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1.
J Neuroimmunol ; 352: 577475, 2021 Mar 15.
Artículo en Inglés | MEDLINE | ID: mdl-33454554

RESUMEN

In this study, we assessed circulating immune cells and plasma cytokine levels in 15 pediatric patients with drug-resistant epilepsy (DRE). DRE patients had a significantly higher percentage of CD14+ monocytes positive for IL-1ß, IL-1 receptor antagonist, IL-6, and TNF-α than controls. Significantly higher intracellular levels of IFN-γ in CD4+ T cells and NK cells were also found in DRE patients. The level of IL-1ß+ CD14+ monocytes correlated with seizure frequency, and intracellular levels of IFN-γ in NKT-like cells were negatively correlated with the duration of epilepsy. Peripheral immune cells might be involved in the pathogenesis of DRE.

2.
Exp Ther Med ; 20(5): 121, 2020 Nov.
Artículo en Inglés | MEDLINE | ID: mdl-33005247

RESUMEN

Obesity is currently a major medical and societal issue. Synoviolin (SYVN1) is an E3 ubiquitin ligase involved in endoplasmic reticulum (ER) stress. Overexpression of Syvn1 has been found in genetically obese mice (ob/ob and db/db), and treatment with a Syvn1 inhibitor suppresses weight gain in some mouse models (C57BL/6J and db/db). However, SYVN1 expression in humans has not yet been elucidated. In the present study, 35 human volunteers were analyzed, and the expression level of SYVN1 mRNA in peripheral blood mononuclear cells (PBMCs) was detected using reverse transcription-quantitative polymerase chain reaction (RT-qPCR) analysis. Expression of SYVN1 mRNA was significantly increased in PBMCs from volunteers with a BMI ≥25.0, compared with volunteers with a BMI <25.0. In addition, PCR array and RT-qPCR of ER stress-responsive genes revealed that the expression of activating transcription factor 6 (ATF6), which plays an important role in the transcriptional activation of SYVN1, was increased in PBMCs from volunteers with a BMI ≥25.0. These results suggest that the ATF6-SYVN1 axis might be an important pathway in the progression of obesity.

3.
J Clin Invest ; 130(11): 6124-6140, 2020 Nov 02.
Artículo en Inglés | MEDLINE | ID: mdl-32809973

RESUMEN

Epstein-Barr virus-induced gene 3 (EBI3) is a subunit common to IL-27, IL-35, and IL-39. Here, we explore an intracellular role of EBI3 that is independent of its function in cytokines. EBI3-deficient naive CD4+ T cells had reduced IFN-γ production and failed to induce T cell-dependent colitis in mice. Similarly reduced IFN-γ production was observed in vitro in EBI3-deficient CD4+ T cells differentiated under pathogenic Th17 polarizing conditions with IL-23. This is because the induction of expression of one of the IL-23 receptor (IL-23R) subunits, IL-23Rα, but not another IL-23R subunit, IL-12Rß1, was selectively decreased at the protein level, but not the mRNA level. EBI3 augmented IL-23Rα expression via binding to the chaperone molecule calnexin and to IL-23Rα in a peptide-dependent manner, but not a glycan-dependent manner. Indeed, EBI3 failed to augment IL-23Rα expression in the absence of endogenous calnexin. Moreover, EBI3 poorly augmented the expression of G149R, an IL-23Rα variant that protects against the development of human colitis, because binding of EBI3 to the variant was reduced. Taken together with the result that EBI3 expression is inducible in T cells, the present results suggest that EBI3 plays a critical role in augmenting IL-23Rα protein expression via calnexin under inflammatory conditions.

4.
Oncoimmunology ; 7(5): e1421892, 2018.
Artículo en Inglés | MEDLINE | ID: mdl-29721372

RESUMEN

Interleukin (IL)-27 is a multifunctional cytokine that belongs to the IL-6/IL-12 family and has potent antitumor activity through various mechanisms. Our novel findings indicate that IL-27 directly acts on hematopoietic stem cells and promotes their expansion and differentiation into myeloid progenitors to control infection and to eradicate tumors.

