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1.
Cell ; 178(5): 1072-1087.e14, 2019 08 22.
Artículo en Inglés | MEDLINE | ID: mdl-31442401

RESUMEN

Nutritional status potentially influences immune responses; however, how nutritional signals regulate cellular dynamics and functionality remains obscure. Herein, we report that temporary fasting drastically reduces the number of lymphocytes by ∼50% in Peyer's patches (PPs), the inductive site of the gut immune response. Subsequent refeeding seemingly restored the number of lymphocytes, but whose cellular composition was conspicuously altered. A large portion of germinal center and IgA+ B cells were lost via apoptosis during fasting. Meanwhile, naive B cells migrated from PPs to the bone marrow during fasting and then back to PPs during refeeding when stromal cells sensed nutritional signals and upregulated CXCL13 expression to recruit naive B cells. Furthermore, temporal fasting before oral immunization with ovalbumin abolished the induction of antigen-specific IgA, failed to induce oral tolerance, and eventually exacerbated food antigen-induced diarrhea. Thus, nutritional signals are critical in maintaining gut immune homeostasis.


Asunto(s)
Linfocitos B/fisiología , Inmunidad Mucosa , Animales , Antígenos/inmunología , Linfocitos B/inmunología , Linfocitos B/metabolismo , Médula Ósea/inmunología , Médula Ósea/metabolismo , Quimiocina CXCL13/genética , Quimiocina CXCL13/metabolismo , Ayuno , Regulación de la Expresión Génica , Glucólisis , Inmunoglobulina A/metabolismo , Masculino , Ratones , Ratones Endogámicos BALB C , Estado Nutricional , Ovalbúmina/inmunología , Ganglios Linfáticos Agregados/inmunología , Ganglios Linfáticos Agregados/metabolismo , Ganglios Linfáticos Agregados/patología , Receptores CXCR5/genética , Receptores CXCR5/metabolismo , Transducción de Señal , Células del Estroma/citología , Células del Estroma/metabolismo , Serina-Treonina Quinasas TOR/metabolismo
2.
Nat Immunol ; 15(6): 571-9, 2014 Jun.
Artículo en Inglés | MEDLINE | ID: mdl-24777532

RESUMEN

Intestinal regulatory T cells (Treg cells) are necessary for the suppression of excessive immune responses to commensal bacteria. However, the molecular machinery that controls the homeostasis of intestinal Treg cells has remained largely unknown. Here we report that colonization of germ-free mice with gut microbiota upregulated expression of the DNA-methylation adaptor Uhrf1 in Treg cells. Mice with T cell-specific deficiency in Uhrf1 (Uhrf1(fl/fl)Cd4-Cre mice) showed defective proliferation and functional maturation of colonic Treg cells. Uhrf1 deficiency resulted in derepression of the gene (Cdkn1a) that encodes the cyclin-dependent kinase inhibitor p21 due to hypomethylation of its promoter region, which resulted in cell-cycle arrest of Treg cells. As a consequence, Uhrf1(fl/fl)Cd4-Cre mice spontaneously developed severe colitis. Thus, Uhrf1-dependent epigenetic silencing of Cdkn1a was required for the maintenance of gut immunological homeostasis. This mechanism enforces symbiotic host-microbe interactions without an inflammatory response.


Asunto(s)
Colitis/inmunología , Colon/inmunología , Inhibidor p21 de las Quinasas Dependientes de la Ciclina/genética , Epigénesis Genética , Proteínas Nucleares/inmunología , Linfocitos T Reguladores/inmunología , Traslado Adoptivo , Animales , Proteínas Potenciadoras de Unión a CCAAT , Puntos de Control del Ciclo Celular , Proliferación Celular , Células Cultivadas , Clostridium/inmunología , Colitis/genética , Colon/microbiología , Metilación de ADN , Perfilación de la Expresión Génica , Interleucina-2 , Ratones , Ratones Endogámicos C57BL , Ratones Transgénicos , Microbiota/inmunología , Proteínas Nucleares/biosíntesis , Proteínas Nucleares/genética , Regiones Promotoras Genéticas , Interferencia de ARN , ARN Interferente Pequeño , Simbiosis/inmunología , Ubiquitina-Proteína Ligasas , Regulación hacia Arriba
3.
Eur J Immunol ; 54(4): e2350800, 2024 Apr.
Artículo en Inglés | MEDLINE | ID: mdl-38282083

RESUMEN

Obesity-induced adipose tissue inflammation plays a critical role in the development of metabolic diseases. For example, NK1.1+ group 1 innate lymphoid cells (G1-ILCs) in adipose tissues are activated in the early stages of inflammation in response to a high-fat diet (HFD). In this study, we examined whether the composition of fatty acids affected adipose inflammatory responses induced by an HFD. Mice were fed a stearic acid (C18:0)-rich HFD (HFD-S) or a linoleic acid (C18:2)-rich HFD (HFD-L). HFD-L-fed mice showed significant obesity compared with HFD-S-fed mice. Visceral and subcutaneous fat pads were enlarged and contained more NK1.1+KLRG1+ cells, indicating that G1-ILCs were activated in HFD-L-fed mice. We examined early changes in adipose tissues during the first week of HFD intake, and found that mice fed HFD-L showed increased levels of NK1.1+CD11b+KLRG1+ cells in adipose tissues. In adipose tissue culture, addition of 4-hydroxynonenal, the most frequent product of lipid peroxidation derived from unsaturated fatty acids, induced NK1.1+CD11b+CD27- cells. We found that calreticulin, a ligand for the NK activating receptor, was induced on the surface of adipocytes after exposure to 4-hydroxynonenal or a 1-week feeding with HFD-L. Thus, excess fatty acid intake and the activation of G1-ILCs initiate and/or modify adipose inflammation.


