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1.
Eur J Immunol ; 51(2): 445-458, 2021 02.
Artículo en Inglés | MEDLINE | ID: mdl-32920851

RESUMEN

B lymphocytes are among the cell types whose effector functions are modulated by mast cells (MCs). The B/MC crosstalk emerged in several pathological settings, notably the colon of inflammatory bowel disease (IBD) patients is a privileged site in which MCs and IgA+ cells physically interact. Herein, by inducing conditional depletion of MCs in red MC and basophil (RMB) mice, we show that MCs control B cell distribution in the gut and IgA serum levels. Moreover, in dextran sulfate sodium (DSS)-treated RMB mice, the presence of MCs is fundamental for the enlargement of the IgA+ population in the bowel and the increase of systemic IgA production. Since both conventional B-2 and peritoneal-derived B cells populate the intestine and communicate with MCs in physiological conditions and during inflammation, we further explored this interplay through the use of co-cultures. We show that MCs finely regulate different aspects of splenic B cell biology while peritoneal B cells are unresponsive to the supporting effects provided by MCs. Interestingly, peritoneal B cells induce a pro-inflammatory skewing in MCs, characterized by increased ST2 and TNF-α expression. Altogether, this study uncovers the versatility of the B/MC liaison and highlights key aspects for the resolution of intestinal inflammation.


Asunto(s)
Linfocitos B/metabolismo , Colon/inmunología , Inmunoglobulina A/inmunología , Mucosa Intestinal/inmunología , Mastocitos/inmunología , Animales , Colitis/inmunología , Colon/microbiología , Sulfato de Dextran/inmunología , Microbioma Gastrointestinal/inmunología , Inflamación/inmunología , Inflamación/microbiología , Enfermedades Inflamatorias del Intestino/inmunología , Enfermedades Inflamatorias del Intestino/microbiología , Mucosa Intestinal/microbiología , Ratones , Ratones Endogámicos C57BL , Factor de Necrosis Tumoral alfa/inmunología
2.
Front Immunol ; 10: 2127, 2019.
Artículo en Inglés | MEDLINE | ID: mdl-31555304

RESUMEN

Neutrophils are known to adopt dynamic and distinct functional phenotypes involved in the modulation of inflammation and immune homeostasis. However, inter-cellular signaling mechanisms that govern neutrophil polarization dynamics are not well understood. Employing a novel model of PHLPP deficient mice, we examined how neutrophils deficient in PHLPP may uniquely modulate immune defense and the host response during acute colitis. We found that PHLPP-/- mice were protected from dextran sodium sulfate (DSS)-induced septic colitis characterized by minimal body weight-loss, alleviated colon tissue destruction and reduced clinical symptoms. PHLPP-/- neutrophils have enhanced immune homeostasis as compared to WT neutrophils, reflected in enhanced migratory capacity toward chemoattractants, and reduced expression of inflammatory mediators due to elevated phosphorylation of AKT, STAT1, and ERK. Further, adoptive transfer of PHLPP deficient neutrophils to WT mice is sufficient to potently alleviate the severity of DSS-induced colitis. Our data reveal that PHLPP deficient neutrophils can be uniquely reprogrammed to a state conducive to host inflammation resolution. As a consequence, PHLPP-/- neutrophils can effectively transfer immune homeostasis in mice subjected to acute colitis. Our findings hold significant and novel insights into the mechanisms by which neutrophils can be effectively reprogrammed into a homeostatic state conducive for treating acute injuries such as septic colitis.


Asunto(s)
Colitis/inmunología , Homeostasis/inmunología , Neutrófilos/inmunología , Fosfoproteínas Fosfatasas/inmunología , Animales , Colitis/inducido químicamente , Sulfato de Dextran/inmunología , Sulfato de Dextran/toxicidad , Ratones , Ratones Endogámicos C57BL , Ratones Noqueados , Infiltración Neutrófila/inmunología , Fosfoproteínas Fosfatasas/deficiencia
3.
Poult Sci ; 98(10): 4449-4456, 2019 Oct 01.
Artículo en Inglés | MEDLINE | ID: mdl-31162611

RESUMEN

Butyric acid is a beneficial feed additive used in animal production, including poultry production. However, there are few reports on butyric acid as a prophylactic treatment against intestinal inflammation in broilers. The current study explored the effect of sodium butyrate (SB) as a prophylactic treatment on the intestinal health and gut microbiota of broilers with intestinal inflammation induced by dextran sulfate sodium (DSS) by monitoring changes in intestinal histopathology, gut leakiness indicators, inflammatory cytokines, and gut microbiota composition. Sodium butyrate supplementation prior to DSS administration significantly reduced the lesion scores of intestinal bleeding (P < 0.05) and increased villus height and the total mucosa of the ileum (P < 0.05). Regardless of intestinal inflammation, supplementation with SB at 300 mg/kg significantly decreased the levels of D (-)-lactate (P < 0.05), interleukin-6, and interleukin-1ß (P < 0.05) but increased the level of interleukin-10 (P < 0.05). The SB treatment did not affect the alpha diversity of intestinal microbiota during intestinal inflammation progression but altered their composition, and the microbial community structure of treated broilers was similar to that of control broilers. Taken together, our results reveal the importance of SB in improving intestinal development, inducing an anti-inflammatory effect during intestinal inflammation progression, and modulating the microbial community in broilers. Sodium butyrate seems to be optimized for anti-inflammatory effects at higher doses (300 mg/kg SB).