5.
Cancer Res ; 78(1): 182-194, 2018 01 01.
Artículo en Inglés | MEDLINE | ID: mdl-29093008

RESUMEN

The interleukin IL27 promotes expansion and differentiation of hematopoietic stem cells into myeloid progenitor cells. Many tumor-infiltrating myeloid cells exert immunosuppressive effects, but we hypothesized that the myeloid cells induced by IL27 would have antitumor activity. In this study, we corroborated this hypothesis as investigated in two distinct mouse transplantable tumor models. Malignant mouse cells engineered to express IL27 exhibited reduced tumor growth in vivo Correlated with this effect was a significant increase in the number of tumor-infiltrating CD11b+ myeloid cells exhibiting a reduced immunosuppressive activity. Notably, these CD11b+ cells were characterized by an activated M1 macrophage phenotype, on the basis of increased expression of inducible nitric oxide synthase and other M1 biomarkers. In vivo depletion of these cells by administering anti-Gr-1 eradicated the antitumor effects of IL27. When admixed with parental tumors, CD11b+ cells inhibited tumor growth and directly killed the tumor in a nitric oxide-dependent manner. Mechanistically, IL27 expanded Lineage-Sca-1+c-Kit+ cells in bone marrow. Transplant experiments in Ly5.1/5.2 congenic mice revealed that IL27 directly acted on these cells and promoted their differentiation into M1 macrophages, which mobilized into tumors. Overall, our results illustrated how IL27 exerts antitumor activity by enhancing the generation of myeloid progenitor cells that can differentiate into antitumorigenic M1 macrophages.Significance: These findings show how the interleukin IL27 exerts potent antitumor activity by enhancing the generation of myeloid progenitor cells that can differentiate into antitumorigenic M1 macrophages.Cancer Res; 78(1); 182-94. ©2017 AACR.


Asunto(s)
Células Madre Hematopoyéticas/citología , Interleucina-27/genética , Macrófagos/citología , Neoplasias Experimentales/inmunología , Animales , Antígeno CD11b/metabolismo , Diferenciación Celular/efectos de los fármacos , Línea Celular Tumoral , Células Madre Hematopoyéticas/fisiología , Inmunosupresión , Interleucina-27/metabolismo , Macrófagos/fisiología , Ratones Endogámicos C57BL , Células Mieloides/inmunología , Células Mieloides/metabolismo , Neoplasias Experimentales/patología , Neoplasias Experimentales/terapia , Óxido Nítrico/metabolismo , Proteínas Recombinantes/genética , Proteínas Recombinantes/metabolismo
6.
Cell Mol Life Sci ; 75(8): 1363-1376, 2018 04.
Artículo en Inglés | MEDLINE | ID: mdl-29218601

RESUMEN

Hematopoiesis is hierarchically orchestrated by a very small population of hematopoietic stem cells (HSCs) that reside in the bone-marrow niche and are tightly regulated to maintain homeostatic blood production. HSCs are predominantly quiescent, but they enter the cell cycle in response to inflammatory signals evoked by severe systemic infection or injury. Thus, hematopoietic stem and progenitor cells (HSPCs) can be activated by pathogen recognition receptors and proinflammatory cytokines to induce emergency myelopoiesis during infection. This emergency myelopoiesis counterbalances the loss of cells and generates lineage-restricted hematopoietic progenitors, eventually replenishing mature myeloid cells to control the infection. Controlled generation of such signals effectively augments host defense, but dysregulated stimulation by these signals is harmful to HSPCs. Such hematopoietic failure often results in blood disorders including chronic inflammatory diseases and hematological malignancies. Recently, we found that interleukin (IL)-27, one of the IL-6/IL-12 family cytokines, has a unique ability to directly act on HSCs and promote their expansion and differentiation into myeloid progenitors. This process resulted in enhanced production of neutrophils by emergency myelopoiesis during the blood-stage mouse malaria infection. In this review, we summarize recent advances in the regulation of myelopoiesis by proinflammatory cytokines including type I and II interferons, IL-6, IL-27, granulocyte colony-stimulating factor, macrophage colony-stimulating factor, and IL-1 in infectious diseases.


Asunto(s)
Regulación de la Expresión Génica/inmunología , Neoplasias Hematológicas/inmunología , Malaria/inmunología , Mielopoyesis/inmunología , Neutrófilos/inmunología , Animales , Ciclo Celular/genética , Ciclo Celular/inmunología , Diferenciación Celular , Proliferación Celular , Factor Estimulante de Colonias de Granulocitos/genética , Factor Estimulante de Colonias de Granulocitos/inmunología , Neoplasias Hematológicas/genética , Neoplasias Hematológicas/patología , Humanos , Interferones/genética , Interferones/inmunología , Interleucina-1/genética , Interleucina-1/inmunología , Interleucina-6/genética , Interleucina-6/inmunología , Interleucinas/genética , Interleucinas/inmunología , Factor Estimulante de Colonias de Macrófagos/genética , Factor Estimulante de Colonias de Macrófagos/inmunología , Malaria/genética , Malaria/parasitología , Malaria/patología , Ratones , Células Progenitoras Mieloides/inmunología , Células Progenitoras Mieloides/parasitología , Células Progenitoras Mieloides/patología , Mielopoyesis/genética , Neutrófilos/parasitología , Neutrófilos/patología , Plasmodium berghei/crecimiento & desarrollo , Plasmodium berghei/inmunología
7.
Front Immunol ; 8: 929, 2017.
Artículo en Inglés | MEDLINE | ID: mdl-28824649