Asunto(s)
Aldehídos , Dieta Alta en Grasa , Ácidos Grasos , Animales , Ratones , Adipocitos , Tejido Adiposo , Calreticulina/metabolismo , Dieta Alta en Grasa/efectos adversos , Ácidos Grasos/metabolismo , Inmunidad Innata , Inflamación/metabolismo , Linfocitos/metabolismo , Obesidad
4.
Int Immunol ; 36(5): 223-240, 2024 Apr 03.
Artículo en Inglés | MEDLINE | ID: mdl-38262747

RESUMEN

The gut microbiota plays a crucial role in maintaining epithelial barrier function. Although multiple studies have demonstrated the significance of dietary factors on the gut microbiota and mucosal barrier function, the impact of a purified diet, which has long been used in various animal experiments, on intestinal homeostasis remains to be elucidated. Here, we compared the impact of two different types of diets, a crude diet and an AIN-93G-formula purified diet, on epithelial integrity and the gut microbiota. Purified diet-fed mice exhibited shorter villi and crypt lengths and slower epithelial turnover, particularly in the ileum. In addition, antimicrobial products, including REG3γ, were substantially decreased in purified diet-fed mice. Purified diet feeding also suppressed α1,2-fucosylation on the epithelial surface. Furthermore, the purified diet induced metabolic rewiring to fatty acid oxidation and ketogenesis. 16S ribosomal RNA gene sequencing of the ileal contents and mucus layer revealed distinct gut microbiota compositions between the purified and crude diet-fed mice. Purified diet feeding reduced the abundance of segmented filamentous bacteria (SFB), which potently upregulate REG3γ and fucosyltransferase 2 (Fut2) by stimulating group 3 innate lymphoid cells (ILC3s) to produce IL-22. These observations illustrate that the intake of a crude diet secures epithelial barrier function by facilitating SFB colonization, whereas a purified diet insufficiently establishes the epithelial barrier, at least partly owing to the loss of SFB. Our data suggest that the influence of purified diets on the epithelial barrier integrity should be considered in experiments using purified diets.


Asunto(s)
Microbioma Gastrointestinal , Ratones , Animales , Inmunidad Innata , Linfocitos , Dieta , Bacterias , Proliferación Celular
5.
Carcinogenesis ; 41(7): 875-886, 2020 07 14.
Artículo en Inglés | MEDLINE | ID: mdl-31738399

RESUMEN

Glutathione S-transferase omega 2 (GSTO2), which belongs to the superfamily of GST omega class, lacks any appreciable GST activity. Although GSTO2 exhibits thioltransferase and glutathione dehydrogenase activities, its precise expression and physiological functions are still unclear. In the present study, we found that GSTO2 is exclusively expressed in the basal cell layer in Ki67-negative non-proliferative cells in the human esophageal mucosa. GSTO2 overexpression in esophageal squamous cell carcinoma (ESCC) cell lines inhibited cell growth and colony formation, and GSTO2-transfected cells formed smaller tumors in nude mice compared with mock-transfected cells. Interestingly, GSTO2 induction suppressed the expressions of E-cadherin and ß-catenin at the cell-cell contact site. We quantified the phosphorylation levels of key proteins of MAPK signaling pathway and identified phosphorylation of p38. Additionally, HSP27, a downstream molecule of p38, was accelerated in GSTO2-transfected cells, unlike in mock-transfected cells. When GSTO2-transfected cells were treated with a p38 inhibitor, the expression of ß-catenin and the membrane localization of E-cadherin was recovered. We next examined GSTO2 expression in 61 ESCC tissues using quantitative reverse transcription polymerase chain reaction and immunostaining. The results showed that GSTO2 mRNA and protein were significantly reduced in ESCC compared with normal tissues. When human ESCC cell lines were treated with 5-aza-2'-deoxycytidine, a DNA-methyltransferase inhibitor, GSTO2 transcription was induced, suggesting that aberrant hypermethylation is the cause of the down-regulated expression. Our results indicate that GSTO2 expression inhibits the membrane localization of E-cadherin, probably by modulation of the p38 signaling pathway. Down-regulation of GSTO2 by DNA hypermethylation contributes to the growth and progression of ESCC.


Asunto(s)
Cadherinas/genética , Carcinoma de Células Escamosas de Esófago/genética , Glutatión Transferasa/genética , beta Catenina/genética , Animales , Línea Celular Tumoral , Proliferación Celular/genética , Metilación de ADN/genética , Carcinoma de Células Escamosas de Esófago/patología , Regulación Neoplásica de la Expresión Génica/genética , Xenoinjertos , Humanos , Ratones , Transducción de Señal/genética
6.
Immunity ; 32(2): 200-13, 2010 Feb 26.
Artículo en Inglés | MEDLINE | ID: mdl-20153219

RESUMEN

Neutrophils rapidly undergo polarization and directional movement to infiltrate the sites of infection and inflammation. Here, we show that an inhibitory MHC I receptor, Ly49Q, was crucial for the swift polarization of and tissue infiltration by neutrophils. During the steady state, Ly49Q inhibited neutrophil adhesion by preventing focal-complex formation, likely by inhibiting Src and PI3 kinases. However, in the presence of inflammatory stimuli, Ly49Q mediated rapid neutrophil polarization and tissue infiltration in an ITIM-domain-dependent manner. These opposite functions appeared to be mediated by distinct use of effector phosphatase SHP-1 and SHP-2. Ly49Q-dependent polarization and migration were affected by Ly49Q regulation of membrane raft functions. We propose that Ly49Q is pivotal in switching neutrophils to their polarized morphology and rapid migration upon inflammation, through its spatiotemporal regulation of membrane rafts and raft-associated signaling molecules.