Asunto(s)
Antiinflamatorios/farmacología , Ácido Butírico/farmacología , Pollos , Microbioma Gastrointestinal/efectos de los fármacos , Inflamación/tratamiento farmacológico , Intestinos/fisiología , Enfermedades de las Aves de Corral/tratamiento farmacológico , Alimentación Animal/análisis , Animales , Antiinflamatorios/administración & dosificación , Ácido Butírico/administración & dosificación , Sulfato de Dextran/administración & dosificación , Sulfato de Dextran/inmunología , Sulfato de Dextran/toxicidad , Dieta/veterinaria , Suplementos Dietéticos/análisis , Relación Dosis-Respuesta a Droga , Femenino , Inflamación/inducido químicamente , Inflamación/inmunología , Inflamación/veterinaria , Enfermedades de las Aves de Corral/inducido químicamente , Enfermedades de las Aves de Corral/inmunología
4.
Front Immunol ; 9: 2764, 2018.
Artículo en Inglés | MEDLINE | ID: mdl-30542349

RESUMEN

Background: Macrophages are pivotal in coordinating a range of important processes in the intestines, including controlling intracellular infections and limiting damaging inflammation against the microbiota. However, it is not clear how gut macrophages, relative to recruited blood monocytes and other myeloid cells, contribute to the intestinal inflammatory milieu, nor how macrophages and their monocyte precursors mediate recruitment of other immune cells to the inflamed intestine. Methods: Myeloid cell populations isolated from colonic inflammatory bowel disease (IBD) or murine dextran sulphate sodium (DSS) induced colitis were assessed using flow cytometry and compared to healthy controls. In addition, mRNA expression profiles in human and murine colon samples, and in macrophages and monocytes from healthy and inflamed murine colons, were analysed by quantitative PCR (qPCR) and mRNA microarray. Results: We show that the monocyte:macrophage balance is disrupted in colon inflammation to favour recruitment of CD14+HLA-DRInt cells in humans, and Ly6CHi monocytes in mice. In addition, we identify that murine blood monocytes receive systemic signals enabling increased release of IL-1ß prior to egress from the blood into the colon. Further, once within the colon and relative to other myeloid cells, monocytes represent the dominant local source of both IL-1ß and TNF. Finally, our data reveal that, independent of inflammation, murine colon macrophages act as a major source of Ccl7 and Ccl8 chemokines that trigger further recruitment of their pro-inflammatory monocyte precursors. Conclusions: Our work suggests that strategies targeting macrophage-mediated monocyte recruitment may represent a promising approach for limiting the chronic inflammation that characterises IBD.


Asunto(s)
Colitis/inmunología , Colon/inmunología , Activación de Macrófagos/inmunología , Macrófagos/inmunología , Monocitos/inmunología , Animales , Quimiocina CCL7/inmunología , Quimiocina CCL8/inmunología , Sulfato de Dextran/inmunología , Femenino , Humanos , Inflamación/inmunología , Enfermedades Inflamatorias del Intestino/inmunología , Interleucina-1beta/inmunología , Ratones , Ratones Endogámicos C57BL , Factores de Necrosis Tumoral/inmunología
5.
Dev Comp Immunol ; 74: 200-208, 2017 09.
Artículo en Inglés | MEDLINE | ID: mdl-28487234

RESUMEN

We recently demonstrated Ang 1-7 reduced inflammation in the dextran sulfate sodium (DSS) colitis model. In this study we examined the effect of Ang 1-7 on modulation of plasma levels of selected cytokines and chemokines and immune cell effector functions (apoptosis, chemotaxis and superoxide release) in vitro. The degree of neutrophil recruitment to the colon was assessed by immunofluorescence and myeloperoxidase activity. Daily Ang 1-7 treatment at 0.01 mg/kg dose which previously ameliorated colitis severity, showed a significant reduction in circulating levels of several cytokines and chemokines, and neutrophil recruitment to the colonic tissue. It also significantly enhanced immune cell apoptosis, and reduced neutrophil chemotaxis and superoxide release in vitro. In contrast, daily administration of the Ang 1-7R antagonist A779 which previously worsened colitis severity showed significant up-regulation of specific mediators. Our results demonstrate a novel anti-inflammatory action of Ang 1-7 through modulation of plasma levels of cytokines/chemokines and immune cell activity.


Asunto(s)
Angiotensina I/uso terapéutico , Antiinflamatorios/uso terapéutico , Colitis/terapia , Colon/inmunología , Neutrófilos/inmunología , Fragmentos de Péptidos/uso terapéutico , Angiotensina I/antagonistas & inhibidores , Angiotensina II/administración & dosificación , Angiotensina II/análogos & derivados , Animales , Apoptosis , Movimiento Celular , Quimiocinas/sangre , Quimiotaxis , Colitis/inmunología , Citocinas/sangre , Sulfato de Dextran/inmunología , Inmunidad Celular , Inmunomodulación , Ratones , Ratones Endogámicos BALB C , Modelos Animales , Fragmentos de Péptidos/administración & dosificación , Fragmentos de Péptidos/antagonistas & inhibidores , Sistema Renina-Angiotensina , Superóxidos/metabolismo
6.
Sci Rep ; 6: 39399, 2016 12 16.
Artículo en Inglés | MEDLINE | ID: mdl-27982124

RESUMEN

The intestinal microbiota of patients with constipated-predominant irritable bowel syndrome (C-IBS) displays chronic dysbiosis. Our aim was to determine whether this microbial imbalance instigates perturbation of the host intestinal mucosal immune response, using a model of human microbiota-associated rats (HMAR) and dextran sulfate sodium (DSS)-induced experimental colitis. The analysis of the microbiota composition revealed a decrease of the relative abundance of Bacteroides, Roseburia-Eubacterium rectale and Bifidobacterium and an increase of Enterobacteriaceae, Desulfovibrio sp., and mainly Akkermansia muciniphila in C-IBS patients compared to healthy individuals. The bacterial diversity of the gut microbiota of healthy individuals or C-IBS patients was maintained in corresponding HMAR. Animals harboring a C-IBS microbiota had reduced DSS colitis with a decreased expression of pro-inflammatory cytokines from innate, Th1, and Th17 responses. The pre-treatment of conventional C57BL/6 mice or HMAR with A. muciniphila, but not with Escherichia coli, prior exposure to DSS also resulted in a reduction of colitis severity, highlighting that the anti-inflammatory effect of the gut microbiota of C-IBS patients is mediated, in part, by A. muciniphila. This work highlights a novel aspect of the crosstalk between the gut microbiota of C-IBS patients and host intestinal homeostasis.