RESUMEN

The use of animal models in chemical safety testing will be significantly limited due to the recent introduction of the 3Rs principle of animal experimentation in research. Although several in vitro assays to predict the sensitizing potential of chemicals have been developed, these methods cannot distinguish chemical respiratory sensitizers and skin sensitizers. In the present study, we describe a novel in vitro assay that can discriminate respiratory sensitizers from chemical skin sensitizers by taking advantage of the fundamental difference between their modes of action, namely the development of the T helper 2 immune response, which is critically important for respiratory sensitization. First, we established a novel three-dimensional (3D) coculture system of human upper airway epithelium using a commercially available scaffold. It consists of human airway epithelial cell line BEAS-2B, immature dendritic cells (DCs) derived from human peripheral blood CD14+ monocytes, and human lung fibroblast cell line MRC-5. Respective cells were first cultured in individual scaffolds and subsequently assembled into a 3D multi-cell tissue model to more closely mimic the in vivo situation. Then, three typical chemicals that are known respiratory sensitizers (ortho-phthaldialdehyde, hexamethylene diisocyanate, and trimellitic anhydride) and skin sensitizers (oxazolone, formaldehyde, and dinitrochlorobenzene) were added individually to the 3D coculture system. Immunohistochemical analysis revealed that DCs do not migrate into other scaffolds under the experimental conditions. Therefore, the 3D structure was disassembled and real-time reverse transcriptase-PCR analysis was performed in individual scaffolds to analyze the expression levels of molecules critical for Th2 differentiation such as OX40 ligand (OX40L), interleukin (IL)-4, IL-10, IL-33, and thymic stromal lymphopoietin. Both sensitizers showed similarly augmented expression of DC maturation markers (e.g., CD86), but among these molecules, OX40L expression in DCs was most consistently and significantly enhanced by respiratory sensitizers as compared to that by skin sensitizers. Thus, we have established a 3D coculture system mimicking the airway upper epithelium that may be successfully applied to discriminate chemical respiratory sensitizers from skin sensitizers by measuring the critical molecule for Th2 differentiation, OX40L, in DCs.

8.
Front Immunol ; 7: 479, 2016.
Artículo en Inglés | MEDLINE | ID: mdl-27867385

RESUMEN

The interleukin (IL)-6/IL-12 family cytokines have pleiotropic functions and play critical roles in multiple immune responses. This cytokine family has very unique characteristics in that they comprise two distinct subunits forming a heterodimer and each cytokine and receptor subunit shares with each other. The members of this cytokine family are increasing; currently, there are more than six cytokines, including the tentatively named cytokines IL-Y (p28/p40), IL-12 (p35/p40), IL-23 (p19/p40), IL-27 [p28/Epstein-Barr virus-induced protein 3 (EBI3)], IL-35 (p35/EBI3), and IL-39 (p19/EBI3). This family of cytokines covers a very broad range of immune responses, including pro-inflammatory responses, such as helper T (Th)1, Th2, and Th17, to anti-inflammatory responses, such as regulatory T (Treg) cells and IL-10-producing Treg cells. IL-12 is the first member of this family, and IL-12, IL-23, and IL-27 are mainly produced by activated antigen-presenting cells, such as dendritic cells and macrophages. IL-12 plays a critical role in the promotion of Th1 immune responses by inducing interferon-γ production to combat pathogens and malignant tumors. IL-23 induces IL-17 production and is necessary to maintain pathogenic Th17 cells that cause inflammatory and autoimmune diseases. IL-27 was initially reported to play a critical role in promotion of Th1 differentiation; however, subsequent studies revealed that IL-27 has broader stimulatory and inhibitory roles by inducing IL-10-producing Treg cells. IL-35 is produced by forkhead box P3+ Treg cells and activated B cells and has immunosuppressive functions to maintain immune tolerance. The most recently identified cytokine, IL-39, is produced by activated B cells and has pro-inflammatory functions. The cytokine tentatively named IL-Y seems to have anti-inflammatory functions by inhibiting Th1 and Th17 differentiation. In addition, individual cytokine subunits were also shown to have self-standing activities. Thus, promiscuity within the IL-6/IL-12 family cytokines complicates structural and functional clarification and assignment of individual cytokines. A better understanding of the recent advances and expanding diversity in molecular structures and functions of the IL-6/IL-12 family cytokines could allow the creation of novel therapeutic strategies by using them as tools and targeted molecules.