Asunto(s)
Microdominios de Membrana/metabolismo , Subfamilia A de Receptores Similares a Lectina de Células NK/metabolismo , Neutrófilos/metabolismo , Proteína Tirosina Fosfatasa no Receptora Tipo 11/metabolismo , Proteína Tirosina Fosfatasa no Receptora Tipo 6/metabolismo , Animales , Movimiento Celular/genética , Movimiento Celular/inmunología , Polaridad Celular/genética , Polaridad Celular/inmunología , Células Cultivadas , Adhesiones Focales/genética , Adhesiones Focales/inmunología , Ratones , Ratones Endogámicos C57BL , Ratones Transgénicos , Subfamilia A de Receptores Similares a Lectina de Células NK/genética , Subfamilia A de Receptores Similares a Lectina de Células NK/inmunología , Activación Neutrófila , Neutrófilos/inmunología , Neutrófilos/patología , Inhibidores de las Quinasa Fosfoinosítidos-3 , Transporte de Proteínas , Proteína Tirosina Fosfatasa no Receptora Tipo 11/inmunología , Proteína Tirosina Fosfatasa no Receptora Tipo 6/inmunología , Familia-src Quinasas/antagonistas & inhibidores
7.
Gut ; 67(2): 362-371, 2018 02.
Artículo en Inglés | MEDLINE | ID: mdl-27789659

RESUMEN

OBJECTIVE: The clinical significance of polymorphisms in the interleukin-28B gene encoding interferon (IFN)-λ3, which has antiviral effects, is known in chronic HCV but not in HBV infection. Thus, we measured IFN-λ3 levels in patients with HBV and investigated its clinical significance and association with nucleos(t)ide (NUC) analogue administration. DESIGN: Serum IFN-λ3 level was measured in 254 patients with HBV with varying clinical conditions using our own high sensitivity method. The resulting values were compared with various clinical variables. In addition, cell lines originating from various organs were cultured with NUCs, and the production of IFN-λ3 was evaluated. RESULTS: Higher serum IFN-λ3 levels were detected in the patients treated with nucleotide analogues (adefovir or tenofovir) compared with those treated with nucleoside analogues (lamivudine or entecavir). There were no other differences in the clinical background between the two groups. A rise in the serum IFN-λ3 levels was observed during additional administration of the nucleotide analogues. In vitro experiments showed that the nucleotide analogues directly and dose-dependently induced IFN-λ3 production only in colon cancer cells. Furthermore, the supernatant from cultured adefovir-treated colon cancer cells significantly induced IFN-stimulated genes (ISGs) and inhibited hepatitis B surface antigen (HBsAg) production in hepatoma cells, as compared with the supernatant from entecavir-treated cells. CONCLUSIONS: We discovered that the nucleotide analogues show an additional pharmacological effect by inducing IFN-λ3 production, which further induces ISGs and results in a reduction of HBsAg production. These findings provide novel insights for HBV treatment and suggest IFN-λ3 induction as a possible target.


Asunto(s)
Antivirales/uso terapéutico , Carcinoma Hepatocelular/sangre , Hepatitis B Crónica/sangre , Hepatitis B Crónica/tratamiento farmacológico , Interleucinas/sangre , Neoplasias Hepáticas/sangre , Adenina/análogos & derivados , Adenina/farmacología , Adenina/uso terapéutico , Adulto , Anciano , Anciano de 80 o más Años , Antivirales/farmacología , Infecciones Asintomáticas , Medios de Cultivo Condicionados/farmacología , ADN Viral/sangre , Femenino , Expresión Génica/efectos de los fármacos , Genotipo , Guanina/análogos & derivados , Guanina/farmacología , Guanina/uso terapéutico , Células HT29 , Células Hep G2 , Antígenos de Superficie de la Hepatitis B/metabolismo , Virus de la Hepatitis B/genética , Humanos , Interferones , Interleucinas/farmacología , Lamivudine/farmacología , Lamivudine/uso terapéutico , Cirrosis Hepática/sangre , Masculino , Persona de Mediana Edad , Organofosfonatos/farmacología , Organofosfonatos/uso terapéutico , Polimorfismo Genético , Proteínas Recombinantes , Tenofovir/farmacología , Tenofovir/uso terapéutico , Regulación hacia Arriba/genética , Adulto Joven
8.
J Immunol ; 197(6): 2269-79, 2016 09 15.
Artículo en Inglés | MEDLINE | ID: mdl-27511731

RESUMEN

ESET/SETDB1, one of the major histone methyltransferases, catalyzes histone 3 lysine 9 (H3K9) trimethylation. ESET is critical for suppressing expression of retroviral elements in embryonic stem cells; however, its role in the immune system is not known. We found that thymocyte-specific deletion of ESET caused impaired T cell development, with CD8 lineage cells being most severely affected. Increased apoptosis of CD8 single-positive cells was observed, and TCR-induced ERK activation was severely inhibited in ESET(-/-) thymocytes. Genome-wide comprehensive analysis of mRNA expression and H3K9 trimethylation revealed that ESET regulates expression of numerous genes in thymocytes. Among them, FcγRIIB, whose signaling can inhibit ERK activation, was strongly and ectopically expressed in ESET(-/-) thymocytes. Indeed, genetic depletion of FcγRIIB in ESET(-/-) thymocytes rescued impaired ERK activation and partially restored defective positive selection in ESET(-/-) mice. Therefore, impaired T cell development in ESET(-/-) mice is partly due to the aberrant expression of FcγRIIB. Collectively, to our knowledge, we identify ESET as the first trimethylated H3K9 histone methyltransferase playing a crucial role in T cell development.


