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.
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/inmunologíaRESUMEN
BACKGROUND: Gait dysfunction associated with spasticity and hyperreflexia is a primary symptom in patients with compression of cervical spinal cord. The objective of this study was to link maximum compression ratio (CR) to spatiotemporal/pedobarographic parameters. METHODS: Quantitative gait analysis was performed by using a pedobarograph in 75 elderly males with a wide range of cervical compression severity. CR values were characterized on T1-weighted magnetic resonance imaging (MRI). Statistical significances in gait analysis parameters (speed, cadence, stride length, step with, and toe-out angle) were evaluated among different CR groups by the non-parametric Kruskal-Wallis test followed by the Mann-Whitney U test using Bonferroni correction. The Spearman test was performed to verify correlations between CR and gait parameters. RESULTS: The Kruskal-Wallis test revealed significant decline in gait speed and stride length and significant increase in toe-out angle with progression of cervical compression myelopathy. The post-hoc Mann-Whitney U test showed significant differences in these parameters between the control group (0.45Asunto(s)
Trastornos Neurológicos de la Marcha/etiología
, Marcha/fisiología
, Compresión de la Médula Espinal/complicaciones
, Anciano
, Vértebras Cervicales
, Trastornos Neurológicos de la Marcha/diagnóstico
, Trastornos Neurológicos de la Marcha/fisiopatología
, Humanos
, Imagen por Resonancia Magnética
, Masculino
, Persona de Mediana Edad
, Compresión de la Médula Espinal/diagnóstico por imagen
, Compresión de la Médula Espinal/fisiopatología
RESUMEN
BACKGROUND: Scapulectomy is an inevitable treatment for sarcomas of the scapula. This procedure is unavoidable because it reduces the local recurrence rate but can impair shoulder movements and affect the activities of daily living. This study investigated the factors influencing functional outcomes after scapulectomy. MATERIALS AND METHODS: The clinical results of 8 patients (5 males, 3 females) who were diagnosed with primary or metastatic sarcomas of the scapula were retrospectively reviewed. The mean age was 49 years (range, 11-86 years). We examined the correlation between the type of excision of the scapula (total, subtotal, or partial) and postoperative functional outcomes according to the Musculoskeletal Tumor Society (MSTS) score. In partial excision, the glenohumeral joint was preserved; in subtotal excision, the glenoid was completely resected and some bony components were preserved; and in total excision, the entire bony component of the scapula was resected. The average follow-up period was 55 months (range, 9-142 months). RESULTS: The partial, subtotal, and total excision groups had mean functional scores of 96.7%, 76.7%, and 62.2%, respectively. Although the mean functional scores were lower in patients who underwent total and subtotal excisions, 3 patients in whom the latissimus dorsi muscle was preserved had better function (mean MSTS score, 76.7%) than the 2 patients in whom it was not preserved (mean MSTS score, 55.0%). CONCLUSION: These results suggest that the latissimus dorsi muscle, along with the deltoid and pectoralis major muscles, is one of the stabilizers of the proximal humerus after scapulectomy.
Asunto(s)
Neoplasias Óseas/cirugía , Neoplasias de los Músculos/secundario , Procedimientos Ortopédicos/métodos , Sarcoma/cirugía , Escápula/cirugía , Músculos Superficiales de la Espalda/cirugía , Actividades Cotidianas , Adolescente , Adulto , Anciano , Anciano de 80 o más Años , Neoplasias Óseas/patología , Niño , Femenino , Humanos , Masculino , Persona de Mediana Edad , Neoplasias de los Músculos/diagnóstico , Neoplasias de los Músculos/cirugía , Estudios Retrospectivos , Sarcoma/diagnóstico , Sarcoma/secundario , Escápula/patología , Músculos Superficiales de la Espalda/diagnóstico por imagen , Músculos Superficiales de la Espalda/fisiopatología , Adulto JovenRESUMEN
OBJECTIVE: Microarray analyses of peripheral blood leukocytes have shown that patients with systemic lupus erythematosus express increased levels of type I interferon (IFN)-regulated genes. In this study we examined gene expression by peripheral blood mononuclear cells (PBMCs) from patients with systemic sclerosis (SSc) to better understand the dysregulation of the immune system in this disease. METHODS: PBMC gene expression was analyzed by microarray and confirmed by real-time polymerase chain reaction (PCR). Surface protein expression of Siglec-1 was analyzed by flow cytometry in PBMCs from healthy control subjects and patients with SSc, and in control PBMCs that were cultured in vitro with Toll-like receptor (TLR) agonists. RESULTS: SSc patients showed increased expression of a cluster of IFN-regulated genes, including Siglec-1 (CD169, sialoadhesin). This result was verified and extended by real-time PCR, showing that a subset of the SSc patients expressed strikingly increased levels of Siglec-1 messenger RNA (mRNA). Flow cytometry of PBMCs from SSc patients and healthy controls showed increased Siglec-1 surface protein expression, which was restricted to CD14+ monocytes. In vitro studies showed that type I IFN and certain TLR agonists, including TLR-7 and TLR-9, induced Siglec-1 mRNA and protein expression. Moreover, TLR induction of surface Siglec-1 was shown to be type I IFN-dependent. Increased numbers of Siglec-1+ cells were observed by immunohistochemistry in the skin of SSc patients compared with healthy controls. CONCLUSION: Increased expression of Siglec-1 in circulating SSc monocytes and tissue macrophages suggests that type I IFN-mediated activation of monocytes occurs in SSc, possibly through TLR activation of IFN secretion. These observations indicate a potential role for type I IFN-activated monocyte/macrophages in the pathogenesis of SSc.