9.
PLoS Pathog ; 12(3): e1005507, 2016 Mar.
Artículo en Inglés | MEDLINE | ID: mdl-26991425

RESUMEN

Emergency myelopoiesis is inflammation-induced hematopoiesis to replenish myeloid cells in the periphery, which is critical to control the infection with pathogens. Previously, pro-inflammatory cytokines such as interferon (IFN)-α and IFN-γ were demonstrated to play a critical role in the expansion of hematopoietic stem cells (HSCs) and myeloid progenitors, leading to production of mature myeloid cells, although their inhibitory effects on hematopoiesis were also reported. Therefore, the molecular mechanism of emergency myelopoiesis during infection remains incompletely understood. Here, we clarify that one of the interleukin (IL)-6/IL-12 family cytokines, IL-27, plays an important role in the emergency myelopoiesis. Among various types of hematopoietic cells in bone marrow, IL-27 predominantly and continuously promoted the expansion of only Lineage-Sca-1+c-Kit+ (LSK) cells, especially long-term repopulating HSCs and myeloid-restricted progenitor cells with long-term repopulating activity, and the differentiation into myeloid progenitors in synergy with stem cell factor. These progenitors expressed myeloid transcription factors such as Spi1, Gfi1, and Cebpa/b through activation of signal transducer and activator of transcription 1 and 3, and had enhanced potential to differentiate into migratory dendritic cells (DCs), neutrophils, and mast cells, and less so into macrophages, and basophils, but not into plasmacytoid DCs, conventional DCs, T cells, and B cells. Among various cytokines, IL-27 in synergy with the stem cell factor had the strongest ability to augment the expansion of LSK cells and their differentiation into myeloid progenitors retaining the LSK phenotype over a long period of time. The experiments using mice deficient for one of IL-27 receptor subunits, WSX-1, and IFN-γ revealed that the blood stage of malaria infection enhanced IL-27 expression through IFN-γ production, and the IL-27 then promoted the expansion of LSK cells, differentiating and mobilizing them into spleen, resulting in enhanced production of neutrophils to control the infection. Thus, IL-27 is one of the limited unique cytokines directly acting on HSCs to promote differentiation into myeloid progenitors during emergency myelopoiesis.


Asunto(s)
Hematopoyesis/fisiología , Células Madre Hematopoyéticas/fisiología , Interleucinas/metabolismo , Mielopoyesis/fisiología , Animales , Linfocitos B/efectos de los fármacos , Médula Ósea/fisiología , Diferenciación Celular , Linaje de la Célula , Citocinas/metabolismo , Ratones , Ratones Endogámicos C57BL , Células Mieloides/fisiología , Células Progenitoras Mieloides/fisiología , Transducción de Señal , Bazo/fisiología
10.
Oncoimmunology ; 4(10): e1042200, 2015 Oct.
Artículo en Inglés | MEDLINE | ID: mdl-26451308

RESUMEN

Since we first reported the antitumor efficacy of IL-27 in 2004, accumulating evidence obtained by several groups using a variety of preclinical mouse models indicates that IL-27 possesses potent antitumor activity against various types of tumors through multiple mechanisms depending on the characteristics of individual tumors without apparent adverse effects.

11.
Cancer Sci ; 106(9): 1103-10, 2015 Sep.
Artículo en Inglés | MEDLINE | ID: mdl-26132605

RESUMEN

Cancer immunotherapies such as sipuleucel-T and ipilimumab are promising new treatments that harness the power of the immune system to fight cancer and achieve long-lasting remission. Interleukin (IL)-27, a member of the IL-12 heterodimeric cytokine family, has pleiotropic functions in the regulation of immune responses with both pro-inflammatory and anti-inflammatory properties. Evidence obtained using a variety of preclinical mouse models indicates that IL-27 possesses potent antitumor activity against various types of tumors through multiple mechanisms without apparent adverse effects. These mechanisms include those mediated not only by CD8(+) T cells, natural killer cells and macrophages, but also by antibody-dependent cell-mediated cytotoxicity, antiangiogenesis, direct antiproliferative effects, inhibition of expression of cyclooxygenase-2 and prostaglandin E2 , and suppression of epithelial-mesenchymal transition, depending on the characteristics of individual tumors. However, the endogenous role of IL-27 subunits and one of its receptor subunits, WSX-1, in the susceptibility to tumor development after transplantation of tumor cell lines or endogenously arising tumors seems to be more complicated. IL-27 functions as a double-edged sword: IL-27 increases IL-10 production and the expression of programmed death ligand 1 and T-cell immunoglobulin and mucin domain-3, and promotes the generation of regulatory T cells, and IL-27 receptor α singling enhances transformation; IL-27 may augment protumor effects as well. Here, we review both facets of IL-27, antitumor effects and protumor effects, and discuss the potential clinical application of IL-27 as an antitumor agent.


