616

RESUMO

Precursor cells have the capacity to repopulate the demyelinated brain, but the molecular mechanisms that facilitate their recruitment are largely unknown. The low-affinity neurotrophin receptor, p75(NTR), may be one of these regulators; however, its expression profile by oligodendroglia within the multiple sclerosis (MS) brain remains uncertain. We therefore assessed the expression profile of this receptor within 8 MS and 4 control brains. We found no evidence of expression of p75(NTR) by mature oligodendrocytes. Instead, we demonstrated the presence of p75(NTR) on a subgroup of NG2-positive oligodendroglial progenitors in a periventricular plaque in one MS sample. Notably, p75(NTR)-expressing cells were also detected within the subventricular zone (SVZ) of this brain, adjacent to the periventricular plaque. In animals with experimental demyelination we observed similar patterns of p75(NTR) expression, initially confined to precursor cells within the SVZ, followed at later stages in the disease course by its expression amongst a subset of oligodendroglial progenitors within the corpus callosum. These data suggest that a population of precursor cells within the SVZ can be induced to express p75(NTR) and to subsequently assume an oligodendroglial progenitor phenotype in response to demyelination in the adjacent white matter.


Assuntos
Encéfalo/citologia , Proteínas de Transporte/biossíntese , Doenças Desmielinizantes/metabolismo , Proteínas do Tecido Nervoso/biossíntese , Oligodendroglia/metabolismo , Receptores de Fatores de Crescimento , Células-Tronco/metabolismo , Adulto , Idoso , Idoso de 80 Anos ou mais , Animais , Química Encefálica/fisiologia , Morte Celular/fisiologia , Quelantes/farmacologia , Cuprizona/farmacologia , Feminino , Humanos , Processamento de Imagem Assistida por Computador , Imuno-Histoquímica , Marcação In Situ das Extremidades Cortadas , Masculino , Camundongos , Camundongos Endogâmicos C57BL , Pessoa de Meia-Idade , Esclerose Múltipla/metabolismo , Fenótipo , Receptores de Fator de Crescimento Neural , Fixação de Tecidos , Regulação para Cima
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