RESUMO
Liposomes and other types of nanoparticles are increasingly being explored for drug delivery in a variety of diseases. There is an impetus in the field to exploit different types of ligands to functionalize nanoparticles to guide them to the diseased site. Most of this work has been conducted in the cancer field, with relatively much less information from autoimmune diseases, such as rheumatoid arthritis (RA). Furthermore, in RA, many drugs are self-administered by patients subcutaneously (SC). In this context, we have examined the attributes of liposomes functionalized with a novel joint-homing peptide (denoted ART-1) for arthritis therapy using the SC route. This peptide was previously identified following phage peptide library screening in the rat adjuvant arthritis (AA) model. Our results show a distinct effect of this peptide ligand on increasing the zeta potential of liposomes. Furthermore, liposomes injected SC into arthritic rats showed preferential homing to arthritic joints, following a migration profile in vivo similar to that of intravenously injected liposomes, except for a less steep decline after the peak. Finally, liposomal dexamethasone administered SC was more effective than the unpackaged (free) drug in suppressing arthritis progression in rats. We suggest that with suitable modifications, this SC liposomal treatment modality can be adapted for human RA therapy.
Assuntos
Artrite Experimental , Artrite Reumatoide , Humanos , Ratos , Animais , Lipossomos/uso terapêutico , Ligantes , Sistemas de Liberação de Medicamentos , Artrite Reumatoide/tratamento farmacológico , Artrite Experimental/tratamento farmacológico , Peptídeos/uso terapêuticoRESUMO
Inflammation is an integral part of autoimmune diseases, which are caused by dysregulation of the immune system. This dysregulation involves an imbalance between pro-inflammatory versus anti-inflammatory mediators. These mediators include various cytokines and chemokines; defined subsets of T helper/T regulatory cells, M1/M2 macrophages, activating/tolerogenic dendritic cells, and antibody-producing/regulatory B cells. Despite the availability of many anti-inflammatory/immunomodulatory drugs, the severe adverse reactions associated with their long-term use and often their high costs are impediments in effectively controlling the disease process. Accordingly, suitable alternatives are being sought for these conventional drugs. Natural products offer promising adjuncts/alternatives in this regard. The availability of specific compounds isolated from dietary/medicinal plant extracts have permitted rigorous studies on their disease-modulating activities and the mechanisms involved therein. Here, we describe the basic characteristics, mechanisms of action, and preventive/therapeutic applications of 5 well-characterized natural product compounds (Resveratrol, Curcumin, Boswellic acids, Epigallocatechin-3-gallate, and Triptolide). These compounds have been tested extensively in animal models of autoimmunity as well as in limited clinical trials in patients having the corresponding diseases. We have focused our description on predominantly T cell-mediated diseases, such as rheumatoid arthritis, multiple sclerosis, Type 1 diabetes, ulcerative colitis, and psoriasis.
Assuntos
Artrite Reumatoide , Doenças Autoimunes , Produtos Biológicos , Animais , Produtos Biológicos/farmacologia , Produtos Biológicos/uso terapêutico , Inflamação , Artrite Reumatoide/tratamento farmacológico , Anti-Inflamatórios/farmacologia , Anti-Inflamatórios/uso terapêutico , MacrófagosRESUMO
Autoimmunity results from the breakdown of immune tolerance to defined target self antigens. Like any foreign antigen, a self antigen is continuously processed by antigen-presenting cells (APCs) and its epitopes are displayed by the major histocompatibility complex on the cell surface (dominant epitopes). However, this self antigen fails to induce a T cell response as the T cells against its dominant epitopes have been purged in the thymus during negative selection. In contrast, the T cells against poorly processed (cryptic) self epitopes escape tolerance induction in the thymus and make it to the periphery. Such T cells are generally harmless as their cognate epitopes in the periphery are not presented efficiently. But, under conditions of inflammation and immune activation, previously cryptic epitopes can be revealed on the APC surface for activation of ambient T cells. This can initiate autoimmunity in individuals who are susceptible owing to their genetic and environmental constellation. Subsequent waves of enhanced processing of other epitopes on the same or different self antigens then cause "diversification" or "spreading" of the initial T cell response, resulting in propagation of autoimmunity. However, depending on the disease process and the self antigen involved, "epitope spreading" may instead contribute to natural regression of autoimmunity. This landmark conceptual framework developed by Eli Sercarz and his team ties together determinant hierarchy, selection of epitope-specific T cells, and the induction/progression of autoimmunity. I am extremely fortunate to have worked with Eli and to have been a part of this fascinating research endeavor.