Asunto(s)
Linfocitos T CD8-positivos/fisiología , Regulación de la Expresión Génica , N-Metiltransferasa de Histona-Lisina/metabolismo , Animales , Apoptosis , Linfocitos T CD8-positivos/inmunología , Linfocitos T CD8-positivos/patología , Diferenciación Celular/genética , Células Madre Embrionarias/metabolismo , Quinasas MAP Reguladas por Señal Extracelular/inmunología , Quinasas MAP Reguladas por Señal Extracelular/metabolismo , Genoma , N-Metiltransferasa de Histona-Lisina/deficiencia , Histonas/metabolismo , Lisina/metabolismo , Metilación , Ratones , Regiones Promotoras Genéticas , Receptores de IgG/genética , Receptores de IgG/metabolismo , Timocitos/inmunología , Timocitos/fisiología
9.
J Clin Biochem Nutr ; 61(2): 100-107, 2017 Sep.
Artículo en Inglés | MEDLINE | ID: mdl-28955126

RESUMEN

Fasting-refeeding in mice induces transient hyperproliferation of colonic epithelial cells, which is dependent on the lactate produced as a metabolite of commensal bacteria. We attempted to manipulate colonic epithelial cell turnover with intermittent fasting to prompt recovery from acute colitis. Acute colitis was induced in C57BL/6 mice by administration of dextran sulfate sodium in the drinking water for 5 days. From day 6, mice were fasted for 36 h and refed normal bait, glucose powder, or lactylated high-amylose starch. On day 9, colon tissues were subjected to analysis of histology and cytokine expression. The effect of lactate on the proliferation of colonocytes was assessed by enema in vivo and primary culture in vitro. Intermittent fasting resulted in restored colonic crypts and less expression of interleukin-1ß and interleukin-17 in the colon than in mice fed ad libitum. Administration of lactate in the colon at refeeding time by enema or by feeding lactylated high-amylose starch increased the number of regenerating crypts. Addition of lactate but not butyrate or acetate supported colony formation of colonocytes in vitro. In conclusion, intermittent fasting in the resolution phase of acute colitis resulted in better recovery of epithelial cells and reduced inflammation.

10.
Immunology ; 147(1): 21-9, 2016 Jan.
Artículo en Inglés | MEDLINE | ID: mdl-26425820

RESUMEN

Group 2 innate lymphoid cells (ILC2s) produce a significant amount of interleukin-5 (IL-5), which supports eosinophil responses in various tissues; they also produce IL-13, which induces mucus production and contributes to tissue repair or fibrosis. The ILC2s are activated by alarmins, such as IL-33 released from epithelia, macrophages and natural killer T (NKT) cells in response to infection and allergen exposure, leading to epithelial injury. We examined gene expression in lung ILC2s and found that ILC2s expressed Ifngr1, the receptor for interferon-γ (IFN-γ). Interferon-γ severely inhibited IL-5 and IL-13 production by lung and kidney ILC2s. To evaluate the effects in vivo, we used α-galactosylceramide (α-GalCer) to induce NKT cells to produce IL-33 and IFN-γ. Intraperitoneal injection of α-GalCer in mice induced NKT cell activation resulting in IL-5 and IL-13 production by ILC2s. Administration of anti-IFN-γ together with α-GalCer significantly enhanced the production of IL-5 and IL-13 by ILC2s in lung and kidney. Conversely, cytokine production from ILC2s was markedly suppressed after injection of exogenous IL-33 in Il33(-/-) mice pre-treated with α-GalCer. Hence, IFN-γ induced or already present in tissues can impact downstream pleiotropic functions mediated by ILC2s, such as inflammation and tissue repair.


Asunto(s)
Inmunidad Innata/efectos de los fármacos , Interferón gamma/metabolismo , Riñón/metabolismo , Pulmón/metabolismo , Linfocitos/metabolismo , Animales , Células Cultivadas , Galactosilceramidas/farmacología , Interferón gamma/inmunología , Interferón gamma/farmacología , Interleucina-13/inmunología , Interleucina-13/metabolismo , Interleucina-33/deficiencia , Interleucina-33/genética , Interleucina-5/genética , Interleucina-5/inmunología , Interleucina-5/metabolismo , Riñón/citología , Riñón/efectos de los fármacos , Riñón/inmunología , Pulmón/citología , Pulmón/efectos de los fármacos , Pulmón/inmunología , Activación de Linfocitos , Linfocitos/efectos de los fármacos , Linfocitos/inmunología , Ratones Endogámicos C57BL , Ratones Transgénicos , Células T Asesinas Naturales/inmunología , Células T Asesinas Naturales/metabolismo , Fenotipo , Receptores de Interferón/agonistas , Receptores de Interferón/genética , Receptores de Interferón/inmunología , Receptor de Interferón gamma
11.
Cytokine ; 69(1): 14-21, 2014 Sep.
Artículo en Inglés | MEDLINE | ID: mdl-25022957