Asunto(s)
Antiinflamatorios/inmunología , Microbioma Gastrointestinal/inmunología , Intestinos/microbiología , Síndrome del Colon Irritable/microbiología , Animales , Colitis/inmunología , Colitis/microbiología , Citocinas/inmunología , Sulfato de Dextran/inmunología , Disbiosis/inmunología , Humanos , Inflamación/inmunología , Ratones , Ratones Endogámicos C57BL , Microbiota/inmunología , Ratas
7.
PLoS One ; 9(11): e112472, 2014.
Artículo en Inglés | MEDLINE | ID: mdl-25379804

RESUMEN

The commensal yeast Candida albicans is part of the human intestinal microflora and is considered a "pathobiont", a resident microbe with pathogenic potential yet harmless under normal conditions. The aim of this study was to investigate the effect of C. albicans on inflammation of the intestinal tract and the role of Bruton's tyrosine kinase (Btk). Btk is an enzyme that modulates downstream signaling of multiple receptors involved in innate and adaptive immunity, including the major anti-fungal receptor Dectin-1. Colitis was induced in wild type and Btk-/- mice by treatment with dextran sodium sulfate (DSS) and the gastrointestinal tract of selected treatment groups were then colonized with C. albicans. Colonization by C. albicans neither dampened nor exacerbated inflammation in wild type mice, but colon length and spleen weight were improved in Btk-deficient mice colonized with C. albicans. Neutrophil infiltration was comparable between wild type and Btk-/- mice, but the knockout mice displayed severely reduced numbers of macrophages in the colon during both DSS and DSS/Candida treatment. Smaller numbers and reduced responsiveness of Btk-/- macrophages might partially explain the improved colon length of Btk-/- mice as a result of Candida colonization. Surprisingly, DSS/Candida-treated Btk-/- animals had higher levels of certain pro-inflammatory cytokines and levels of the anti-inflammatory cytokine TGF-ß were reduced compared to wild type. A clustering and correlation analysis showed that for wild type animals, spleen TGF-ß and colon IL-10 and for Btk-/- spleen and colon levels of IL-17A best correlated with the inflammatory parameters. We conclude that in Btk-/- immunocompromised animals, colonization of the gastrointestinal tract by the commensal yeast C. albicans alters inflammatory symptoms associated with colitis.


Asunto(s)
Candida albicans/inmunología , Candidiasis/inmunología , Citocinas/inmunología , Mediadores de Inflamación/inmunología , Intestinos/inmunología , Proteínas Tirosina Quinasas/inmunología , Agammaglobulinemia Tirosina Quinasa , Animales , Candida albicans/fisiología , Candidiasis/metabolismo , Candidiasis/microbiología , Colitis/genética , Colitis/inmunología , Colitis/microbiología , Colon/inmunología , Colon/metabolismo , Colon/patología , Citocinas/metabolismo , Sulfato de Dextran/inmunología , Interacciones Huésped-Patógeno/inmunología , Humanos , Inmunohistoquímica , Mediadores de Inflamación/metabolismo , Interleucina-10/inmunología , Interleucina-10/metabolismo , Interleucina-17/inmunología , Interleucina-17/metabolismo , Mucosa Intestinal/metabolismo , Intestinos/microbiología , Macrófagos/inmunología , Macrófagos/metabolismo , Macrófagos/microbiología , Ratones Noqueados , Tamaño de los Órganos/inmunología , Proteínas Tirosina Quinasas/genética , Proteínas Tirosina Quinasas/metabolismo , Bazo/inmunología , Bazo/metabolismo , Bazo/patología , Factor de Crecimiento Transformador beta/inmunología , Factor de Crecimiento Transformador beta/metabolismo
8.
Cell Mol Immunol ; 11(4): 355-66, 2014 Jul.
Artículo en Inglés | MEDLINE | ID: mdl-24727542

RESUMEN

Chemerin is present in various inflammatory sites and is closely involved in tissue inflammation. Recent studies have demonstrated that chemerin treatment can cause either anti-inflammatory or pro-inflammatory effects according to the disease model being investigated. Elevated circulating chemerin was recently found in patients with inflammatory bowel disease (IBD); however, the role of chemerin in intestinal inflammation remains unknown. In this study, we demonstrated that the administration of exogenous chemerin (aa17-156) aggravated the severity of dextran sulfate sodium (DSS)-induced colitis, which was characterized by higher clinical scores, extensive mucosal damage and significantly increased local and systemic production of pro-inflammatory cytokines, including IL-6, TNF-α and interferon (IFN-γ). Interestingly, chemerin did not appear to influence the magnitudes of inflammatory infiltrates in the colons, but did result in significantly decreased colonic expression of M2 macrophage-associated genes, including Arginase 1 (Arg-1), Ym1, FIZZ1 and IL-10, following DSS exposure, suggesting an impaired M2 macrophage skewing in vivo. Furthermore, an in vitro experiment showed that the addition of chemerin directly suppressed M2 macrophage-associated gene expression and STAT6 phosphorylation in IL-4-stimulated macrophages. Significantly elevated chemerin levels were found in colons from DSS-exposed mice and from ulcerative colitis (UC) patients and appeared to positively correlate with disease severity. Moreover, the in vivo administration of neutralizing anti-chemerin antibody significantly improved intestinal inflammation following DSS exposure. Taken together, our findings reveal a pro-inflammatory role for chemerin in DSS-induced colitis and the ability of chemerin to suppress the anti-inflammatory M2 macrophage response. Our study also suggests that upregulated chemerin in inflamed colons may contribute to the pathogenesis of IBD.


