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1.
J Immunol ; 195(5): 2343-52, 2015 Sep 01.
Artículo en Inglés | MEDLINE | ID: mdl-26209628

RESUMEN

Macrophage migration inhibitory factor (MIF), a proinflammatory cytokine and counterregulator of glucocorticoids, is a potential therapeutic target. MIF is markedly different from other cytokines because it is constitutively expressed, stored in the cytoplasm, and present in the circulation of healthy subjects. Thus, the concept of targeting MIF for therapeutic intervention is challenging because of the need to neutralize a ubiquitous protein. In this article, we report that MIF occurs in two redox-dependent conformational isoforms. We show that one of the two isoforms of MIF, that is, oxidized MIF (oxMIF), is specifically recognized by three mAbs directed against MIF. Surprisingly, oxMIF is selectively expressed in the plasma and on the cell surface of immune cells of patients with different inflammatory diseases. In patients with acute infections or chronic inflammation, oxMIF expression correlated with inflammatory flare-ups. In addition, anti-oxMIF mAbs alleviated disease severity in mouse models of acute and chronic enterocolitis and improved, in synergy with glucocorticoids, renal function in a rat model of crescentic glomerulonephritis. We conclude that oxMIF represents the disease-related isoform of MIF; oxMIF is therefore a new diagnostic marker for inflammation and a relevant target for anti-inflammatory therapy.


Asunto(s)
Inflamación/inmunología , Inflamación/prevención & control , Factores Inhibidores de la Migración de Macrófagos/inmunología , Terapia Molecular Dirigida/métodos , Animales , Anticuerpos Monoclonales/inmunología , Anticuerpos Monoclonales/uso terapéutico , Western Blotting , Dexametasona/inmunología , Dexametasona/uso terapéutico , Modelos Animales de Enfermedad , Enterocolitis/inmunología , Enterocolitis/metabolismo , Enterocolitis/prevención & control , Citometría de Flujo , Glomerulonefritis/inmunología , Glomerulonefritis/metabolismo , Glomerulonefritis/prevención & control , Glucocorticoides/inmunología , Glucocorticoides/uso terapéutico , Humanos , Inflamación/metabolismo , Factores Inhibidores de la Migración de Macrófagos/química , Factores Inhibidores de la Migración de Macrófagos/metabolismo , Masculino , Ratones Endogámicos C57BL , Ratones Noqueados , Oxidación-Reducción , Conformación Proteica , Isoformas de Proteínas/química , Isoformas de Proteínas/inmunología , Isoformas de Proteínas/metabolismo , Conejos , Ratas Endogámicas WKY
2.
FASEB J ; 28(1): 474-84, 2014 Jan.
Artículo en Inglés | MEDLINE | ID: mdl-24107315

RESUMEN

Glucocorticoid-induced TNF receptor family-related protein (GITR) regulates the function of both T cells and antigen-presenting cells (APCs), while the function of GITR ligand (GITR-L) is largely unknown. Here we evaluate the role of GITR-L, whose expression is restricted to APCs, in the development of enterocolitis. On injecting naive CD4(+) T cells, GITR-L(-/-)Rag(-/-) mice develop a markedly milder colitis than Rag(-/-) mice, which correlates with a 50% reduction of Ly6C(+)CD11b(+)MHCII(+) macrophages in the lamina propria and mesenteric lymph nodes. The same result was observed in αCD40-induced acute colitis and during peritonitis, suggesting an altered monocyte migration. In line with these observations, the number of nondifferentiated monocytes was approximately 3-fold higher in the spleen of GITR-L(-/-)Rag(-/-) mice than in Rag(-/-) mice after αCD40 induction. Consistent with the dynamic change in the formation of an active angiotensin II type 1 receptor (AT1) dimer in GITR-L(-/-) splenic monocytes during intestinal inflammation, the migratory capability of splenic monocytes from GITR-L-deficient mice was impaired in an in vitro transwell migration assay. Conversely, αGITR-L reduces the number of splenic Ly6C(hi) monocytes, concomitantly with an increase in AT1 dimers. We conclude that GITR-L regulates the number of proinflammatory macrophages in sites of inflammation by controlling the egress of monocytes from the splenic reservoir.


