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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.
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.

3.
J Clin Invest ; 129(8): 3201-3213, 2019 07 02.
Artículo en Inglés | MEDLINE | ID: mdl-31264967

RESUMEN

Acute liver failure (ALF) is a life-threatening condition, and liver transplantation is the only therapeutic option. Although immune dysregulation is central to its pathogenesis, the precise mechanism remains unclear. Here, we show that the number of peripheral and hepatic plasmacytoid DCs (pDCs) decrease during acute liver injury in both humans and mice. Selective depletion of pDCs in Siglechdtr/+ mice exacerbated concanavalin A-induced acute liver injury. In contrast, adoptively transferred BM-derived pDCs preferentially accumulated in the inflamed liver and protected against liver injury. This protective effect was independent of TLR7 and TLR9 signaling, since a similar effect occurred following transfer of MyD88-deficient pDCs. Alternatively, we found an unexpected immunosuppressive role of pDCs in an IL-35-dependent manner. Both Il12a and Ebi3, heterodimeric components of IL-35, were highly expressed in transferred pDCs and CD4+CD25+ Tregs. However, the protective effect of pDC transfer was completely lost in mice depleted of Tregs by anti-CD25 antibody. Moreover, pDCs derived from IL-35-deficient mice had less of a protective effect both in vivo and in vitro even in the presence of Tregs. These results highlight a unique aspect of pDCs in association with Tregs, serving as a guide for immunotherapeutic options in ALF.


Asunto(s)
Células Dendríticas/inmunología , Interleucinas/inmunología , Fallo Hepático Agudo/inmunología , Linfocitos T Reguladores/inmunología , Adolescente , Adulto , Anciano , Animales , Células Dendríticas/patología , Femenino , Humanos , Subunidad p35 de la Interleucina-12/genética , Subunidad p35 de la Interleucina-12/inmunología , Interleucinas/genética , Fallo Hepático Agudo/genética , Fallo Hepático Agudo/patología , Fallo Hepático Agudo/prevención & control , Masculino , Glicoproteínas de Membrana/genética , Glicoproteínas de Membrana/inmunología , Ratones , Ratones Noqueados , Persona de Mediana Edad , Antígenos de Histocompatibilidad Menor/genética , Antígenos de Histocompatibilidad Menor/inmunología , Factor 88 de Diferenciación Mieloide/genética , Factor 88 de Diferenciación Mieloide/inmunología , Receptores de Citocinas/genética , Receptores de Citocinas/inmunología , Linfocitos T Reguladores/patología , Receptor Toll-Like 7/genética , Receptor Toll-Like 7/inmunología , Receptor Toll-Like 9/genética , Receptor Toll-Like 9/inmunología
4.
iScience ; 15: 536-551, 2019 May 31.
Artículo en Inglés | MEDLINE | ID: mdl-31132747

RESUMEN

A short form of cellular FLICE-inhibitory protein encoded by CFLARs promotes necroptosis. Although necroptosis is involved in various pathological conditions, the detailed mechanisms are not fully understood. Here we generated transgenic mice wherein CFLARs was integrated onto the X chromosome. All male CFLARs Tg mice died perinatally due to severe ileitis. Although necroptosis was observed in various tissues of CFLARs Tg mice, large numbers of intestinal epithelial cells (IECs) died by apoptosis. Deletion of Ripk3 or Mlkl, essential genes of necroptosis, prevented both necroptosis and apoptosis, and rescued lethality of CFLARs Tg mice. Type 3 innate lymphoid cells (ILC3s) were activated and recruited to the small intestine along with upregulation of interleukin-22 (Il22) in CFLARs Tg mice. Deletion of ILC3s or Il22 rescued lethality of CFLARs Tg mice by preventing apoptosis, but not necroptosis of IECs. Together, necroptosis-dependent activation of ILC3s induces lethal ileitis in an IL-22-dependent manner.