RESUMEN

Tumor necrosis factor (TNF)-α is a major effector in various inflammatory conditions. TNF-like weak inducer of apoptosis (TWEAK) is a member of the TNF superfamily that promotes inflammatory tissue damage through its receptor, FGF-inducible molecule 14 (Fn14). Since both TWEAK and TNF-α have been shown to mediate pathological responses through inter-dependent or independent pathways by in vitro, the potential interplay of these pathways was investigated in a mouse colitis model. Acute colitis was induced by rectal injection of trinitrobenzene sulfonic acid (TNBS), with administration of control IgG, TNF receptor (TNFR)-Ig chimeric protein, anti-TWEAK monoclonal antibody, or the combination of TNFR-Ig and anti-TWEAK antibody. On day 4, disease severity was evaluated and gene expression profiling was analyzed using whole colon tissue. NF-κB activation was investigated with Western blot. Levels of transcript of TWEAK, Fn14 and NF-κB-related molecules were measured in purified colon epithelial cells (ECs). As a result, activation of the canonical (p50/RelA), but not noncanonical (p100/RelB)-mediated pathway was the hallmark of inflammatory responses in this model. Inflammation induced upregulation of Fn14 only in ECs but not in other cell types. Combination treatment of TNFR-Ig and anti-TWEAK antibody synergistically reduced disease severity in comparison with the control antibody or single agent treatment. Gene expression profile of the colon indicated downregulation of canonical NF-κB pathway with combination treatment. In conclusion, synergistic activation of canonical NF-κB by TWEAK and TNF-α is critical for the induction of inflammatory tissue damage in acute inflammation.


Asunto(s)
Colitis/patología , FN-kappa B/metabolismo , Receptores del Factor de Necrosis Tumoral/metabolismo , Factor de Necrosis Tumoral alfa/metabolismo , Factores de Necrosis Tumoral/metabolismo , Animales , Anticuerpos Monoclonales/inmunología , Colitis/inducido químicamente , Colon/citología , Colon/patología , Citocina TWEAK , Perfilación de la Expresión Génica , Inflamación/inmunología , Inflamación/patología , Mucosa Intestinal/citología , Mucosa Intestinal/patología , Masculino , Ratones , Ratones Endogámicos C57BL , FN-kappa B/biosíntesis , Subunidad p50 de NF-kappa B/biosíntesis , Receptores del Factor de Necrosis Tumoral/biosíntesis , Receptor de TWEAK , Factor de Transcripción ReIA/biosíntesis , Ácido Trinitrobencenosulfónico
12.
J Immunol ; 188(9): 4690-700, 2012 May 01.
Artículo en Inglés | MEDLINE | ID: mdl-22467657

RESUMEN

Immune cells are known to express specific recognition molecules for cell surface glycans. However, mechanisms involved in glycan-mediated cell-cell interactions in mucosal immunity have largely been left unaccounted for. We found that several glycans preferentially expressed in nonmalignant colonic epithelial cells serve as ligands for sialic acid-binding Ig-like lectins (siglecs), the immunosuppressive carbohydrate-recognition receptors carried by immune cells. The siglec ligand glycans in normal colonic epithelial cells included disialyl Lewis(a), which was found to have binding activity to both siglec-7 and -9, and sialyl 6-sulfo Lewis(x), which exhibited significant binding to siglec-7. Expression of these siglec-7/-9 ligands was impaired upon carcinogenesis, and they were replaced by cancer-associated glycans sialyl Lewis(a) and sialyl Lewis(x), which have no siglec ligand activity. When we characterized immune cells expressing siglecs in colonic lamina propriae by flow cytometry and confocal microscopy, the majority of colonic stromal immune cells expressing siglec-7/-9 turned out to be resident macrophages characterized by low expression of CD14/CD89 and high expression of CD68/CD163. A minor subpopulation of CD8(+) T lymphocytes also expressed siglec-7/-9. Siglec-7/-9 ligation suppressed LPS-induced cyclooxygenase-2 expression and PGE(2) production by macrophages. These results suggest that normal glycans of epithelial cells exert a suppressive effect on cyclooxygenase-2 expression by resident macrophages, thus maintaining immunological homeostasis in colonic mucosal membranes. Our results also imply that loss of immunosuppressive glycans by impaired glycosylation during colonic carcinogenesis enhances inflammatory mediator production.


Asunto(s)
Antígenos CD/inmunología , Antígenos de Diferenciación Mielomonocítica/inmunología , Transformación Celular Neoplásica/inmunología , Colon/inmunología , Neoplasias del Colon/inmunología , Mucosa Intestinal/inmunología , Lectinas/inmunología , Macrófagos/inmunología , Animales , Antígenos CD/biosíntesis , Antígenos de Diferenciación Mielomonocítica/biosíntesis , Linfocitos T CD8-positivos/inmunología , Linfocitos T CD8-positivos/metabolismo , Linfocitos T CD8-positivos/fisiología , Línea Celular Tumoral , Transformación Celular Neoplásica/metabolismo , Transformación Celular Neoplásica/patología , Colon/metabolismo , Colon/patología , Neoplasias del Colon/metabolismo , Neoplasias del Colon/patología , Ciclooxigenasa 2/biosíntesis , Ciclooxigenasa 2/inmunología , Células Epiteliales/inmunología , Células Epiteliales/metabolismo , Células Epiteliales/patología , Regulación de la Expresión Génica/inmunología , Glicosilación , Humanos , Mediadores de Inflamación/inmunología , Mediadores de Inflamación/metabolismo , Mucosa Intestinal/metabolismo , Mucosa Intestinal/patología , Lectinas/biosíntesis , Antígenos del Grupo Sanguíneo de Lewis , Lipopolisacáridos/farmacología , Macrófagos/metabolismo , Macrófagos/patología , Ratones , Oligosacáridos/inmunología , Oligosacáridos/metabolismo , Lectinas Similares a la Inmunoglobulina de Unión a Ácido Siálico , Células del Estroma/inmunología , Células del Estroma/metabolismo , Células del Estroma/patología
13.
Cell Rep ; 43(7): 114490, 2024 Jul 23.
Artículo en Inglés | MEDLINE | ID: mdl-38990720

RESUMEN

Although oral tolerance is a critical system in regulating allergic disorders, the mechanisms by which dietary factors regulate the induction and maintenance of oral tolerance remain unclear. To address this, we explored the differentiation and function of various immune cells in the intestinal immune system under fasting and ad libitum-fed conditions before oral ovalbumin (OVA) administration. Fasting mitigated OVA-specific Treg expansion, which is essential for oral tolerance induction. This abnormality mainly resulted from functional defects in the CX3CR1+ cells responsible for the uptake of luminal OVA and reduction of tolerogenic CD103+ dendritic cells. Eventually, fasting impaired the preventive effect of oral OVA administration on asthma and allergic rhinitis development. Specific food ingredients, namely carbohydrates and arginine, were indispensable for oral tolerance induction by activating glycolysis and mTOR signaling. Overall, prior food intake and nutritional signals are critical for maintaining immune homeostasis by inducing tolerance to ingested food antigens.