Asunto(s)
Quimerina 1/administración & dosificación , Colitis Ulcerosa/inmunología , Colitis/inmunología , Colon/inmunología , Macrófagos/inmunología , Fragmentos de Péptidos/administración & dosificación , Animales , Arginasa/genética , Arginasa/metabolismo , Diferenciación Celular/genética , Células Cultivadas , Colitis/inducido químicamente , Citocinas/metabolismo , Sulfato de Dextran/inmunología , Modelos Animales de Enfermedad , Progresión de la Enfermedad , Regulación hacia Abajo , Femenino , Humanos , Mediadores de Inflamación/metabolismo , Péptidos y Proteínas de Señalización Intercelular/genética , Péptidos y Proteínas de Señalización Intercelular/metabolismo , Lectinas/genética , Lectinas/metabolismo , Ratones , Ratones Endogámicos C57BL , Factor de Transcripción STAT6/metabolismo , beta-N-Acetilhexosaminidasas/genética , beta-N-Acetilhexosaminidasas/metabolismo
9.
Int Immunopharmacol ; 17(2): 314-20, 2013 Oct.
Artículo en Inglés | MEDLINE | ID: mdl-23856612

RESUMEN

BACKGROUND AND AIMS: Although a series of studies have shown that curcumin can exert anti-inflammatory effects in colitis by inhibiting NF-κB activation, whether these anti-inflammatory effects of curcumin are also attributed to its ability to inhibiting STAT3 pathway has never been tested in experimental colitis to date. The purpose of the study was to investigate whether curcumin could exert its therapeutic effects in experimental colitis by inhibiting STAT3 pathway. MATERIALS AND METHODS: Curcumin was administered in experimental colitis induced by dextran sulfate sodium (DSS). The disease activity index (DAI) and histological score were observed. The phospho-STAT3 was assessed by western blot analysis. The DNA-binding activity of STAT3 dimers was evaluated by electrophoretic mobility shift assay (EMSA). The expression of tumor necrosis factor (TNF)-α and interleukin (IL)-1ß was measured by enzyme-linked immunosorbent assay. Myeloperoxidase (MPO) activity was determined by using MPO assay kit. RESULTS: A significant improvement was observed in DAI and histological score in mice with curcumin, and the increases in phospho-STAT3 activity, DNA-binding activity of STAT3 dimers, MPO activity, IL-1ß, and TNF-α expression in mice with DSS-induced colitis were significantly reduced following treatment with curcumin. CONCLUSION: Curcumin exerts beneficial effects in experimental colitis by the suppression of STAT3 pathway, which may therefore provide a better understanding of the mechanism of action for curcumin in treating colitis.


Asunto(s)
Colitis/tratamiento farmacológico , Colon/efectos de los fármacos , Curcumina/administración & dosificación , Factor de Transcripción STAT3/metabolismo , Animales , Colitis/inmunología , Colon/inmunología , Sulfato de Dextran/inmunología , Regulación hacia Abajo , Interleucina-1beta/metabolismo , Masculino , Ratones , Ratones Endogámicos BALB C , Peroxidasa/metabolismo , Fosforilación/efectos de los fármacos , Transducción de Señal/efectos de los fármacos , Transducción de Señal/inmunología , Factor de Necrosis Tumoral alfa/metabolismo
10.
Immunity ; 39(1): 111-22, 2013 Jul 25.
Artículo en Inglés | MEDLINE | ID: mdl-23871208

RESUMEN

Immune cells sense microbial products through Toll-like receptors (TLR), which trigger host defense responses including type 1 interferons (IFNs) secretion. A coding polymorphism in the protein tyrosine phosphatase nonreceptor type 22 (PTPN22) gene is a susceptibility allele for human autoimmune and infectious disease. We report that Ptpn22 selectively regulated type 1 IFN production after TLR engagement in myeloid cells. Ptpn22 promoted host antiviral responses and was critical for TLR agonist-induced, type 1 IFN-dependent suppression of inflammation in colitis and arthritis. PTPN22 directly associated with TNF receptor-associated factor 3 (TRAF3) and promotes TRAF3 lysine 63-linked ubiquitination. The disease-associated PTPN22W variant failed to promote TRAF3 ubiquitination, type 1 IFN upregulation, and type 1 IFN-dependent suppression of arthritis. The findings establish a candidate innate immune mechanism of action for a human autoimmunity "risk" gene in the regulation of host defense and inflammation.


Asunto(s)
Autoinmunidad/inmunología , Inmunidad/inmunología , Interferón Tipo I/inmunología , Proteína Tirosina Fosfatasa no Receptora Tipo 22/inmunología , Receptores Toll-Like/inmunología , Animales , Artritis/genética , Artritis/inmunología , Autoinmunidad/genética , Línea Celular , Células Cultivadas , Colitis/inducido químicamente , Colitis/genética , Colitis/inmunología , Sulfato de Dextran/inmunología , Células HEK293 , Interacciones Huésped-Patógeno/inmunología , Humanos , Inmunidad/genética , Immunoblotting , Interferón Tipo I/genética , Interferón Tipo I/metabolismo , Coriomeningitis Linfocítica/genética , Coriomeningitis Linfocítica/inmunología , Coriomeningitis Linfocítica/virología , Virus de la Coriomeningitis Linfocítica/inmunología , Virus de la Coriomeningitis Linfocítica/fisiología , Ratones , Ratones Endogámicos C57BL , Ratones Noqueados , Ratones Transgénicos , Células Mieloides/inmunología , Células Mieloides/metabolismo , Proteína Tirosina Fosfatasa no Receptora Tipo 22/genética , Proteína Tirosina Fosfatasa no Receptora Tipo 22/metabolismo , Reacción en Cadena de la Polimerasa de Transcriptasa Inversa , Factor 3 Asociado a Receptor de TNF/genética , Factor 3 Asociado a Receptor de TNF/inmunología , Factor 3 Asociado a Receptor de TNF/metabolismo , Receptores Toll-Like/genética , Receptores Toll-Like/metabolismo , Ubiquitinación/inmunología
11.
J Pharm Sci ; 101(1): 233-44, 2012 Jan.
Artículo en Inglés | MEDLINE | ID: mdl-21953499