Asunto(s)
Antineoplásicos/inmunología , Interleucina-27/inmunología , Neoplasias/inmunología , Neoplasias/terapia , Animales , Humanos , Inmunoterapia/métodos
12.
Drug Des Devel Ther ; 8: 1151-9, 2014.
Artículo en Inglés | MEDLINE | ID: mdl-25187697

RESUMEN

BACKGROUND: A subset of patients with chronic myeloid leukemia (CML) can sustain a complete molecular response after discontinuing imatinib mesylate (IM). We focused on microRNAs (miRNAs), with the aim of finding a molecular biomarker to discriminate which patients can safely and successfully discontinue IM use. METHODS: To identify miRNAs that showed altered expression in patients who had discontinued IM (STOP-IM group), we first screened miRNA expression of peripheral blood mononuclear cells by using a TaqMan miRNA array on samples from five unselected patients from the STOP-IM group, seven CML patients receiving IM (IM group), and five healthy volunteers. We then performed miRNA quantification in 49 CML patients with deep molecular response. Mann-Whitney U and chi-square tests were used to determine statistical significance for comparisons between the control (healthy volunteers) and test groups (STOP-IM and IM groups). Multiple groups were compared by one-way analysis of variance. RESULTS: Downregulation of miR-148b was noted in patients in the STOP-IM group and in a subset of the IM group. We then subdivided the IM patients into two groups: one with downregulated miR-148b expression (IM-1; less than the cut-off value) and the other without downregulated miR-148b expression (IM-2; greater than the cut-off value). The number of patients who had a sustained stable molecular response was significantly lower in IM-2 group. This group also had a significantly lower percentage of natural killer cells. CONCLUSION: Downregulated miR-148 may contribute to immune surveillance in STOP-IM patients and may therefore have potential as additive information in managing CML patients undergoing treatment with IM.


Asunto(s)
Benzamidas/uso terapéutico , Leucemia Mielógena Crónica BCR-ABL Positiva/tratamiento farmacológico , Leucocitos Mononucleares/metabolismo , MicroARNs/genética , Piperazinas/uso terapéutico , Pirimidinas/uso terapéutico , Adulto , Anciano , Análisis de Varianza , Antineoplásicos/administración & dosificación , Antineoplásicos/uso terapéutico , Benzamidas/administración & dosificación , Biomarcadores de Tumor/metabolismo , Estudios de Casos y Controles , Regulación hacia Abajo , Femenino , Humanos , Mesilato de Imatinib , Células Asesinas Naturales/metabolismo , Leucemia Mielógena Crónica BCR-ABL Positiva/genética , Leucemia Mielógena Crónica BCR-ABL Positiva/patología , Masculino , Persona de Mediana Edad , Análisis de Secuencia por Matrices de Oligonucleótidos , Piperazinas/administración & dosificación , Pirimidinas/administración & dosificación , Estadísticas no Paramétricas
13.
Oncoimmunology ; 3: e28861, 2014.
Artículo en Inglés | MEDLINE | ID: mdl-25057448

RESUMEN

Tyrosine kinase inhibitors have dramatically improved the treatment of chronic myeloid leukemia. Recent evidence revealed that some patients with chronic myeloid leukemia can stop imatinib without relapse after achieving a complete molecular response. This review discusses the possible predictive markers to identify these patients who can stop imatinib without relapse.

14.
PLoS One ; 9(4): e96120, 2014.
Artículo en Inglés | MEDLINE | ID: mdl-24760014

RESUMEN

The testis is an organ with immune privilege. The comprehensive blood-testis barrier formed by Sertoli cells protects autoimmunogenic spermatozoa and spermatids from attack by the body's immune system. The interleukin (IL)-6/IL-12 family cytokines IL-12 (p35/p40), IL-23 (p19/p40), IL-27 (p28/Epstein-Barr virus-induced gene 3 [EBI3]), and IL-35 (p35/EBI3) play critical roles in the regulation of various immune responses, but their roles in testicular immune privilege are not well understood. In the present study, we investigated whether these cytokines are expressed in the testes and whether they function in the testicular immune privilege by using mice deficient in their subunits. Expression of EBI3 was markedly increased at both mRNA and protein levels in the testes of 10- or 12-week-old wild-type mice as compared with levels in 2-week-old mice, whereas the mRNA expression of p40 was markedly decreased and that of p35 was conserved between these two groups. Lack of EBI3, p35, and IL-12 receptor ß2 caused enhanced infiltration of lymphocytes into the testicular interstitium, with increased interferon-γ expression in the testes and autoantibody production against mainly acrosomal regions of spermatids. Spermatogenic disturbance was more frequently observed in the seminiferous tubules, especially when surrounded by infiltrating lymphocytes, of these deficient mice than in those of wild-type mice. In particular, p35-deficient mice showed the most severe spermatogenic disturbance. Immunohistochemical analyses revealed that endothelial cells and peritubular cells in the interstitium were highly positive for p35 at both ages, and CD163+ resident macrophages positive for p35 and EBI3, possibly producing IL-35, were also detected in the interstitium of 12-week-old mice but not those of 2-week-old mice. These results suggest that p35 helps in maintaining the testicular immune privilege, in part in an IL-35-dependent manner.