Asunto(s)
Glucocorticoides/farmacología , Mucosa Intestinal/metabolismo , Intestinos/inmunología , Monocitos/citología , Receptores del Factor de Necrosis Tumoral/metabolismo , Animales , Antígenos CD40 , Ratones , Ratones Noqueados , Ratones Mutantes , Monocitos/efectos de los fármacos
3.
FASEB J ; 27(8): 3123-31, 2013 Aug.
Artículo en Inglés | MEDLINE | ID: mdl-23629864

RESUMEN

The costimulatory receptor Slamf6 partially controls lupus-related autoimmunity in congenic Sle1b mice; for instance, the presence of the protein isoform Slamf6-H1 in Sle1b.Slamf6-H1 mice mitigates disease. Here, we report that young Sle1b mice, but not Sle1b.Slamf6-H1 or B6 mice, contain a memory T-helper cell subset identified by ]mt]2-fold increase in expression of 17 genes, chief among which is Spp1, encoding the cytokine osteopontin (OPN). These T follicular helper (TFH) cells, including OPN(+) TFH cells, expand concomitantly with severity of the disease. By contrast, Sle1b.Slamf6-H1 or Sle1b.SAP(-)/(-) mice do not develop autoantibodies and the number of T(FH) cells is 5 times lower than in age-matched Sle1b mice. By comparing Sle1b and Sle1b.OPN(-)/(-) mice, we find that the lack of OPN expression impedes early autoantibody production. Furthermore, on the adoptive transfer of Sle1b.OPN(-)/(-) CD4(+) T cells into bm12 recipients autoantibody production and germinal center formation is reduced compared to recipients of Sle1b.OPN(+/+) CD4(+) T cells. We propose a model in which OPN provides a survival signal for a precursor T(FH) cell subset, which is a key factor in autoimmunity.


Asunto(s)
Antígenos CD/inmunología , Autoinmunidad/inmunología , Osteopontina/inmunología , Receptores de Superficie Celular/inmunología , Linfocitos T Colaboradores-Inductores/inmunología , Animales , Antígenos CD/genética , Antígenos CD/metabolismo , Antígenos de Diferenciación/genética , Antígenos de Diferenciación/inmunología , Antígenos de Diferenciación/metabolismo , Autoinmunidad/genética , Western Blotting , Linfocitos T CD4-Positivos/inmunología , Linfocitos T CD4-Positivos/metabolismo , Proliferación Celular , Femenino , Citometría de Flujo , Lupus Eritematoso Sistémico/genética , Lupus Eritematoso Sistémico/inmunología , Lupus Eritematoso Sistémico/metabolismo , Masculino , Ratones , Ratones Noqueados , Osteopontina/genética , Osteopontina/metabolismo , Receptor de Muerte Celular Programada 1 , Isoformas de Proteínas/genética , Isoformas de Proteínas/inmunología , Isoformas de Proteínas/metabolismo , Receptores CXCR5/genética , Receptores CXCR5/inmunología , Receptores CXCR5/metabolismo , Receptores de Superficie Celular/genética , Receptores de Superficie Celular/metabolismo , Reacción en Cadena de la Polimerasa de Transcriptasa Inversa , Familia de Moléculas Señalizadoras de la Activación Linfocitaria , Miembro 1 de la Familia de Moléculas Señalizadoras de la Activación Linfocitaria , Linfocitos T Colaboradores-Inductores/citología , Linfocitos T Colaboradores-Inductores/metabolismo , Transcriptoma/inmunología
4.
Gastroenterology ; 143(6): 1544-1554.e7, 2012 Dec.
Artículo en Inglés | MEDLINE | ID: mdl-22960654

RESUMEN

BACKGROUND & AIMS: Signaling lymphocyte activation molecule (Slamf)1 is a co-stimulatory receptor on T cells and regulates cytokine production by macrophages and dendritic cells. Slamf1 regulates microbicidal mechanisms in macrophages, therefore we investigated whether the receptor affects development of colitis in mice. METHODS: We transferred CD45RB(hi) CD4(+) T cells into Rag(-/-) or Slamf1(-/-)Rag(-/-) mice to induce colitis. We also induced colitis by injecting mice with an antibody that activates CD40. We determined the severity of enterocolitis based on disease activity index, histology scores, and levels of cytokine production, and assessed the effects of antibodies against Slamf1 on colitis induction. We quantified migration of monocytes and macrophage to inflamed tissues upon induction of colitis or thioglycollate-induced peritonitis and in response to tumor necrosis factor-α in an air-pouch model of leukocyte migration. RESULTS: Colitis was reduced in Slamf1(-/-)Rag(-/-) mice, compared with Rag(-/-) mice, after transfer of CD45RB(hi) CD4(+) T cells or administration of the CD40 agonist. The numbers of monocytes and macrophages were reduced in inflamed tissues of Slamf1(-/-)Rag(-/-) mice, compared with Rag(-/-) mice, after induction of colitis and other inflammatory disorders. An antibody that inhibited Slamf1 reduced the level of enterocolitis in Rag(-/-) mice. CONCLUSIONS: Slamf1 contributes to the development of colitis in mice. It appears to indirectly regulate the appearance of monocytes and macrophages in inflamed intestinal tissues. Antibodies that inhibit Slamf1 reduce colitis in mice, so human SLAMF1 might be a therapeutic target for inflammatory bowel disease.


