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1.
Mol Cell Biol ; 26(17): 6623-32, 2006 Sep.
Artículo en Inglés | MEDLINE | ID: mdl-16914744

RESUMEN

Cybr (also known as Cytip, CASP, and PSCDBP) is an interleukin-12-induced gene expressed exclusively in hematopoietic cells and tissues that associates with Arf guanine nucleotide exchange factors known as cytohesins. Cybr levels are dynamically regulated during T-cell development in the thymus and upon activation of peripheral T cells. In addition, Cybr is induced in activated dendritic cells and has been reported to regulate dendritic cell (DC)-T-cell adhesion. Here we report the generation and characterization of Cybr-deficient mice. Despite the selective expression in hematopoietic cells, there was no intrinsic defect in T- or B-cell development or function in Cybr-deficient mice. The adoptive transfer of Cybr-deficient DCs showed that they migrated efficiently and stimulated proliferation and cytokine production by T cells in vivo. However, competitive stem cell repopulation experiments showed a defect in the abilities of Cybr-deficient T cells to develop in the presence of wild-type precursors. These data suggest that Cybr is not absolutely required for hematopoietic cell development or function, but stem cells lacking Cybr are at a developmental disadvantage compared to wild-type cells. Collectively, these data demonstrate that despite its selective expression in hematopoietic cells, the role of Cybr is limited or largely redundant. Previous in vitro studies using overexpression or short interfering RNA inhibition of the levels of Cybr protein appear to have overestimated its immunological role.


Asunto(s)
Proteínas Portadoras/metabolismo , Diferenciación Celular , Reactividad Cruzada/inmunología , Células Dendríticas/citología , Células Dendríticas/inmunología , Proteínas de la Membrana/metabolismo , Linfocitos T/citología , Linfocitos T/inmunología , Animales , Proteínas Portadoras/genética , Diferenciación Celular/efectos de los fármacos , Citocinas/farmacología , Células Dendríticas/efectos de los fármacos , Exones/genética , Regulación de la Expresión Génica/efectos de los fármacos , Marcación de Gen , Humanos , Inmunidad Innata/inmunología , Lipopolisacáridos/inmunología , Subgrupos Linfocitarios/inmunología , Proteínas de la Membrana/deficiencia , Proteínas de la Membrana/genética , Ratones , Ratones Noqueados , Células Mieloides/inmunología , ARN Mensajero/genética , ARN Mensajero/metabolismo , Linfocitos T/efectos de los fármacos
2.
J Exp Med ; 205(12): 2803-12, 2008 Nov 24.
Artículo en Inglés | MEDLINE | ID: mdl-19001140

RESUMEN

Tpl2 (Tumor progression locus 2), also known as Cot/MAP3K8, is a hematopoietically expressed serine-threonine kinase. Tpl2 is known to have critical functions in innate immunity in regulating tumor necrosis factor-alpha, Toll-like receptor, and G protein-coupled receptor signaling; however, our understanding of its physiological role in T cells is limited. We investigated the potential roles of Tpl2 in T cells and found that it was induced by interleukin-12 in human and mouse T cells in a Stat4-dependent manner. Deficiency of Tpl2 was associated with impaired interferon (IFN)-gamma production. Accordingly, Tpl2(-/-) mice had impaired host defense against Toxoplasma gondii with reduced parasite clearance and decreased IFN-gamma production. Furthermore, reconstitution of Rag2(-/-) mice with Tpl2-deficient T cells followed by T. gondii infection recapitulated the IFN-gamma defect seen in the Tpl2-deficient mice, confirming a T cell-intrinsic defect. CD4(+) T cells isolated from Tpl2(-/-) mice showed poor induction of T-bet and failure to up-regulate Stat4 protein, which is associated with impaired TCR-dependent extracellular signal-regulated kinase activation. These data underscore the role of Tpl2 as a regulator of T helper cell lineage decisions and demonstrate that Tpl2 has an important functional role in the regulation of Th1 responses.