RESUMEN

The objective of the present study was to evaluate immunological activities of chitosan-dextran sulfate (CS-DS) nanoparticle formulation of pertussis toxoid (PTXd) and its combination with a potential immunological adjuvant, immunoglobulin A (IgA). CS-DS nanoparticles were prepared using a complex coacervation (polyelectrolyte complexation) technique. CS-DS nanoparticle formulations with size and zeta potential in a range of 300-350 nm and +40-+55 mV, respectively, were obtained. An entrapment efficiency of more than 90% was obtained for pertussis toxin and IgA in CS-DS nanoparticles. All loaded nanoparticle formulations showed less than 20% of release within 24 h in in vitro release studies. The immunological evaluation of developed formulations in female Balb/c mice groups showed that the CS-DS nanoparticles formulations induced significantly higher serum IgG and IgG1 titers (p < 0.05) as compared with conventional alum-adjuvanted PTXd formulation administered by subcutaneous route. This study indicated the potential of CS-DS nanoparticles to be a simple and effective particulate delivery system with in-built immunological adjuvant property for acellular protein antigens. The study also revealed the potential important role of IgA-loaded CS-DS nanoparticles as a novel immunological adjuvant for vaccine delivery.


Asunto(s)
Quitosano/administración & dosificación , Sulfato de Dextran/administración & dosificación , Inmunoglobulina A/administración & dosificación , Inmunoglobulina A/inmunología , Nanopartículas/administración & dosificación , Toxoides/inmunología , Adyuvantes Inmunológicos/administración & dosificación , Adyuvantes Inmunológicos/química , Compuestos de Alumbre/administración & dosificación , Compuestos de Alumbre/química , Animales , Química Farmacéutica/métodos , Quitosano/química , Quitosano/inmunología , Sulfato de Dextran/química , Sulfato de Dextran/inmunología , Portadores de Fármacos/administración & dosificación , Portadores de Fármacos/química , Sistemas de Liberación de Medicamentos/métodos , Femenino , Inmunoglobulina A/química , Inmunoglobulina G/sangre , Ratones , Ratones Endogámicos BALB C , Nanopartículas/química , Toxoides/antagonistas & inhibidores
12.
Cancer Res ; 71(24): 7423-32, 2011 Dec 15.
Artículo en Inglés | MEDLINE | ID: mdl-22028324

RESUMEN

Patients with inflammatory bowel disease (IBD) have an increased risk of developing colorectal cancer due to chronic inflammation. In IBD, chronic inflammation relies upon a TGFß signaling blockade, but its precise mechanistic relationship to colitis-associated colorectal cancer (CAC) remains unclear. In this study, we investigated the role of the TGFß signaling inhibitor Smad7 in CAC pathogenesis. In human colonic specimens, Smad7 was downregulated in CD4(+) T cells located in the lamina propria of patients with complicated IBD compared with uncomplicated IBD. Therefore, we assessed CAC susceptibility in a transgenic mouse model where Smad7 was overexpressed specifically in T cells. In this model, Smad7 overexpression increased colitis severity, but the mice nevertheless developed fewer tumors than nontransgenic mice. Protection was associated with increased expression of IFNγ and increased accumulation of cytotoxic CD8(+) and natural killer T cells in the tumors and peritumoral areas. Moreover, genetic deficiency in IFNγ abolished the Smad7-dependent protection against CAC. Taken together, our findings defined a novel and unexpected role for Smad7 in promoting a heightened inflammatory response that protects against CAC.


Asunto(s)
Colitis/metabolismo , Neoplasias Colorrectales/metabolismo , Proteína smad7/metabolismo , Linfocitos T/metabolismo , Adulto , Anciano , Animales , Linfocitos T CD8-positivos/inmunología , Linfocitos T CD8-positivos/metabolismo , Línea Celular Tumoral , Colitis/genética , Colitis/inmunología , Neoplasias Colorrectales/genética , Neoplasias Colorrectales/inmunología , Citotoxicidad Inmunológica/inmunología , Sulfato de Dextran/inmunología , Femenino , Citometría de Flujo , Expresión Génica , Humanos , Interferón gamma/genética , Interferón gamma/inmunología , Interferón gamma/metabolismo , Masculino , Ratones , Ratones Endogámicos C57BL , Ratones Noqueados , Ratones Transgénicos , Persona de Mediana Edad , Células T Asesinas Naturales/inmunología , Células T Asesinas Naturales/metabolismo , Proteína smad7/genética , Linfocitos T/inmunología , Linfocitos T/patología , Células TH1/inmunología , Células TH1/metabolismo , Adulto Joven
13.
Lab Invest ; 90(9): 1295-305, 2010 Sep.
Artículo en Inglés | MEDLINE | ID: mdl-20498653