Asunto(s)
Barrera Hematotesticular/inmunología , Subunidad p35 de la Interleucina-12/inmunología , Interleucinas/inmunología , Receptores de Citocinas/inmunología , Testículo/inmunología , Animales , Autoanticuerpos/metabolismo , Células Endoteliales/metabolismo , Subunidad p35 de la Interleucina-12/genética , Interleucinas/genética , Macrófagos/metabolismo , Masculino , Ratones , Ratones Endogámicos C57BL , Antígenos de Histocompatibilidad Menor , Receptores de Citocinas/genética , Túbulos Seminíferos/citología , Túbulos Seminíferos/metabolismo , Testículo/crecimiento & desarrollo
15.
PLoS One ; 8(10): e76159, 2013.
Artículo en Inglés | MEDLINE | ID: mdl-24155891

RESUMEN

Interleukin (IL)-27 is a member of the IL-6/IL-12 cytokine family and possesses potent antitumor activity, which is mediated by multiple mechanisms. Toll-like receptor (TLR)3 is the critical sensor of the innate immune system that serves to identify viral double-stranded RNA. TLR3 is frequently expressed by various types of malignant cells, and recent studies reported that a synthetic TLR3 agonist, polyinosinic-polycytidylic acid [poly(I:C)], induces antitumor effects on malignant cells. In the present study, we have explored the effect of IL-27 on human melanomas and uncovered a previously unknown mechanism. We found that IL-27 inhibits in vitro tumor growth of human melanomas and greatly enhances the expression of TNF-related apoptosis inducing ligand (TRAIL) in a dose-dependent manner. Neutralizing antibody against TRAIL partly but significantly blocked the IL-27-mediated inhibition of tumor growth. In addition, IL-27 and poly(I:C) cooperatively augmented TRAIL expression and inhibited tumor growth. The cooperative effect could be ascribed to the augmented expression of TLR3, but not retinoic acid-inducible gene-I or anti-melanoma differentiation-associated gene 5, by IL-27. The inhibition of tumor growth by the combination was also significantly abrogated by anti-TRAIL neutralizing antibody. Moreover, IL-27 and poly(I:C) cooperatively suppressed in vivo tumor growth of human melanoma in immunodeficient mice. Taken together, these results suggest that IL-27 enhances the expression of TRAIL and TLR3 in human melanomas and inhibits their tumor growth in cooperation with poly(I:C), partly in a TRAIL-dependent manner. Thus, IL-27 and the combination of IL-27 and poly(I:C) may be attractive candidates for cancer immunotherapy.


Asunto(s)
Interleucina-27/farmacología , Melanoma/metabolismo , Melanoma/patología , Poli I-C/farmacología , Ligando Inductor de Apoptosis Relacionado con TNF/metabolismo , Receptor Toll-Like 3/agonistas , Receptor Toll-Like 3/metabolismo , Animales , Línea Celular Tumoral , Proliferación Celular/efectos de los fármacos , Regulación Neoplásica de la Expresión Génica/efectos de los fármacos , Células HEK293 , Humanos , Melanoma/genética , Ratones , Ratones Endogámicos C57BL , Ratones SCID , Modelos Biológicos , Receptor Toll-Like 3/genética
16.
Clin Dev Immunol ; 2013: 968549, 2013.
Artículo en Inglés | MEDLINE | ID: mdl-23956763

RESUMEN

T-helper 17 (Th17) cells are characterized by producing interleukin-17 (IL-17, also called IL-17A), IL-17F, IL-21, and IL-22 and potentially TNF- α and IL-6 upon certain stimulation. IL-23, which promotes Th17 cell development, as well as IL-17 and IL-22 produced by the Th17 cells plays essential roles in various inflammatory diseases, such as experimental autoimmune encephalomyelitis, rheumatoid arthritis, colitis, and Concanavalin A-induced hepatitis. In this review, we summarize the characteristics of the functional role of Th17 cells, with particular focus on the Th17 cell-related cytokines such as IL-17, IL-22, and IL-23, in mouse models and human inflammatory diseases.


Asunto(s)
Citocinas/metabolismo , Inflamación/inmunología , Inflamación/metabolismo , Células Th17/inmunología , Células Th17/metabolismo , Animales , Humanos , Interleucina-17/metabolismo , Interleucina-23/metabolismo , Interleucinas/metabolismo
17.
Cancer Sci ; 104(9): 1146-53, 2013 Sep.
Artículo en Inglés | MEDLINE | ID: mdl-23758044