Asunto(s)
Antígenos CD/fisiología , Colitis/fisiopatología , Receptores de Superficie Celular/fisiología , Animales , Antígenos CD/genética , Antígenos CD40/efectos adversos , Movimiento Celular , Quimiocina CCL2/sangre , Quimiocina CCL7/sangre , Colitis/sangre , Colitis/inducido químicamente , Modelos Animales de Enfermedad , Intestinos/patología , Macrófagos/patología , Ratones , Ratones Endogámicos BALB C , Ratones Endogámicos C57BL , Ratones Noqueados , Receptores de Superficie Celular/deficiencia , Receptores de Superficie Celular/genética , Miembro 1 de la Familia de Moléculas Señalizadoras de la Activación Linfocitaria
5.
J Bacteriol ; 194(13): 3327-35, 2012 Jul.
Artículo en Inglés | MEDLINE | ID: mdl-22522892

RESUMEN

The capacity of pathogens to respond to environmental signals, such as iron concentration, is key to bacterial survival and establishment of a successful infection. Bacillus cereus is a widely distributed bacterium with distinct pathogenic properties. Hemolysin II (HlyII) is one of its pore-forming cytotoxins and has been shown to be involved in bacterial pathogenicity in a number of cell and animal models. Unlike many other B. cereus pathogenicity factors, HlyII is not regulated by pleiotropic transcriptional regulator PlcR but is controlled by its own regulator, HlyIIR. Using a combination of in vivo and in vitro techniques, we show that hlyII expression is also negatively regulated by iron by the global regulator Fur via direct interaction with the hlyII promoter. DNase I footprinting and in vitro transcription experiments indicate that Fur prevents RNA polymerase binding to the hlyII promoter. HlyII expression profiles demonstrate that both HlyIIR and Fur regulate HlyII expression in a concerted fashion, with the effect of Fur being maximal in the early stages of bacterial growth. In sum, these results show that Fur serves as a transcriptional repressor for hlyII expression.


Asunto(s)
Bacillus cereus/metabolismo , Proteínas Bacterianas/metabolismo , Regulación Bacteriana de la Expresión Génica , Proteínas Hemolisinas/metabolismo , Hierro/metabolismo , Proteínas Represoras/metabolismo , Bacillus cereus/genética , Bacillus cereus/crecimiento & desarrollo , Proteínas Bacterianas/genética , ARN Polimerasas Dirigidas por ADN/metabolismo , Proteínas Hemolisinas/genética , Regiones Promotoras Genéticas/fisiología , Unión Proteica , Proteínas Represoras/genética
6.
Immunol Lett ; 153(1-2): 15-21, 2013 Jun.
Artículo en Inglés | MEDLINE | ID: mdl-23806511

RESUMEN

Mutations affecting the SLAM-associated protein (SAP) are responsible for the X-linked lympho-proliferative syndrome (XLP), a severe primary immunodeficiency syndrome with disease manifestations that include fatal mononucleosis, B cell lymphoma and dysgammaglobulinemia. It is well accepted that insufficient help by SAP-/- CD4+ T cells, in particular during the germinal center reaction, is a component of dysgammaglobulinemia in XLP patients and SAP-/- animals. It is however not well understood whether in XLP patients and SAP-/- mice B cell functions are affected, even though B cells themselves do not express SAP. Here we report that B cell intrinsic responses to haptenated protein antigens are impaired in SAP-/- mice and in Rag-/- mice into which B cells derived from SAP-/- mice together with wt CD4+ T cells had been transferred. This impaired B cells functions are in part depending on the genetic background of the SAP-/- mouse, which affects B cell homeostasis. Surprisingly, stimulation with an agonistic anti-CD40 causes strong in vivo and in vitro B cell responses in SAP-/- mice. Taken together, the data demonstrate that genetic factors play an important role in the SAP-related B cell functions. The finding that anti-CD40 can in part restore impaired B cell responses in SAP-/- mice, suggests potentially novel therapeutic interventions in subsets of XLP patients.


Asunto(s)
Linfocitos B/inmunología , Linfocitos T CD4-Positivos/inmunología , Péptidos y Proteínas de Señalización Intracelular/genética , Trastornos Linfoproliferativos/genética , Trastornos Linfoproliferativos/inmunología , Animales , Linfocitos B/citología , Linfocitos T CD4-Positivos/trasplante , Antígenos CD40/inmunología , Antígenos CD40/metabolismo , Proteínas de Homeodominio/genética , Leucosialina/metabolismo , Activación de Linfocitos/inmunología , Masculino , Ratones , Ratones Endogámicos BALB C , Ratones Endogámicos C57BL , Ratones Noqueados , Proteína Asociada a la Molécula de Señalización de la Activación Linfocitaria
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