RESUMEN
Multiple sclerosis (MS) is a debilitating autoimmune disease affecting over 2.3 million people worldwide, and it is characterized by inflammation and demyelination of nerve cells. The currently available biomarkers for the diagnosis and management of MS have inherent limitations, therefore, additional new biomarkers are needed. We studied the microRNA (miRNA) profile of splenocytes of mice having experimental autoimmune encephalomyelitis (EAE), a model of human MS. A miRNA-microarray analysis revealed increased expression of nine miRNAs (let-7e, miR-23b, miR-31, miR-99b, miR-125a, miR-146b, miR-155, miR-193b, and miR-221) following EAE development. Interestingly, serum levels of miR-99b, miR-125a, and miR-146b were significantly higher in EAE mice compared to normal mice. Bioinformatics analysis revealed the experimentally validated as well as predicted gene targets of specific miRNAs that are important for disease progression in MS. Specifically, we observed inverse correlation in the levels of miR-99b versus LIF, and between miR-125a versus BDNF and LIF. Our results suggest that above-mentioned miRNAs may play a crucial role in the pathogenesis of MS, and that miR-99b, miR-125a, and miR-146b in particular may serve as useful biomarkers for disease activity.
Asunto(s)
Encefalomielitis Autoinmune Experimental/genética , Encefalomielitis Autoinmune Experimental/metabolismo , MicroARNs/genética , MicroARNs/metabolismo , Animales , Biomarcadores/metabolismo , Diferenciación Celular/genética , Diferenciación Celular/fisiología , Humanos , Esclerosis Múltiple/genética , Esclerosis Múltiple/metabolismo , Transducción de Señal/genética , Transducción de Señal/fisiologíaRESUMEN
Rheumatoid arthritis (RA) is a chronic autoimmune disease of the joints affecting about 0.3â»1% of the population in different countries. About 50â»60 percent of RA patients respond to presently used drugs. Moreover, the current biomarkers for RA have inherent limitations. Consequently, there is a need for additional, new biomarkers for monitoring disease activity and responsiveness to therapy of RA patients. We examined the micro-RNA (miRNA) profile of immune (lymphoid) cells of arthritic Lewis rats and arthritic rats treated with celastrol, a natural triterpenoid. Experimental and bioinformatics analyses revealed 8 miRNAs (miR-22, miR-27a, miR-96, miR-142, miR-223, miR-296, miR-298, and miR-451) and their target genes in functional pathways important for RA pathogenesis. Interestingly, 6 of them (miR-22, miR-27a, miR-96, miR-142, miR-223, and miR-296) were further modulated by celastrol treatment. Interestingly, serum levels of miR-142, miR-155, and miR-223 were higher in arthritic versus control rats, whereas miR-212 showed increased expression in celastrol-treated rats compared with arthritic rats or control rats. This is the first study on comprehensive miRNA expression profiling in the adjuvant-induced arthritis (AA) model and it also has revealed new miRNA targets for celastrol in arthritis. We suggest that subsets of the above miRNAs may serve as novel biomarkers of disease activity and therapeutic response in arthritis.
Asunto(s)
Artritis Reumatoide/sangre , Enfermedades Autoinmunes/sangre , MicroARNs/sangre , Animales , Artritis Reumatoide/tratamiento farmacológico , Artritis Reumatoide/genética , Enfermedades Autoinmunes/tratamiento farmacológico , Enfermedades Autoinmunes/genética , Células Cultivadas , Masculino , Medicina Tradicional China , Triterpenos Pentacíclicos , Ratas , Triterpenos/uso terapéuticoRESUMEN
Rheumatoid arthritis (RA) is a chronic, debilitating illness characterized by painful swelling of the joints, inflammation of the synovial lining of the joints, and damage to cartilage and bone. Several anti-inflammatory and disease-modifying drugs are available for RA therapy. However, the prolonged use of these drugs is associated with severe side effects. Furthermore, these drugs are effective only in a proportion of RA patients. Hence, there is a need to search for new therapeutic agents that are effective yet safe. Interestingly, a variety of herbs and other natural products offer a vast resource for such anti-arthritic agents. We discuss here the basic features of RA pathogenesis; the commonly used animal models of RA; the mainstream drugs used for RA; the use of well-characterized natural products possessing anti-arthritic activity; the application of nanoparticles for efficient delivery of such products; and the interplay between dietary products and the host microbiome for maintenance of health and disease induction. We believe that with several advances in the past decade in the characterization and functional studies of natural products, the stage is set for widespread clinical testing and/or use of these products for the treatment of RA and other diseases.