RESUMEN

Epiregulin (EPI) and amphiregulin (AR) are epidermal growth factor receptor (EGFR) ligands implicated in mucosal repair and tumorigenesis. We have shown that Toll-like receptor 4 (TLR4) induces intestinal epithelial cell (IEC) proliferation by activating EGFR through AR expression. We examined whether TLR4 differentially regulates expression of EGFR ligands in response to mucosal injury. The human IEC line SW480 was examined expression of EGFR ligands, EGFR phosphorylation, and proliferation in response to lipopolysaccharide (LPS). Small-interfering RNA (siRNA) was used to block TLR4. Neutralizing antibodies to EGFR ligands were used to examine inhibition of LPS-dependent EGFR activation. Acute colitis and recovery were examined in the mice given 2.5% dextran sodium sulfate (DSS). Colonic secretion of EPI and AR was analyzed by enzyme-linked immunosorbent assay. LPS selectively induces EPI and AR but not other EGFR ligands. LPS induced early EPI mRNA expression between 30 min and 24 h. The neutralizing antibodies to EPI and AR prevented activation of EGFR by LPS. LPS induces IEC proliferation (200%, P=0.01) in 24 h but blocking EPI and AR significantly decreased proliferation. In vivo, mucosal EPI and AR expression are significantly decreased in TLR4(-/-) mice (P=0.02) compared to wild-type mice during acute colitis. EPI and AR exhibit different kinetics in response to mucosal damage: EPI expression is upregulated acutely at day 7 of DSS, but falls during recovery at day 14. By contrast, a sustained upregulation of AR expression is seen during mucosal injury and repair. We show that TLR4 regulates EPI and AR expression and that both these EGFR ligands are necessary for optimal proliferation of IEC. The diverse kinetics of EPI and AR expression suggest that they function in distinct roles with respect to acute injury vs repair. Our results highlight the role of bacterial sensing for IEC homeostasis and may lead to targeted therapy for mucosal healing and prevention of tumorigenesis.


Asunto(s)
Factor de Crecimiento Epidérmico/genética , Factor de Crecimiento Epidérmico/metabolismo , Receptor Toll-Like 4/inmunología , Receptor Toll-Like 4/metabolismo , Anfirregulina , Animales , Anticuerpos Neutralizantes , Línea Celular , Proliferación Celular/efectos de los fármacos , Colitis/genética , Colitis/inmunología , Colitis/metabolismo , Sulfato de Dextran/inmunología , Sulfato de Dextran/metabolismo , Sulfato de Dextran/farmacología , Familia de Proteínas EGF , Ensayo de Inmunoadsorción Enzimática , Factor de Crecimiento Epidérmico/inmunología , Epirregulina , Células Epiteliales/inmunología , Células Epiteliales/metabolismo , Receptores ErbB/genética , Receptores ErbB/inmunología , Receptores ErbB/metabolismo , Glicoproteínas , Humanos , Péptidos y Proteínas de Señalización Intercelular , Lipopolisacáridos/inmunología , Lipopolisacáridos/metabolismo , Ratones , Ratones Noqueados , Membrana Mucosa/metabolismo , Receptor Toll-Like 4/genética , Regulación hacia Arriba/efectos de los fármacos
14.
J Immunol ; 184(1): 203-11, 2010 Jan 01.
Artículo en Inglés | MEDLINE | ID: mdl-19949090

RESUMEN

Because of their large surface area, the lungs appear an attractive route for noninvasive vaccine delivery, harboring the potential to induce local mucosal immune responses in addition to systemic immunity. To evoke adaptive immunity, Ags require the addition of adjuvants that not only enhance the strength of the immune response but also determine the type of response elicited. In this study, we evaluate the adjuvant characteristics of polyelectrolyte microcapsules (PEMs) consisting of the biopolymers dextran-sulfate and poly-L-arginine. PEMs form an entirely new class of microcapsules that are generated by the sequential adsorption of oppositely charged polymers (polyelectrolytes) onto a sacrificial colloidal template, which is subsequently dissolved leaving a hollow microcapsule surrounded by a thin shell. Following intratracheal instillation, PEMs were not only efficiently taken up by APCs but also enhanced their activation status. Pulmonary adaptive immune responses were characterized by the induction of a strongly Th17-polarized response. When compared with a mixture of soluble Ag with empty microcapsules, Ag encapsulation significantly enhanced the strength of this local mucosal response. Given their unique property to selectively generate Th17-polarized immune responses, PEMs may become of significant interest in the development of effective vaccines against fungal and bacterial species.


Asunto(s)
Implantes Absorbibles , Adyuvantes Inmunológicos/administración & dosificación , Cápsulas/administración & dosificación , Interleucina-17/inmunología , Pulmón/inmunología , Vacunación/métodos , Adyuvantes Inmunológicos/síntesis química , Animales , Células Presentadoras de Antígenos/inmunología , Antígenos/administración & dosificación , Antígenos/inmunología , Lavado Broncoalveolar , Cápsulas/síntesis química , Sulfato de Dextran/inmunología , Electrólitos/inmunología , Femenino , Citometría de Flujo , Inmunidad Mucosa/inmunología , Activación de Linfocitos/inmunología , Ratones , Ratones Endogámicos C57BL , Péptidos/inmunología , Reacción en Cadena de la Polimerasa de Transcriptasa Inversa
15.
Inflamm Bowel Dis ; 16(6): 1017-28, 2010 Jun.
Artículo en Inglés | MEDLINE | ID: mdl-19834971