Asunto(s)
Arginina , Células Dendríticas , Tolerancia Inmunológica , Ovalbúmina , Linfocitos T Reguladores , Serina-Treonina Quinasas TOR , Animales , Arginina/metabolismo , Linfocitos T Reguladores/inmunología , Ovalbúmina/inmunología , Células Dendríticas/inmunología , Células Dendríticas/metabolismo , Ratones , Serina-Treonina Quinasas TOR/metabolismo , Ratones Endogámicos C57BL , Administración Oral , Receptor 1 de Quimiocinas CX3C/metabolismo , Intestinos/inmunología , Antígenos CD/metabolismo , Cadenas alfa de Integrinas/metabolismo , Azúcares/metabolismo , Glucólisis , Ayuno , Transducción de Señal , Mucosa Intestinal/inmunología , Mucosa Intestinal/metabolismo , Femenino
14.
Retrovirology ; 10: 83, 2013 Aug 05.
Artículo en Inglés | MEDLINE | ID: mdl-23915234

RESUMEN

BACKGROUND: Viral protein R (Vpr), a protein of human immunodeficiency virus type-1 (HIV-1) with various biological functions, was shown to be present in the blood of HIV-1-positive patients. However, it remained unclear whether circulating Vpr in patients' blood is biologically active. Here, we examined the activity of blood Vpr using an assay system by which retrotransposition of long interspersed element-1 (L1-RTP) was detected. We also investigated the in vivo effects of recombinant Vpr (rVpr) by administrating it to transgenic mice harboring human L1 as a transgene (hL1-Tg mice). Based on our data, we discuss the involvement of blood Vpr in the clinical symptoms of acquired immunodeficiency syndrome (AIDS). RESULTS: We first discovered that rVpr was active in induction of L1-RTP. Biochemical analyses revealed that rVpr-induced L1-RTP depended on the aryl hydrocarbon receptor, mitogen-activated protein kinases, and CCAAT/enhancer-binding protein ß. By using a sensitive L1-RTP assay system, we showed that 6 of the 15 blood samples from HIV-1 patients examined were positive for induction of L1-RTP. Of note, the L1-RTP-inducing activity was blocked by a monoclonal antibody specific for Vpr. Moreover, L1-RTP was reproducibly induced in various organs, including the kidney, when rVpr was administered to hL1-Tg mice. CONCLUSIONS: Blood Vpr is biologically active, suggesting that its monitoring is worthwhile for clarification of the roles of Vpr in the pathogenesis of AIDS. This is the first report to demonstrate a soluble factor in patients' blood active for L1-RTP activity, and implies the involvement of L1-RTP in the development of human diseases.


Asunto(s)
Productos del Gen vpr/sangre , Productos del Gen vpr/metabolismo , VIH-1/enzimología , Elementos de Nucleótido Esparcido Largo , Recombinación Genética , Adulto , Animales , Humanos , Masculino , Ratones , Ratones Transgénicos , Adulto Joven
15.
J Biochem ; 173(5): 383-392, 2023 Apr 26.
Artículo en Inglés | MEDLINE | ID: mdl-36689741

RESUMEN

Jaw1/LRMP is a membrane protein that is localized to the endoplasmic reticulum and outer nuclear membrane. Previously, we revealed that Jaw1 functions to maintain nuclear shape by interacting with microtubules as a Klarsicht/ANC-1/Syne/homology (KASH) protein. The loss of several KASH proteins causes defects in the position and shape of the Golgi apparatus as well as the nucleus, but the effects of Jaw1 depletion on the Golgi apparatus were poorly understood. Here, we found that siRNA-mediated Jaw1 depletion causes Golgi fragmentation with disordered ribbon structure in the melanoma cell, accompanied by the change in the localization of the Golgi-derived microtubule network. Thus, we suggest that Jaw1 is a novel protein to maintain the Golgi ribbon structure, associated with the microtubule network.


Asunto(s)
Núcleo Celular , Aparato de Golgi , Membrana Nuclear , Núcleo Celular/metabolismo , Citoesqueleto/metabolismo , Aparato de Golgi/metabolismo , Microtúbulos , Membrana Nuclear/metabolismo
16.
Gastroenterology ; 141(2): 621-32, 2011 Aug.
Artículo en Inglés | MEDLINE | ID: mdl-21669204