Asunto(s)
Antiinflamatorios/uso terapéutico , Artritis/tratamiento farmacológico , Artritis/inmunología , Enfermedades Autoinmunes/tratamiento farmacológico , Productos Biológicos/uso terapéutico , Animales , Antiinflamatorios/farmacología , Artritis/etiología , Artritis Reumatoide/tratamiento farmacológico , Artritis Reumatoide/etiología , Artritis Reumatoide/patología , Enfermedades Autoinmunes/etiología , Productos Biológicos/farmacología , Biomarcadores , Modelos Animales de Enfermedad , Portadores de Fármacos , Sistemas de Liberación de Medicamentos , Evaluación Preclínica de Medicamentos , Humanos , Mediadores de Inflamación/metabolismo , Microbiota , Terapia Molecular Dirigida , Nanopartículas/química , Preparaciones de Plantas/farmacología , Preparaciones de Plantas/uso terapéuticoRESUMEN
Celastrol is a bioactive compound derived from traditional Chinese medicinal herbs of the Celastraceae family. Celastrol is known to possess anti-inflammatory and anti-oxidant activities. Our studies have highlighted the immunomodulatory attributes of celastrol in adjuvant-induced arthritis (AA), an experimental model of human rheumatoid arthritis (RA). RA is an autoimmune disease characterized by chronic inflammation of the synovial lining of the joints, leading eventually to tissue damage and deformities. Identification of the molecular targets of celastrol such as the NF-κB pathway, MAPK pathway, JAK/STAT pathway and RANKL/OPG pathway has unraveled its strategic checkpoints in controlling arthritic inflammation and tissue damage in AA. The pathological events that are targeted and rectified by celastrol include increased production of pro-inflammatory cytokines; an imbalance between pathogenic T helper 17 and regulatory T cells; enhanced production of chemokines coupled with increased migration of immune cells into the joints; and increased release of mediators of osteoclastic bone damage. Accordingly, celastrol is a promising candidate for further testing in the clinic for RA therapy. Furthermore, the results of other preclinical studies suggest that celastrol might also be beneficial for the treatment of a few other autoimmune diseases besides arthritis.
Asunto(s)
Enfermedades Autoinmunes/etiología , Enfermedades Autoinmunes/metabolismo , Productos Biológicos/farmacología , Inflamación/etiología , Inflamación/metabolismo , Triterpenos/farmacología , Animales , Enfermedades Autoinmunes/diagnóstico , Enfermedades Autoinmunes/tratamiento farmacológico , Autoinmunidad/efectos de los fármacos , Productos Biológicos/química , Productos Biológicos/uso terapéutico , Moléculas de Adhesión Celular/genética , Moléculas de Adhesión Celular/metabolismo , Comunicación Celular/efectos de los fármacos , Comunicación Celular/inmunología , Citocinas/genética , Citocinas/metabolismo , Modelos Animales de Enfermedad , Medicamentos Herbarios Chinos/química , Medicamentos Herbarios Chinos/farmacología , Medicamentos Herbarios Chinos/uso terapéutico , Regulación de la Expresión Génica/efectos de los fármacos , Humanos , Inmunomodulación/efectos de los fármacos , Inflamación/diagnóstico , Inflamación/tratamiento farmacológico , Triterpenos Pentacíclicos , Transducción de Señal/efectos de los fármacos , Subgrupos de Linfocitos T/efectos de los fármacos , Subgrupos de Linfocitos T/inmunología , Subgrupos de Linfocitos T/metabolismo , Triterpenos/química , Triterpenos/uso terapéuticoRESUMEN
Interleukin-27 (IL-27) is a new member of the IL-12 family. It is produced by activated antigen-presenting cells and plays an important role in the regulation of CD4+ T cell differentiation and immune response. IL-27 activates multiple signaling cascades, including the JAK-STAT and p38 MAPK pathways. Several studies have revealed that IL-27 promotes the differentiation of Th1 and Tr1, but inhibits Th2, Th17, and Treg cells. However, a few studies have shown an opposite effect on certain T cell subsets, such as Treg. IL-27 displays both pro- and anti- inflammatory activities in different autoimmune diseases. Here, we have discussed the role of IL-27 in rheumatoid arthritis, multiple sclerosis, colitis, lupus, psoriasis, type 1 diabetes, and uveitis. Most of this information is derived from experimental models of these autoimmune diseases. The mechanistic basis of the dual role of IL-27 in inflammation and autoimmunity is still not fully defined. In general, the pro-/anti-inflammatory activity of IL-27 is influenced by the underlying immune effector pathways, the phase of the disease, the presence or absence of counter-regulatory cytokines/T cell subsets, and the tissue/cell type under study. Despite a spectrum of outcomes in various autoimmune diseases, mostly anti-inflammatory and immunomodulatory effects of IL-27 have been observed in this category of diseases. Accordingly, IL-27 represents a novel, promising target/agent for the treatment of autoimmune diseases.
Asunto(s)
Autoinmunidad , Interleucina-27/inmunología , Animales , Células Presentadoras de Antígenos/inmunología , Linfocitos B/inmunología , Linfocitos T CD4-Positivos/citología , Linfocitos T CD4-Positivos/inmunología , Diferenciación Celular , Humanos , Activación de LinfocitosRESUMEN
Cytokines are the key mediators of inflammation in the course of autoimmune arthritis and other immune-mediated diseases. Uncontrolled production of the pro-inflammatory cytokines such as interferon-γ (IFN-γ), tumor necrosis factor α (TNFα), interleukin-6 (IL-6), and IL-17 can promote autoimmune pathology, whereas anti-inflammatory cytokines including IL-4, IL-10, and IL-27 can help control inflammation and tissue damage. The pro-inflammatory cytokines are the prime targets of the strategies to control rheumatoid arthritis (RA). For example, the neutralization of TNFα, either by engineered anti-cytokine antibodies or by soluble cytokine receptors as decoys, has proven successful in the treatment of RA. The activity of pro-inflammatory cytokines can also be downregulated either by using specific siRNA to inhibit the expression of a particular cytokine or by using small molecule inhibitors of cytokine signaling. Furthermore, the use of anti-inflammatory cytokines or cytokine antagonists delivered via gene therapy has proven to be an effective approach to regulate autoimmunity. Unexpectedly, under certain conditions, TNFα, IFN-γ, and few other cytokines can display anti-inflammatory activities. Increasing awareness of this phenomenon might help develop appropriate regimens to harness or avoid this effect. Furthermore, the relatively newer cytokines such as IL-32, IL-34 and IL-35 are being investigated for their potential role in the pathogenesis and treatment of arthritis.