Asunto(s)
Interferón Tipo I/agonistas , Glicoproteínas de Membrana/sangre , Monocitos/metabolismo , Receptores Inmunológicos/sangre , Esclerodermia Sistémica/sangre , Receptores Toll-Like/agonistas , Adolescente , Adulto , Anciano , Biomarcadores/sangre , Estudios de Casos y Controles , Células Cultivadas , Femenino , Regulación de la Expresión Génica , Humanos , Interferón Tipo I/fisiología , Receptores de Lipopolisacáridos/metabolismo , Masculino , Glicoproteínas de Membrana/genética , Análisis por Micromatrices , Persona de Mediana Edad , Monocitos/inmunología , ARN Mensajero/genética , ARN Mensajero/metabolismo , Receptores Inmunológicos/genética , Esclerodermia Sistémica/metabolismo , Lectina 1 Similar a Ig de Unión al Ácido Siálico , Receptores Toll-Like/fisiologíaRESUMEN
Type I interferons (IFN) (IFN-alpha/beta) are recognized as both inhibitors and effectors of autoimmune disease. In multiple sclerosis, IFN-beta therapy appears beneficial, in part, due to its suppression of autoimmune inflammatory Th cell responses. In contrast, in systemic lupus erythematosus (SLE) triggering of plasmacytoid DC (pDC) Toll-like receptors (TLRs) by autoimmune complexes (autoICs) results in circulating type I IFN that appear to promote disease by driving autoantigen presentation and autoantibody production. To investigate how pDC-derived type I IFN might regulate Th cells in SLE, we examined a model in which sustained pDC stimulation by autoICs is mimicked by pretreating normal human PBMC with TLR9 agonist, CpG-A. Subsequently, PBMC Th cells are activated with superantigen, and APC are activated with CD40L. The role of CpG-A/TLR9-induced type I IFN in regulating PBMC is determined by blocking with virus-derived soluble type I IFN receptor, B18R. In summary, pretreatment with either rhIFN-alpha/beta or CpG-A inhibits PBMC secretion of superantigen-induced IFN-gamma and IL-17, and CD40L-induced IL-12p70 and IL-23. B18R prevents these effects. Data indicate that CpG-A-induced type I IFN inhibit IL-12p70-dependent PBMC IFN-gamma secretion by enhancing IL-10. Our results suggest that in SLE, circulating type I IFN may potentially act to inhibit inflammatory cytokine secretion.
Asunto(s)
Citocinas/inmunología , Células Dendríticas/inmunología , Lupus Eritematoso Sistémico/inmunología , Modelos Inmunológicos , Oligodesoxirribonucleótidos/farmacología , Linfocitos T Colaboradores-Inductores/inmunología , Receptor Toll-Like 9/agonistas , Presentación de Antígeno/efectos de los fármacos , Presentación de Antígeno/inmunología , Autoantígenos/inmunología , Ligando de CD40/inmunología , Ligando de CD40/farmacología , Células Cultivadas , Islas de CpG/inmunología , Citocinas/metabolismo , Citocinas/farmacología , Citocinas/uso terapéutico , Células Dendríticas/metabolismo , Células Dendríticas/patología , Humanos , Lupus Eritematoso Sistémico/tratamiento farmacológico , Lupus Eritematoso Sistémico/metabolismo , Activación de Linfocitos/efectos de los fármacos , Activación de Linfocitos/inmunología , Esclerosis Múltiple/dietoterapia , Esclerosis Múltiple/inmunología , Oligodesoxirribonucleótidos/inmunología , Superantígenos/inmunología , Superantígenos/farmacología , Linfocitos T Colaboradores-Inductores/metabolismo , Linfocitos T Colaboradores-Inductores/patología , Receptor Toll-Like 9/inmunologíaRESUMEN
Type I IFNs, IFN-alpha and IFN-beta, are early effectors of innate immune responses against microbes that can also regulate subsequent adaptive immunity by promoting antimicrobial Th1-type responses. In contrast, the ability of IFN-beta to inhibit autoimmune Th1 responses is thought to account for some of the beneficial effects of IFN-beta therapy in the treatment of relapsing remitting multiple sclerosis. To understand the basis of the paradoxical effects of IFN-beta on the expression of Th1-type immune responses, we developed an in vitro model of monocyte-derived dendritic cell (DC)-dependent, human naive Th cell differentiation, in which one can observe both positive and negative effects of IFN-beta on the generation of Th1 cells. In this model we found that the timing of IFN-beta exposure determines whether IFN-beta will have a positive or a negative effect on naive Th cell differentiation into Th1 cells. Specifically, the presence of IFN-beta during TNF-alpha-induced DC maturation strongly augments the capacity of DC to promote the generation of IFN-gamma-secreting Th1 cells. In contrast, exposure to IFN-beta during mature DC-mediated primary stimulation of naive Th cells has the opposite effect, in that it inhibits Th1 cell polarization and promotes the generation of an IL-10-secreting T cell subset. Studies with blocking mAbs and recombinant cytokines indicate that the mechanism by which IFN-beta mediates these contrasting effects on Th1 cell generation is at least in part by differentially regulating DC expression of IL-12 family cytokines (IL-12 and/or IL-23, and IL-27) and IL-18.