RESUMEN

A number of CML patients who achieve a sustained complete molecular response (CMR) for at least 2 years during imatinib (IM) therapy can discontinue IM without relapse. With the long-term goal of developing immunological criteria for managing IM therapy in CML patients, we compared the immunophenotypic profiles of three groups of CML patients: those who received IM and had a CMR for more than two consecutive years (CMR group); patients who received IM and did not have a sustained CMR but maintained a major molecular response for more than 2 years (fluctuating CMR group); and patients with a sustained CMR for more than 6 months after IM discontinuation (STOP-IM group), together with healthy controls. The percentages of effector populations of natural killer (NK) cells, such as interferon (IFN)-γ(+) CD3(-) CD56(+) cells, were significantly higher in the STOP-IM and CMR groups than in the fluctuating CMR and control groups. The elevated levels of these effector NK cells were sustained for more than 3 years after IM discontinuation. In contrast, the percentages of effector memory CD8(+) T cells, such as IFN-γ(+) CCR7(-) CD45RO(+) CD8(+) cells, were significantly higher in the STOP-IM and control groups than in the CMR and fluctuating CMR groups, possibly owing to IM intake. These results suggest that the immunological activation status of NK cells contributes to CMR maintenance. Higher activation levels of effector NK cells in CML patients being treated with IM might reflect minimization of BCR-ABL1 transcript levels and therefore could be additive information for determining whether to stop IM.


Asunto(s)
Benzamidas/uso terapéutico , Células Asesinas Naturales/metabolismo , Leucemia Mielógena Crónica BCR-ABL Positiva/metabolismo , Piperazinas/uso terapéutico , Pirimidinas/uso terapéutico , Linfocitos T CD8-positivos/metabolismo , Femenino , Proteínas de Fusión bcr-abl/genética , Proteínas de Fusión bcr-abl/metabolismo , Humanos , Mesilato de Imatinib , Leucemia Mielógena Crónica BCR-ABL Positiva/tratamiento farmacológico , Leucemia Mielógena Crónica BCR-ABL Positiva/genética , Masculino , Persona de Mediana Edad , Recurrencia Local de Neoplasia/genética , Recurrencia Local de Neoplasia/metabolismo , Resultado del Tratamiento , Regulación hacia Arriba
18.
Immunobiology ; 218(4): 628-34, 2013 Apr.
Artículo en Inglés | MEDLINE | ID: mdl-22925810

RESUMEN

Interleukin (IL)-27, a member of the IL-6/IL-12 heterodimeric cytokine family, induces pro-inflammatory responses including early T helper (Th)1 differentiation and generation of cytotoxic T lymphocytes, and also anti-inflammatory responses including the differentiation to IL-10-producing regulatory T cells, inhibition of Th2 and Th17 differentiation, and suppression of pro-inflammatory cytokine production. Nitric oxide (NO) is a potent source of reactive nitrogen species that play an important role in killing intracellular pathogens and forms a crucial component of host defense. Inducible NO synthase (iNOS), which catalyzes the production of NO, is induced by a range of stimuli including cytokines and microbes. Recently, IL-27 was reported to play an anti-inflammatory role in microglia by blocking oncostatin M-induced iNOS expression and neuronal toxicity. In the present study, we investigated the effects of IL-27 on NO production in thioglycollate-elicited peritoneal macrophages. IL-27 together with lipopolysaccharide (LPS) induced morphological change into more spread and elongated cells and synergistically enhanced NO production. The combined stimulation also enhanced iNOS mRNA expression and the NO production was abrogated by an iNOS inhibitor, NG-monomethyl L-arginine. The synergistic NO production could be attributed to the augmented Toll-like receptor (TLR)4 mRNA expression by the combination. Signal transducer and activator of transcription (STAT)1 was indispensable for the morphological change and NO production. The combination induced nuclear factor κB (NF-κB) translocation into nuclear and phosphorylation of extracellular signal-regulated kinase (ERK), c-Jun N-terminal kinase (JNK) and p38 mitogen-activated protein kinase (MAPK), and their inhibitors suppressed NO production. These results suggest that in contrast to the anti-proinflammatory role in microglia, IL-27 exerts a pro-inflammatory role by enhancing NO production in peritoneal macrophages stimulated with LPS through activation of STAT1, NF-κB and MAPKs.


Asunto(s)
Quinasas MAP Reguladas por Señal Extracelular/inmunología , Interleucinas/inmunología , Lipopolisacáridos/farmacología , Macrófagos Peritoneales/inmunología , FN-kappa B/inmunología , Óxido Nítrico/inmunología , Factor de Transcripción STAT1/inmunología , Transporte Activo de Núcleo Celular/efectos de los fármacos , Transporte Activo de Núcleo Celular/inmunología , Animales , Núcleo Celular/inmunología , Núcleo Celular/metabolismo , Inhibidores Enzimáticos/farmacología , Quinasas MAP Reguladas por Señal Extracelular/metabolismo , Regulación Enzimológica de la Expresión Génica/efectos de los fármacos , Regulación Enzimológica de la Expresión Génica/inmunología , Interleucinas/metabolismo , Macrófagos Peritoneales/metabolismo , Macrófagos Peritoneales/patología , Ratones , FN-kappa B/metabolismo , Óxido Nítrico/biosíntesis , Óxido Nítrico Sintasa de Tipo II/antagonistas & inhibidores , Óxido Nítrico Sintasa de Tipo II/biosíntesis , Óxido Nítrico Sintasa de Tipo II/inmunología , Factor de Transcripción STAT1/metabolismo , Receptor Toll-Like 4/inmunología , Receptor Toll-Like 4/metabolismo , omega-N-Metilarginina/farmacología
19.
Eur J Immunol ; 41(10): 2828-39, 2011 Oct.
Artículo en Inglés | MEDLINE | ID: mdl-21953641