Asunto(s)
Interferón gamma/inmunología , Quinasas Quinasa Quinasa PAM/inmunología , Proteínas Proto-Oncogénicas/inmunología , Linfocitos T/inmunología , Toxoplasma/inmunología , Animales , Linaje de la Célula , Proteínas de Unión al ADN/genética , Proteínas de Unión al ADN/inmunología , Perfilación de la Expresión Génica , Humanos , Interleucina-12/inmunología , Quinasas Quinasa Quinasa PAM/genética , Ratones , Ratones Noqueados , Análisis por Micromatrices , Proteínas Proto-Oncogénicas/genética , Factor de Transcripción STAT4/inmunología , Proteínas de Dominio T Box/inmunología , Células TH1/citología , Células TH1/inmunología , Toxoplasmosis Animal/inmunología
3.
Proc Natl Acad Sci U S A ; 103(4): 1000-5, 2006 Jan 24.
Artículo en Inglés | MEDLINE | ID: mdl-16418296

RESUMEN

Cytokines that use the common gamma chain gammac are critical for lymphoid development and function. Mutations of the IL-7 receptor, gammac, or its associated kinase, Jak3, are the major cause of human severe combined immunodeficiency. Although activated by IL-7, Stat5a/b (Stat, signal transducer and activator of transcription) have been thought to play limited roles in lymphoid development. However, we now show that mice completely deficient in Stat5a/b have severely impaired lymphoid development and differentiation. Absence of Stat5 also abrogates T cell receptor gamma rearrangement and survival of peripheral CD8(+) T cells. Thus, deficiency of Stat5 results in severe combined immunodeficiency, similar in many respects to deficiency of IL-7R, gammac, and Jak3.


Asunto(s)
Linfocitos/citología , Factor de Transcripción STAT5/fisiología , Animales , Linfocitos B/inmunología , Linfocitos T CD8-positivos/virología , Diferenciación Celular , Proliferación Celular , Trasplante de Células , Citocinas/metabolismo , Citometría de Flujo , Receptores de Hialuranos/biosíntesis , Janus Quinasa 3 , Hígado/embriología , Ratones , Ratones SCID , Mutación , Proteínas Tirosina Quinasas/genética , Proteínas Tirosina Quinasas/metabolismo , ARN/metabolismo , Receptores de Antígenos de Linfocitos T/metabolismo , Receptores de Interleucina-7/genética , Reacción en Cadena de la Polimerasa de Transcriptasa Inversa , Factor de Transcripción STAT5/genética , Bazo/embriología , Linfocitos T/inmunología , Linfocitos T/metabolismo , Factores de Tiempo
4.
J Biol Chem ; 280(17): 17408-14, 2005 Apr 29.
Artículo en Inglés | MEDLINE | ID: mdl-15611059

RESUMEN

Janus kinases (Jaks) are a small family of cytoplasmic tyrosine kinases, critical for signaling by Type I and II cytokine receptors. The importance of Jaks in signaling by these receptors has been firmly established by analysis of mutant cell lines, the generation of Jak knock-out mice, and the identification of patients with Jak3 mutations. While a number of other ligands that do not bind Type I and II cytokine receptors have also been reported to activate Jaks, the requirement for Jaks in signaling by these receptors is less clear. Chemokines for example, which bind seven transmembrane receptors, have been reported to activate Jaks, and principally through the use of pharmacological inhibitors, it has been argued that Jaks are essential for chemokine signaling. In the present study, we focused on CXCR4, which binds the chemokine CXCL12 or stromal cell-derived factor-1, a chemokine that has been reported to activate Jak2 and Jak3. We found that the lack of Jak3 had no effect on CXCL12 signaling or chemotaxis nor did overexpression of wild-type versions of the kinase. Similarly, overexpression of wild-type or catalytically inactive Jak2 or "knocking-down" Jak2 expression using siRNA also had no effect. We also found that in primary lymphocytes, CXCL12 did not induce appreciable phosphorylation of any of the Jaks compared with cytokines for which these kinases are required. Additionally, little or no Stat (signal transducer and activator of transcription) phosphorylation was detected. Thus, we conclude that in contrast to previous reports, Jaks, especially Jak3, are unlikely to play an essential role in chemokine signaling.