Asunto(s)
Células Dendríticas/citología , Células Dendríticas/inmunología , Interferón beta/fisiología , Interleucina-12/biosíntesis , Interleucina-18/biosíntesis , Activación de Linfocitos/inmunología , Linfocitos T Colaboradores-Inductores/inmunología , Células TH1/inmunología , Diferenciación Celular/inmunología , Células Cultivadas , Células Dendríticas/metabolismo , Inhibidores de Crecimiento/antagonistas & inhibidores , Inhibidores de Crecimiento/fisiología , Humanos , Interferón gamma/antagonistas & inhibidores , Interferón gamma/metabolismo , Interleucina-12/fisiología , Interleucina-18/fisiología , Interfase/inmunología , Subunidades de Proteína/fisiología , Linfocitos T Colaboradores-Inductores/citología , Células TH1/citología , Células TH1/metabolismo , Factores de Tiempo , Factor de Necrosis Tumoral alfa/antagonistas & inhibidores , Factor de Necrosis Tumoral alfa/metabolismoRESUMEN
A cell-free biomaterial derived from porcine small intestinal submucosa (SIS) has been used successfully in many models as a xenogeneic scaffolding material without generating immune-mediated inflammatory reactions. We investigated whether this absence of inflammation is due to the presence of porcine transforming growth factor beta (TGF-beta) activity found in SIS that may have immunosuppressive properties on helper T (Th) cell subset activation and differentiation. We used in vitro models for the generation of human Th1 and Th2 cells to investigate the influence of SIS. We found that SIS partially suppressed Th1 cell expansion and secretion of interleukin 12 (IL-12) and interferon gamma (IFN-gamma) in a TGF-beta-dependent manner, but Th1 cell expansion and IFN-gamma secretion could be fully overcome by addition of recombinant IL-12. The suppression by SIS of Th cell activation also involved the induction of Th cell apoptosis. In addition, SIS completely abolished the generation of Th2 cells in vitro, but this effect of SIS was not reversed by neutralizing TGF-beta antibodies. Our results indicate the presence in SIS of factors that can suppress Th cell activation through both the inhibition of IL-12 secretion and the induction of Th cell apoptosis. We established further that these factors include TGF-beta and at least one other factor.
Asunto(s)
Diferenciación Celular/fisiología , Matriz Extracelular/fisiología , Intestino Delgado/metabolismo , Linfocitos T Colaboradores-Inductores/fisiología , Adyuvantes Inmunológicos/farmacología , Animales , Humanos , Interleucina-12/farmacología , Porcinos , Linfocitos T Colaboradores-Inductores/efectos de los fármacos , Factor de Crecimiento Transformador beta/metabolismoRESUMEN
Interferon-beta is thought to provide clinical improvement to multiple sclerosis (MS) patients, in part, through its ability to suppress the generation of IL-12-dependent autoimmune T helper type 1 (Th1) cells by monocyte-derived dendritic cells (DC). We now describe how pre-incubation with 1000 U/ml of IFN-beta differentially regulates expression of multiple IL-12 family members in activated, immature human DC, inhibiting CD40/IFN-gamma-induced p35 and p40 message levels, while enhancing p19 and Epstein-Barr virus-induced gene 3 (EBI3) levels. IFN-beta-mediated inhibition of p40 mRNA and augmentation of p19 mRNA both require de novo protein synthesis. These findings indicate that IFN-beta will be found to have contrasting effects on DC secretion of the various IL-12 family homo- and heterodimers.