RESUMEN

BACKGROUND: Inflammatory bowel disease (IBD) results from the chronic dysregulation of the mucosal immune system and the aberrant activation of both the innate and the adaptive immune responses. We used two complementary models of colonic inflammation to examine the roles of interleukin (IL)-19 in colonic inflammation and thus its possible role in IBD. METHODS: Using gene-targeting, we generated IL-19-deficient mice. To study the activation of the innate immune response during colonic inflammation we characterized an innate immune-mediated model of colitis induced by dextran sulfate sodium (DSS). DSS can induce not only acute colitis but also chronic colitis. In addition to the acute DSS-induced colitis model, we used a chronic DSS-induced colitis model that is associated with the activation of both Th1 and Th2 cytokines as well as innate immune response in the colon. RESULTS: We show that IL-19-deficient mice are more susceptible to experimental acute colitis induced by DSS, and this increased susceptibility is correlated with the accumulation of macrophages and the increased production of IFN-gamma, IL-1beta, IL-6, IL-12, TNF-alpha, and KC. Additionally, cytokine production in IL-19-deficient macrophages was enhanced on stimulation of lipopolysaccharide (LPS) through reduced phosphorylation of STAT1 and STAT3. Moreover, our results clearly demonstrate that IL-19 is required for B-cell infiltration during chronic DSS-induced colitis, which may be mediated by IL-13 and IL-6. CONCLUSIONS: The finding that IL-19 drives pathogenic innate immune responses in the colon suggests that the selective targeting of IL-19 may be an effective therapeutic approach in the treatment of human IBD.


Asunto(s)
Colitis/inmunología , Inmunidad Innata , Interleucina-10/fisiología , Inmunidad Adaptativa , Animales , Colitis/genética , Citocinas/análisis , Sulfato de Dextran/inmunología , Modelos Animales de Enfermedad , Predisposición Genética a la Enfermedad , Interleucina-10/genética , Interleucina-10/farmacología , Interleucinas , Macrófagos/efectos de los fármacos , Ratones , Ratones Endogámicos C57BL , Ratones Noqueados , Células TH1/inmunología , Células Th2/inmunología
16.
Inflamm Bowel Dis ; 15(12): 1812-23, 2009 Dec.
Artículo en Inglés | MEDLINE | ID: mdl-19714742

RESUMEN

BACKGROUND: Inflammatory bowel disease (IBD) is a critical public health issue; more and more people are affected, but treatment options remain limited. Complement activation and the anaphylatoxin C5a have been shown to play a role in IBD. In this study, mouse models of acute and chronic dextran sulfate-induced colitis were used to further elucidate the impact of C5a and its receptor (C5aR) on disease development. METHODS: In C57BL/6J wildtype and C5aR(-/-) mice the extent of complement activation, changes in weight, and water/food consumption were determined. Disease severity was evaluated via a clinical score, histology, cytokine- and myeloperoxidase-determination as well as real-time reverse-transcriptase polymerase chain reaction (RT-PCR) for expression of anaphylatoxin receptors and inflammatory mediators. RESULTS: C5aR(-/-) mice showed milder disease symptoms, less histological damage, and a lower expression of inflammatory mediators in acute colitis, a setting where complement was activated. In chronic colitis the knockout mice exhibited aggravated weight loss, a higher degree of histological damage and granulocyte infiltration. Intriguingly, increases in C3a-receptor and C5L2 mRNA were dependent on C5aR. Compared to wildtype mice, C5aR(-/-) animals displayed smaller lymph nodes in acute colitis, but extensive swelling and diminished IL-4 and IFN-γ responses in the chronic disease, demonstrating that C5aR modifies T-helper cell polarization. CONCLUSIONS: C5aR exerts detrimental functions in acute colitis, strongly supporting the idea that a C5aR-antagonist might be useful for IBD treatment. However, since the absence of C5aR was no longer protective and in some regards disadvantageous in chronic IBD, future studies should address the efficacy and the possible side effects of a sustained antagonist treatment.


Asunto(s)
Enfermedades Inflamatorias del Intestino/inmunología , Receptor de Anafilatoxina C5a/inmunología , Enfermedad Aguda , Animales , Polaridad Celular/inmunología , Activación de Complemento/inmunología , Sulfato de Dextran/inmunología , Sulfato de Dextran/toxicidad , Enfermedades Inflamatorias del Intestino/inducido químicamente , Enfermedades Inflamatorias del Intestino/patología , Interferón gamma/inmunología , Interleucina-4/inmunología , Masculino , Ratones , Ratones Endogámicos C57BL , Ratones Noqueados , Receptor de Anafilatoxina C5a/genética , Índice de Severidad de la Enfermedad , Linfocitos T Colaboradores-Inductores/inmunología
17.
Eur J Immunol ; 39(3): 833-42, 2009 Mar.
Artículo en Inglés | MEDLINE | ID: mdl-19189310

RESUMEN

Deleted in malignant brain tumors 1 (DMBT1) is a secreted glycoprotein displaying a broad bacterial-binding spectrum. Recent functional and genetic studies linked DMBT1 to the suppression of LPS-induced TLR4-mediated NF-kappaB activation and to the pathogenesis of Crohn's disease. Here, we aimed at unraveling the molecular basis of its function in mucosal protection and of its broad pathogen-binding specificity. We report that DMBT1 directly interacts with dextran sulfate sodium (DSS) and carrageenan, a structurally similar sulfated polysaccharide, which is used as a texturizer and thickener in human dietary products. However, binding of DMBT1 does not reduce the cytotoxic effects of these agents to intestinal epithelial cells in vitro. DSS and carrageenan compete for DMBT1-mediated bacterial aggregation via interaction with its bacterial-recognition motif. Competition and ELISA studies identify poly-sulfated and poly-phosphorylated structures as ligands for this recognition motif, such as heparansulfate, LPS, and lipoteichoic acid. Dose-response studies in Dmbt1(-/-) and Dmbt1(+/+) mice utilizing the DSS-induced colitis model demonstrate a differential response only to low but not to high DSS doses. We propose that DMBT1 functions as pattern-recognition molecule for poly-sulfated and poly-phosphorylated ligands providing a molecular basis for its broad bacterial-binding specificity and its inhibitory effects on LPS-induced TLR4-mediated NF-kappaB activation.