5.
Medicine (Baltimore) ; 97(37): e12340, 2018 Sep.
Artículo en Inglés | MEDLINE | ID: mdl-30212985

RESUMEN

RATIONALE: Since primary pure squamous cell carcinoma of the breast is a rare disease, few reports describe the characteristic findings on performing preoperative imaging that can be used to distinguish it from normal breast cancer. The rapid evolution and lack of an established method of treatment has resulted in several reports of advanced cases of primary pure squamous cell carcinoma of the breast. PATIENT CONCERNS: Case 1 was a 44-year-old woman with an elastic, hard tumor in the left C region. Ultrasonographic analysis revealed a maximal 11-mm hypoechoic area. Histologically, the tumor was a well-differentiated squamous cell carcinoma with prominent keratinization, and there was prominent inflammatory cell infiltration, necrosis, and fibrosis. Case 2 was a 58-year-old woman with an elastic, hard tumor in the left C/D region. Ultrasonographic analysis revealed a maximal 31-mm hypoechoic area with partially calcified areas and a hyperechoic margin. Histologically, the tumor was a squamous cell carcinoma with prominent keratinization exhibiting an infiltrative growth pattern. The tumor had no connection to the epidermis and partially transitioned into the atypical ductal epithelium in the area surrounding the focus. DIAGNOSES: The patient in Case 1 was preoperatively diagnosed with T1cN0M0 Stage I cancer of the left breast, but both patients were finally diagnosed with T2N0M0 Stage IIA cancer. INTERVENTIONS: Case 1: left partial mastectomy and axillary lymph node dissection were performed. The patient was administered 4 courses of FEC100 and 4 courses of DTX as postoperative adjuvant therapy. Case 2: left modified radical mastectomy and axillary lymph node dissection were performed without any postoperative adjuvant therapy. OUTCOMES: Case 1: no sign of relapse was observed, but the patient moved away from the area to another hospital in March 2014 and eventually died due to relapse in January 2016. Case 2: four years after surgery, no relapse has been observed. LESSONS: We should always keep the presence of primary pure squamous cell carcinoma among breast cancers in mind although the crisis rate is very low. Due to its high malignancy, needle biopsy and aspiration biopsy cytology should be performed to make a definitive diagnosis.


Asunto(s)
Neoplasias de la Mama/patología , Carcinoma de Células Escamosas/patología , Adulto , Neoplasias de la Mama/cirugía , Carcinoma de Células Escamosas/cirugía , Femenino , Humanos , Mastectomía Segmentaria/métodos , Persona de Mediana Edad , Enfermedades Raras/patología , Enfermedades Raras/cirugía
6.
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.

7.
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
8.
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
9.
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.

10.
EMBO J ; 36(16): 2390-2403, 2017 08 15.
Artículo en Inglés | MEDLINE | ID: mdl-28673932

RESUMEN

Hematopoietic homeostasis depends on the maintenance of hematopoietic stem cells (HSCs), which are regulated within a specialized bone marrow (BM) niche. When HSC sense external stimuli, their adhesion status may be critical for determining HSC cell fate. The cell surface molecule, integrin αvß3, is activated through HSC adhesion to extracellular matrix and niche cells. Integrin ß3 signaling maintains HSCs within the niche. Here, we showed the synergistic negative regulation of the pro-inflammatory cytokine interferon-γ (IFNγ) and ß3 integrin signaling in murine HSC function by a novel definitive phenotyping of HSCs. Integrin αvß3 suppressed HSC function in the presence of IFNγ and impaired integrin ß3 signaling mitigated IFNγ-dependent negative action on HSCs. During IFNγ stimulation, integrin ß3 signaling enhanced STAT1-mediated gene expression via serine phosphorylation. These findings show that integrin ß3 signaling intensifies the suppressive effect of IFNγ on HSCs, which indicates that cell adhesion via integrin αvß3 within the BM niche acts as a context-dependent signal modulator to regulate the HSC function under both steady-state and inflammatory conditions.


Asunto(s)
Proliferación Celular , Células Madre Hematopoyéticas/fisiología , Integrina alfaVbeta3/metabolismo , Interferón gamma/metabolismo , Animales , Regulación de la Expresión Génica , Ratones , Fosforilación , Procesamiento Proteico-Postraduccional , Factor de Transcripción STAT1/metabolismo , Transducción de Señal
11.
Arch Dermatol Res ; 309(4): 315-321, 2017 May.
Artículo en Inglés | MEDLINE | ID: mdl-28299442

RESUMEN

The interleukin (IL)-23/IL-17 axis is strongly implicated in the pathogenesis of psoriasis. Previous studies showed that IL-18 was elevated in early active and progressive plaque-type psoriatic lesions and that serum or plasma levels of IL-18 correlated with the Psoriasis Area and Severity Index. However, the mechanism whereby IL-18 affects disease severity remains unknown. In this study, we investigated the effects of IL-18 on a psoriasis-like skin inflammation model induced by recombinant mouse IL-23. We found that IL-18, cooperatively with IL-23, induced prominent inflammation and enhanced psoriasis-like epidermal hyperplasia. In the skin of mice treated with IL-23 plus IL-18, the expression of interferon-γ was significantly upregulated and that of chemokine (C-X-C motif) ligand 9 (CXCL9) was synergistically increased. Histologically, strong positive signals of CXCL9 were observed around the infiltrating inflammatory cells. The current results suggest that IL-18 might synergize with IL-23 to induce a T helper 1 immune reaction, without inhibiting the IL-23/IL-17 axis, and thus may aggravate psoriatic inflammation.