RESUMEN

IL-23 plays a critical role in the expansion of highly proinflammatory Th17 cells secreting IL-17 and IL-22. Recently, we demonstrated that Notch signaling drives IL-22 secretion through the aryl hydrocarbon receptor (AHR) and plays a protective role in Con A-induced hepatitis. In this study, we investigated the role of IL-23 in hepatitis using IL-23p19- and IL-17-deficient mice. In WT mice, the injection of Con A induced the upregulation of various cytokines, which included IL-23, IL-22, IL-17, IFN-γ and TNF-α. In IL-23p19-deficient mice, exacerbated hepatitis was observed and serum IL-22 and IL-17 levels were greatly reduced, whereas in IL-17-deficient mice, ameliorated hepatitis was observed. The injection of exogenous IL-22 protected p19-deficient mice from hepatitis, whereas the injection of exogenous IL-23 significantly increased the serum levels of not only IL-22 but also IL-17, and less effectively protected against hepatitis in IL-17-dependent and -independent manners. Finally, it was revealed that STAT3, STAT4 and Notch contributed to the production of both the cytokines, and that the AHR was important only for IL-22 production in response to Con A and IL-23 in liver mononuclear cells. These results suggest that IL-23 plays a protective role in hepatitis through IL-22 production and also a pathological role via IL-17-dependent and -independent mechanisms.


Asunto(s)
Hepatitis Animal/inmunología , Hepatitis Animal/metabolismo , Interleucina-17/metabolismo , Subunidad p19 de la Interleucina-23/metabolismo , Interleucina-23 , Interleucinas/metabolismo , Animales , Concanavalina A , Citocinas/biosíntesis , Interleucina-17/sangre , Interleucina-17/genética , Interleucina-23/administración & dosificación , Interleucina-23/biosíntesis , Interleucina-23/metabolismo , Interleucina-23/farmacología , Subunidad p19 de la Interleucina-23/genética , Interleucinas/administración & dosificación , Interleucinas/sangre , Ratones , Ratones Endogámicos C57BL , Ratones Noqueados , Receptores de Hidrocarburo de Aril/metabolismo , Receptores Notch/metabolismo , Reacción en Cadena de la Polimerasa de Transcriptasa Inversa , Factor de Transcripción STAT3/metabolismo , Factor de Transcripción STAT4/metabolismo , Transducción de Señal/efectos de los fármacos , Células Th17/inmunología , Células Th17/metabolismo
20.
Clin Dev Immunol ; 20102010.
Artículo en Inglés | MEDLINE | ID: mdl-20885915

RESUMEN

The interleukin (IL)-12 family, which is composed of heterodimeric cytokines including IL-12, IL-23, and IL-27, is produced by antigen-presenting cells such as macrophages and dendritic cells and plays critical roles in the regulation of helper T (Th) cell differentiation. IL-12 induces IFN-γ production by NK and T cells and differentiation to Th1 cells. IL-23 induces IL-17 production by memory T cells and expands and maintains inflammatory Th17 cells. IL-27 induces the early Th1 differentiation and generation of IL-10-producing regulatory T cells. In addition, these cytokines induce distinct immune responses to tumors. IL-12 activates signal transducers and activator of transcription (STAT)4 and enhances antitumor cellular immunity through interferon (IFN)-γ production. IL-27 activates STAT1, as does IFN-γ and STAT3 as well, and enhances antitumor immunity by augmenting cellular and humoral immunities. In contrast, although exogenously overexpressed IL-23 enhances antitumor immunity via memory T cells, endogenous IL-23 promotes protumor immunity through STAT3 activation by inducing inflammatory responses including IL-17 production.


Asunto(s)
Células Presentadoras de Antígenos/metabolismo , Interleucina-12/inmunología , Neoplasias/inmunología , Diferenciación Celular , Regulación de la Expresión Génica/inmunología , Humanos , Interleucina-12/metabolismo , Interleucina-17/inmunología , Interleucina-17/metabolismo , Interleucina-23/inmunología , Interleucina-23/metabolismo , Linfocitos T Colaboradores-Inductores/citología , Linfocitos T Colaboradores-Inductores/inmunología
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