Asunto(s)
Carragenina/inmunología , Sulfato de Dextran/inmunología , Receptores de Superficie Celular/inmunología , Bacterias/inmunología , Bacterias/metabolismo , Proteínas de Unión al Calcio , Carragenina/farmacología , Carragenina/toxicidad , Línea Celular , Proteínas de Unión al ADN , Sulfato de Dextran/farmacología , Sulfato de Dextran/toxicidad , Células Epiteliales/inmunología , Células Epiteliales/metabolismo , Células Epiteliales/microbiología , Humanos , Mucosa Intestinal/metabolismo , Intestinos/inmunología , Intestinos/microbiología , Ligandos , Fosfatos/inmunología , Fosfatos/metabolismo , Receptores de Superficie Celular/antagonistas & inhibidores , Receptores de Superficie Celular/genética , Receptores de Superficie Celular/metabolismo , Proteínas Supresoras de Tumor
18.
Mol Immunol ; 45(16): 4084-94, 2008 Oct.
Artículo en Inglés | MEDLINE | ID: mdl-18722664

RESUMEN

Complement is an essential part of the innate immune system and plays a crucial role in organ and islet transplantation. Its activation, triggered for example by ischemia/reperfusion (I/R), significantly influences graft survival, and blocking of complement by inhibitors has been shown to attenuate I/R injury. Another player of innate immunity are the dendritic cells (DC), which form an important link between innate and adaptive immunity. DC are relevant in the induction of an immune response as well as in the maintenance of tolerance. Modulation or inhibition of both components, complement and DC, may be crucial to improve the clinical outcome of solid organ as well as islet transplantation. Low molecular weight dextran sulfate (DXS), a well-known complement inhibitor, has been shown to prevent complement-mediated damage of the donor graft endothelium and is thus acting as an endothelial protectant. In this review we will discuss the evidence for this cytoprotective effect of DXS and also highlight recent data which show that DXS inhibits the maturation of human DC. Taken together the available data suggest that DXS may be a useful reagent to prevent the activation of innate immunity, both in solid organ and islet transplantation.


Asunto(s)
Proteínas del Sistema Complemento/metabolismo , Sulfato de Dextran/farmacología , Trasplante de Islotes Pancreáticos/inmunología , Trasplante de Órganos , Sustancias Protectoras/farmacología , Sulfato de Dextran/química , Sulfato de Dextran/inmunología , Humanos , Modelos Inmunológicos , Peso Molecular
19.
Int J Mol Med ; 22(2): 181-5, 2008 Aug.
Artículo en Inglés | MEDLINE | ID: mdl-18636171

RESUMEN

Interleukin (IL)-17 acts as a potent inflammatory cytokine, and IL-17-producing cells (Th17 cells) have received much attention. However, the involvement of commensal and/or probiotic bacteria in IL-17 production has not been evaluated. In this study, we examined the suppressive effects of five bacteria species on IL-17 production in vitro and ex vivo. Among the five species studied, Bifidobacterium infantis inhibited IL-17 production but enhanced IL-27 production most potently in TGF-beta plus IL-6-stimulated murine splenocytes. B. infantis also inhibited IL-17 and eotaxin production from a dextran sodium sulfate-treated colon organ culture. The induction of IL-10 by B. infantis was observed both in the splenocytes and in the colon culture and was assumed, to a certain extent, to be important for suppressing IL-17 production. These findings suggest a novel immunomodulatory function of commensal bifidobacteria and further imply that these bacteria may be useful in the treatment of Th17-mediated diseases.


Asunto(s)
Bifidobacterium/inmunología , Sulfato de Dextran/inmunología , Inflamación/inmunología , Interleucina-17/inmunología , Intestinos/inmunología , Intestinos/patología , Bazo/citología , Animales , Células Cultivadas , Quimiocina CCL11/metabolismo , Quimiocinas/metabolismo , Femenino , Humanos , Interleucina-10/inmunología , Interleucinas/inmunología , Intestinos/anatomía & histología , Ratones , Ratones Endogámicos BALB C , Probióticos , Bazo/inmunología , Técnicas de Cultivo de Tejidos
20.
J Biomater Sci Polym Ed ; 14(9): 875-85, 2003.
Artículo en Inglés | MEDLINE | ID: mdl-14661867

RESUMEN

Bioartificial pancreas, in which the islets of Langerhans (islets) are enclosed in an artificial membrane to be protected from the host immune system, is expected to be a promising medical device to treat patients who suffer from insulin-dependent diabetes. Our strategy for preparation of a bioartificial pancreas involves utilizing a membrane including polymeric materials that can inhibit the complement. In our series of studies, we have examined interactions of various polyanions with the complement system to search for potential complement inhibitors. In this study, we concentrated our efforts to clarify the effects of dextran sulfate on the complement system. All of the dextran sulfates examined inhibited the complement activation through both classical and alternative pathways as previously reported. In addition to their inhibitory effects, a certain species of dextran sulfate (molecular mass 10 kDa, degree of sulfonation in a pyranose ring 1.99) specifically degraded C3 without complement activation and, thus, anaphylatoxins that trigger inflammatory reactions were not generated. These facts suggest that a membrane including dextran sulfate effectively protects the islet cells from humoral immunity in addition to not triggering inflammatory reactions. These properties of the membrane make it suitable for a bioratificial pancreas.


Asunto(s)
Complemento C3/inmunología , Complemento C4b , Sulfato de Dextran/química , Sulfato de Dextran/inmunología , Membranas Artificiales , Órganos Bioartificiales , Complemento C4/inmunología , Complemento C4/metabolismo , Complemento C5/inmunología , Humanos , Páncreas/inmunología , Fragmentos de Péptidos/inmunología , Fragmentos de Péptidos/metabolismo , Suero/química , Suero/inmunología
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