Asunto(s)
Epidermis/patología , Mediadores de Inflamación/metabolismo , Interleucina-18/inmunología , Interleucina-23/inmunología , Psoriasis/inmunología , Animales , Células Cultivadas , Quimiocina CXCL9/genética , Quimiocina CXCL9/metabolismo , Femenino , Humanos , Hiperplasia , Inyecciones Intradérmicas , Interferón gamma/genética , Interferón gamma/metabolismo , Ratones , Ratones Endogámicos C57BL
12.
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.

13.
Cancer Sci ; 107(9): 1206-14, 2016 Sep.
Artículo en Inglés | MEDLINE | ID: mdl-27384869

RESUMEN

Although it has been suspected that inflammation is associated with increased tumor metastasis, the exact type of immune response required to initiate cancer progression and metastasis remains unknown. In this study, by using an in vivo tumor progression model in which low tumorigenic cancer cells acquire malignant metastatic phenotype after exposure to inflammation, we found that IL-17A is a critical cue for escalating cancer cell malignancy. We further demonstrated that the length of exposure to an inflammatory microenvironment could be associated with acquiring greater tumorigenicity and that IL-17A was critical for amplifying such local inflammation, as observed in the production of IL-1ß and neutrophil infiltration following the cross-talk between cancer and host stromal cells. We further determined that γδT cells expressing Vδ1 semi-invariant TCR initiate cancer-promoting inflammation by producing IL-17A in an MyD88/IL-23-dependent manner. Finally, we identified CD30 as a key molecule in the inflammatory function of Vδ1T cells and the blockade of this pathway targeted this cancer immune-escalation process. Collectively, these results reveal the importance of IL-17A-producing CD30(+) Vδ1T cells in triggering inflammation and orchestrating a microenvironment leading to cancer progression.


Asunto(s)
Inflamación/inmunología , Inflamación/metabolismo , Interleucina-17/biosíntesis , Antígeno Ki-1/metabolismo , Neoplasias/etiología , Neoplasias/metabolismo , Subgrupos de Linfocitos T/inmunología , Subgrupos de Linfocitos T/metabolismo , Animales , Línea Celular Tumoral , Modelos Animales de Enfermedad , Progresión de la Enfermedad , Inmunidad , Inflamación/complicaciones , Ratones , Ratones Noqueados , Modelos Biológicos , Neoplasias/patología , Microambiente Tumoral/inmunología
14.
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
15.
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.

16.
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
17.
Oncol Rep ; 33(1): 292-6, 2015 Jan.
Artículo en Inglés | MEDLINE | ID: mdl-25394516

RESUMEN

Immunotherapy has gained special attention due to its specific effects on tumor cells and systemic action to block metastasis. We recently demonstrated that ovalbumin (OVA) conjugated to the surface of nanoparticles (NPs) (OVA­NPs) can manipulate humoral immune responses. In the present study, we aimed to ascertain whether vaccination with OVA-NPs entrapping IL-7 (OVA-NPs-IL-7) are able to induce antitumor immune responses in vivo. Pretreatment with a subcutaneous inoculation of OVA-NPs delayed the growth of thymic lymphoma cells expressing a model tumor antigen OVA (E.G7-OVA), and OVA-NPs-IL-7 substantially blocked the growth of E.G7-OVA tumor cells, although NPs-IL-7 alone had a meager effect, as assessed by the mean tumor size and the percentage of tumor-free mice. However, pretreatment with OVA-NPs-IL-7 failed to reduce the growth of parental thymic tumor cells, suggesting that the antitumor effect was antigen-specific. A tetramer assay revealed that vaccination with OVA-NPs-IL-7 tended to enhance the proportion of cytotoxic T cells (CTLs) specific for OVA. When the tumor-free mice inoculated with OVA-NPs-IL-7 plus EG.7 cells were rechallenged with E.G7-OVA cells, they demonstrated reduced growth compared with that in the control mice. Thus, a single subcutaneous injection of OVA-NPs-IL-7 into mice induced tumor-specific and also memory-like immune responses, resulting in regression of tumor cells. Antigens on NPs entrapping IL-7 would be a promising carrier to develop and enhance immune responses, including humoral and cellular immunity as well as a method of drug delivery to a specific target of interest.


Asunto(s)
Interleucina-7/administración & dosificación , Nanocápsulas/administración & dosificación , Ovalbúmina/administración & dosificación , Timoma/terapia , Vacunación , Animales , Línea Celular Tumoral , Proliferación Celular , Citotoxicidad Inmunológica , Femenino , Memoria Inmunológica , Ratones Endogámicos C57BL , Ovalbúmina/inmunología , Ovalbúmina/metabolismo , Timoma/inmunología , Ensayos Antitumor por Modelo de Xenoinjerto
18.
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
19.
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.

20.
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
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