RESUMEN

BACKGROUND & AIMS: Epithelial cells that cover the intestinal mucosal surface maintain immune homeostasis and tolerance in the gastrointestinal tract. However, little is known about the molecular mechanisms that regulate epithelial immune functions. Epithelial cells are distinct in that they are highly polarized; this polarity is, at least in part, established by the epithelium-specific polarized sorting factor adaptor protein (AP)-1B. We investigated the role of AP-1B-mediated protein sorting in the maintenance of gastrointestinal immune homeostasis. METHODS: The role of AP-1B in intestinal immunity was examined in AP-1B-deficient mice (Ap1m2(-/-)) by monitoring their phenotypes, intestinal morphology, and epithelial barrier functions. AP-1B-mediated protein sorting was examined in polarized epithelial cells from AP-1B knockdown and Ap1m2(-/-) mice. RESULTS: Ap1m2(-/-) mice developed spontaneous chronic colitis, characterized by accumulation of interleukin-17A-producing, T-helper 17 cells. Deficiency of AP-1B caused epithelial immune dysfunction, such as reduced expression of antimicrobial proteins and impaired secretion of immunoglobulin A. These defects promoted intestinal dysbiosis and increased bacterial translocation within the mucosa. Importantly, AP-1B deficiency led to mistargeting of a subset of basolateral cytokine receptors to the apical plasma membrane in a polarized epithelial cell line and in colonic epithelial cells from mice. AP1M2 expression was reduced significantly in colonic epithelium samples from patients with Crohn's disease. CONCLUSIONS: AP-1B is required for proper localization of a subset of cytokine receptors in polarized epithelial cells, which allows them to respond to cytokine signals from underlying lamina propria cells. The AP-1B-mediated protein sorting machinery is required for maintenance of immune homeostasis and prevention of excessive inflammation.


Asunto(s)
Complejo 1 de Proteína Adaptadora/inmunología , Complejo 1 de Proteína Adaptadora/metabolismo , Subunidades beta de Complejo de Proteína Adaptadora/inmunología , Subunidades beta de Complejo de Proteína Adaptadora/metabolismo , Membrana Celular/metabolismo , Colitis/inmunología , Células Epiteliales/metabolismo , Homeostasis/inmunología , Mucosa Intestinal/metabolismo , Receptores de Citocinas/inmunología , Proteínas de Fase Aguda/metabolismo , Complejo 1 de Proteína Adaptadora/deficiencia , Subunidades beta de Complejo de Proteína Adaptadora/deficiencia , Subunidades mu de Complejo de Proteína Adaptadora/metabolismo , Animales , Péptidos Catiónicos Antimicrobianos , Catelicidinas/metabolismo , Membrana Celular/fisiología , Permeabilidad de la Membrana Celular , Colitis/microbiología , Colon , Enfermedad de Crohn/metabolismo , Regulación hacia Abajo , Células Epiteliales/inmunología , Células Epiteliales/patología , Humanos , Inmunoglobulina A/metabolismo , Interleucina-17/metabolismo , Mucosa Intestinal/inmunología , Mucosa Intestinal/microbiología , Mucosa Intestinal/patología , Lipocalina 2 , Lipocalinas/metabolismo , Ratones , Ratones Noqueados , Muramidasa/metabolismo , Proteínas Oncogénicas/metabolismo , Proteínas/metabolismo , Receptores de Citocinas/metabolismo , Ribonucleasa Pancreática/metabolismo , Ribonucleasas/metabolismo , Proteínas S100/metabolismo , Transducción de Señal , Células Th17/metabolismo , Factor de Necrosis Tumoral alfa/metabolismo , alfa-Defensinas/metabolismo , beta-Defensinas/metabolismo
17.
Gastroenterology ; 141(6): 2119-2129.e8, 2011 Dec.
Artículo en Inglés | MEDLINE | ID: mdl-21893119

RESUMEN

BACKGROUND & AIMS: TWEAK, a member of the tumor necrosis factor (TNF) superfamily, promotes intestinal epithelial cell injury and signals through the receptor Fn14 following irradiation-induced tissue damage and during development of colitis in mice. Interleukin (IL)-13, an effector of tissue damage in similar models, has been associated with the pathogenesis of ulcerative colitis (UC). We investigated interactions between TWEAK and IL-13 following mucosal damage in mice. METHODS: We compared patterns of gene expression in intestinal tissues from wild-type and TWEAK knockout mice following γ-irradiation. Intestinal explants from these mice were used to detect cell damage induced by IL-13 and TNF-α. Levels of messenger RNA for IL-13, TWEAK, and Fn14 were measured in mucosal samples from patients with UC. RESULTS: Based on gene expression analysis, TWEAK mediates γ-irradiation-induced epithelial cell cycle arrest and apoptosis. However, TWEAK alone did not induce damage or apoptosis of primary intestinal epithelial cells. On the other hand, exogenous IL-13 activated caspase-3 in naïve intestinal explants; this process required TWEAK, Fn14, and secretion of endogenous TNF-α which was mediated by ADAM17. Conversely, activation of caspase by exogenous TNF-α required IL-13, TWEAK, and Fn14. In mucosa from patients with UC, messenger RNA levels of IL-13, TWEAK, and Fn14 increased with level of disease severity. CONCLUSIONS: IL-13-induced damage of intestinal epithelial cells requires TWEAK, its receptor (Fn14), and TNF-α. IL-13, TNF-α, TWEAK, and Fn14 could perpetuate and aggravate intestinal inflammation in patients with UC.


Asunto(s)
Colitis Ulcerosa/patología , Regulación de la Expresión Génica/fisiología , Interleucina-13/metabolismo , Mucosa Intestinal/patología , Receptores del Factor de Necrosis Tumoral/genética , Factores de Necrosis Tumoral/genética , Animales , Muerte Celular , Colitis Ulcerosa/genética , Citocina TWEAK , Mucosa Intestinal/metabolismo , Ratones , Ratones Endogámicos C57BL , Ratones Noqueados , ARN Mensajero/genética , Reacción en Cadena de la Polimerasa de Transcriptasa Inversa , Transducción de Señal/fisiología , Receptor de TWEAK , Factor de Necrosis Tumoral alfa/farmacología
18.
J Immunoassay Immunochem ; 33(3): 291-301, 2012.
Artículo en Inglés | MEDLINE | ID: mdl-22738652

RESUMEN

We recently found that chemokine-driven peritoneal cell aggregation is the primary mechanism of postoperative adhesion in a mouse model. To investigate this in humans, paired samples of peritoneal lavage fluid were obtained from seven patients immediately after incision (preoperative) and before closure (postoperative), and were assayed for the presence of 27 cytokines and chemokines using multiplex beads assay. As a result, IL-6 and CCL5 showed the most striking increase during operation. Recombinant CCL5 or lavage fluid induced chemotaxis of human peripheral blood mononuclear cells. We propose that CCL5 is possibly involved in the mechanism of postoperative adhesion in humans.