Asunto(s)
Quimiocinas CXC/metabolismo , Proteínas Tirosina Quinasas/metabolismo , Proteínas Proto-Oncogénicas/metabolismo , Western Blotting , Calcio/metabolismo , Catálisis , Línea Celular , Línea Celular Transformada , Quimiocina CXCL12 , Quimiocinas/metabolismo , Citocinas/metabolismo , ADN Complementario/metabolismo , Relación Dosis-Respuesta a Droga , Electroforesis en Gel de Poliacrilamida , Humanos , Inmunoprecipitación , Interleucina-2/metabolismo , Janus Quinasa 2 , Janus Quinasa 3 , Células Jurkat , Leucocitos Mononucleares/citología , Leucocitos Mononucleares/metabolismo , Ligandos , Linfocitos/metabolismo , Mutación , Mutación Missense , Fosforilación , Plásmidos/metabolismo , ARN Interferente Pequeño/metabolismo , Transducción de Señal , Factores de Tiempo , Transfección
5.
Immunol Rev ; 202: 139-56, 2004 Dec.
Artículo en Inglés | MEDLINE | ID: mdl-15546391

RESUMEN

Produced in response to a variety of pathogenic organisms, interleukin (IL)-12 and IL-23 are key immunoregulatory cytokines that coordinate innate and adaptive immune responses. These dimeric cytokines share a subunit, designated p40, and bind to a common receptor chain, IL-12R beta 1. The receptor for IL-12 is composed of IL-12R beta 1 and IL-12R beta 2, whereas IL-23 binds to a receptor composed of IL-12R beta 1 and IL-23R. Both cytokines activate the Janus kinases Tyk2 and Jak2, the transcription factor signal transducer and activator of transcription 4 (STAT4), as well as other STATs. A major action of IL-12 is to promote the differentiation of naive CD4+ T cells into T-helper (Th) 1 cells, which produce interferon (IFN)-gamma, and deficiency of IL-12, IL-12R subunits or STAT4 is similar in many respects. In contrast, IL-23 promotes end-stage inflammation. Targeting IL-12, IL-23, and their downstream signaling elements would therefore be logical strategies for the treatment of immune-mediated diseases.


Asunto(s)
Proteínas de Unión al ADN/fisiología , Interleucina-12/fisiología , Interleucinas/fisiología , Transducción de Señal/fisiología , Transactivadores/fisiología , Animales , Proteínas de Unión al ADN/química , Proteínas de Unión al ADN/deficiencia , Proteínas de Unión al ADN/inmunología , Humanos , Interleucina-12/deficiencia , Interleucina-23 , Subunidad p19 de la Interleucina-23 , Interleucinas/deficiencia , Receptores de Interleucina/fisiología , Receptores de Interleucina-12 , Factor de Transcripción STAT4 , Transducción de Señal/inmunología , Transactivadores/química , Transactivadores/deficiencia , Transactivadores/inmunología
6.
Proc Natl Acad Sci U S A ; 99(5): 2625-9, 2002 Mar 05.
Artículo en Inglés | MEDLINE | ID: mdl-11867758

RESUMEN

Cytokines regulate lymphocyte development and differentiation, but precisely how they control these processes is still poorly understood. By using microarray technology to detect cytokine-induced genes, we identified a cDNA encoding Cybr, which was increased markedly in cells incubated with IL-2 and IL-12. The mRNA was most abundant in hematopoietic cells and tissues. The predicted amino acid sequence is similar to that of GRP-1-associated protein (GRASP), a recently identified retinoic acid-induced cytohesin-binding protein. Physical interaction, dependent on the coiled-coil domains of Cybr and cytohesin-1, was demonstrated by coimmunoprecipitation of the overexpressed proteins from 293T cells. Cytohesin-1, in addition to its role in cell adhesion, is a guanine nucleotide-exchange protein activator of ARF GTPases. Acceleration of guanosine 5prime prime or minute-O-(thiotriphosphate) binding to ARF by cytohesin-1 in vitro was enhanced by Cybr. Because the binding protein modified activation of ADP ribosylation factor by cytohesin-1, we designate this cytokine-inducible protein Cybr (cytohesin binder and regulator).


Asunto(s)
Proteínas Portadoras/metabolismo , Moléculas de Adhesión Celular/metabolismo , Interleucina-12/farmacología , Interleucina-2/farmacología , Proteínas de la Membrana/metabolismo , Proteínas/metabolismo , Secuencia de Aminoácidos , Animales , Línea Celular , Clonación Molecular , Expresión Génica , Factores de Intercambio de Guanina Nucleótido/metabolismo , Humanos , Ratones , Datos de Secuencia Molecular , Proteínas/genética , Homología de Secuencia de Aminoácido , Factores de Transcripción
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