Asunto(s)
Líquido Ascítico/química , Quimiocinas/análisis , Adulto , Anciano , Células Cultivadas , Quimiocina CCL5/análisis , Quimiocina CCL5/farmacología , Quimiotaxis/efectos de los fármacos , Femenino , Humanos , Laparotomía , Leucocitos Mononucleares/efectos de los fármacos , Leucocitos Mononucleares/fisiología , Masculino , Persona de Mediana Edad , Lavado Peritoneal , Proteínas Recombinantes/farmacología
19.
Immunology ; 134(4): 448-58, 2011 Dec.
Artículo en Inglés | MEDLINE | ID: mdl-22044210

RESUMEN

The intestinal epithelium is rich in γδ T cells and the gut is a site of residence for a wide variety of pathogens, including nematodes. Although CD4+ T-cell receptor (TCR) -αß+ T helper type 2 T cells are essential for the expulsion of intestinal nematodes, little information is available on the function of γδ T cells in this type of infection. Here, we demonstrate two major functions of γδ T cells as a potently protective T-cell population against Nippostrongylus brasiliensis infection using γδ T-cell-deficient (TCR-δ(-/-) ) mice. First, γδ T cells are required to initiate rapid expulsion of adult worms from the intestine and to limit egg production. Second, γδ T cells prevent the pathological intestinal damage associated with nematode infection, evident by increased clinical disease and more severe microscopic lesions in infected TCR-δ(-/-) mice. γδ T-cell deficiency led to delayed goblet cell hyperplasia in association with reduced expression of phosphorylated STAT6, MUC2, Trefoil factor-3 (TFF3) and T helper type 2 cytokines including interleukin-13 (IL-13). TCR-δ(-/-) mice also produced more interferon-γ than wild-type mice. Within the intraepithelial lymphocyte compartment, γδ T cells produced IL-13. Adoptive transfer of γδ T cells or administration of recombinant IL-13 to TCR-δ(-/-) mice successfully reduced the egg production by N. brasiliensis. Collectively, these data provide strong evidence that γδ T cells play an important role in controlling infection with intestinal nematodes and limiting infection-induced pathology.


Asunto(s)
Células Caliciformes/inmunología , Inmunidad Mucosa , Nippostrongylus/inmunología , Receptores de Antígenos de Linfocitos T gamma-delta/inmunología , Infecciones por Strongylida/inmunología , Subgrupos de Linfocitos T/inmunología , Animales , Proliferación Celular , Células Caliciformes/patología , Interleucina-13/inmunología , Intestino Delgado/inmunología , Intestino Delgado/patología , Ratones , Mucina 2/inmunología , Mucinas/inmunología , Factor de Transcripción STAT6/inmunología , Factor Trefoil-3
20.
Blood ; 114(8): 1518-27, 2009 Aug 20.
Artículo en Inglés | MEDLINE | ID: mdl-19528537

RESUMEN

Toll-like receptor (TLR) 9 recognizes unmethylated microorganismal cytosine guanine dinucleotide (CpG) DNA and elicits innate immune responses. However, the regulatory mechanisms of the TLR signaling remain elusive. We recently reported that Ly49Q, an immunoreceptor tyrosine-based inhibitory motif-bearing inhibitory receptor belonging to the natural killer receptor family, is crucial for TLR9-mediated type I interferon production by plasmacytoid dendritic cells. Ly49Q is expressed in plasmacytoid dendritic cells, macrophages, and neutrophils, but not natural killer cells. In this study, we showed that Ly49Q regulates TLR9 signaling by affecting endosome/lysosome behavior. Ly49Q colocalized with CpG in endosome/lysosome compartments. Cells lacking Ly49Q showed a disturbed redistribution of TLR9 and CpG. In particular, CpG-induced tubular endolysosomal extension was impaired in the absence of Ly49Q. Consistent with these findings, cells lacking Ly49Q showed impaired cytokine production in response to CpG-oligodeoxynucleotide. Our data highlight a novel mechanism by which TLR9 signaling is controlled through the spatiotemporal regulation of membrane trafficking by the immunoreceptor tyrosine-based inhibitory motif-bearing receptor Ly49Q.


Asunto(s)
Subfamilia A de Receptores Similares a Lectina de Células NK/fisiología , Receptor Toll-Like 9/genética , Receptor Toll-Like 9/metabolismo , Animales , Células Cultivadas , Citocinas/metabolismo , Células Dendríticas/efectos de los fármacos , Células Dendríticas/metabolismo , Endosomas/efectos de los fármacos , Endosomas/metabolismo , Macrófagos/efectos de los fármacos , Macrófagos/metabolismo , Ratones , Ratones Noqueados , Subfamilia A de Receptores Similares a Lectina de Células NK/antagonistas & inhibidores , Subfamilia A de Receptores Similares a Lectina de Células NK/genética , Oligodesoxirribonucleótidos/metabolismo , Transporte de Proteínas/efectos de los fármacos , Transporte de Proteínas/genética , ARN Interferente Pequeño/farmacología , Factores de Tiempo , Distribución Tisular/efectos de los fármacos , Distribución Tisular/genética
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