Assuntos
Apresentação de Antígeno , Autoantígenos , Autoimunidade , Epitopos , Humanos , Linfócitos TRESUMO
Rheumatoid arthritis (RA) is an autoimmune disease characterized by chronic inflammation of the synovial joints. Inflammation, new blood vessel formation (angiogenesis) and bone resorption (osteoclastogenesis) are three key processes involved in the joint damage and deformities of arthritis. Various gut microbiota-derived metabolites are implicated in RA pathogenesis. However, there is barely any information about the impact of two such metabolites, indole-3-aldehyde (IAld) and indole-3-acetic acid (I3AA), on arthritis-related processes. We conducted a comparative analysis of IAld and I3AA using established cell-based models to understand how they might influence RA pathogenesis. Although structurally similar, the bioactivities of these two metabolites were profoundly different. IAld but not I3AA, inhibited the expression of pro-inflammatory cytokines (IL-1ß and IL-6) in RAW 264.7 (RAW) cells stimulated with heat-killed M. tuberculosis sonicate (Mtb) and lipopolysaccharide (LPS). IAld also exhibited pro-angiogenic activity and pro-osteoclastogenic activity. In contrast, I3AA exhibited anti-angiogenic activity on endothelial cell tube formation but had no effect on osteoclastogenesis. Both IAld and I3AA have been proposed as aryl hydrocarbon receptor (AhR) agonists. Use of CH-223191, an inhibitor of the AhR, suppressed the anti-angiogenic activity of I3AA but failed to mitigate the effects of IAld. Further investigation of the anti-inflammatory activities of IAld and I3AA in LPS-treated RAW cells indicated that inhibition of MyD88-dependent activation of NF-κB and MAPK pathways was not likely involved. Our results suggest that the relative bioavailability of these indole derivatives may differentially impact RA progression and possibly other diseases that share similar cellular processes.
Assuntos
Artrite Reumatoide/imunologia , Doenças Autoimunes/imunologia , Citocinas/imunologia , Ácidos Indolacéticos/imunologia , Indóis/imunologia , Microbiota/imunologia , Animais , Artrite Reumatoide/metabolismo , Doenças Autoimunes/metabolismo , Diferenciação Celular/efeitos dos fármacos , Diferenciação Celular/imunologia , Células Cultivadas , Citocinas/metabolismo , Temperatura Alta , Células Endoteliais da Veia Umbilical Humana/efeitos dos fármacos , Células Endoteliais da Veia Umbilical Humana/imunologia , Células Endoteliais da Veia Umbilical Humana/fisiologia , Humanos , Ácidos Indolacéticos/metabolismo , Ácidos Indolacéticos/farmacologia , Indóis/metabolismo , Indóis/farmacologia , Lipopolissacarídeos/imunologia , Lipopolissacarídeos/farmacologia , Macrófagos/efeitos dos fármacos , Macrófagos/imunologia , Macrófagos/metabolismo , Camundongos , Mycobacterium tuberculosis/imunologia , Mycobacterium tuberculosis/metabolismo , Neovascularização Fisiológica/efeitos dos fármacos , Neovascularização Fisiológica/imunologia , Osteoclastos/citologia , Osteoclastos/efeitos dos fármacos , Osteoclastos/imunologia , Células RAW 264.7RESUMO
Until recently, autoimmune disease research has primarily been focused on elucidating the role of the adaptive immune system. In the past decade or so, the role of the innate immune system in the pathogenesis of autoimmunity has increasingly been realized. Recent findings have elucidated paradigm-shifting concepts, for example, the implications of "trained immunity" and a dysbiotic microbiome in the susceptibility of predisposed individuals to clinical autoimmunity. In addition, the application of modern technologies such as the quantum dot (Qdot) system and 'Omics' (e.g., genomics, proteomics, and metabolomics) data-processing tools has proven fruitful in revisiting mechanisms underlying autoimmune pathogenesis and in identifying novel therapeutic targets. This review highlights recent findings discussed at the American Autoimmune Related Disease Association (AARDA) 2019 colloquium. The findings covering autoimmune diseases and autoinflammatory diseases illustrate how new developments in common innate immune pathways can contribute to the better understanding and management of these immune-mediated disorders.
Assuntos
Doenças Autoimunes/imunologia , Autoimunidade/imunologia , Imunidade Inata/imunologia , Memória Imunológica/imunologia , Inflamação/imunologia , Alarminas/imunologia , Animais , Disbiose/imunologia , Doenças Hereditárias Autoinflamatórias/imunologia , Humanos , Microbiota/imunologia , Moléculas com Motivos Associados a Patógenos/imunologiaRESUMO
Using phage peptide library screening, we identified peptide-encoding phages that selectively home to the inflamed central nervous system (CNS) of mice with experimental autoimmune encephalomyelitis (EAE), a model of human multiple sclerosis (MS). A phage peptide display library encoding cyclic 9-amino-acid random peptides was first screened ex-vivo for binding to the CNS tissue of EAE mice, followed by in vivo screening in the diseased mice. Phage insert sequences that were present at a higher frequency in the CNS of EAE mice than in the normal (control) mice were identified by DNA sequencing. One of the phages selected in this manner, denoted as MS-1, was shown to selectively recognize CNS tissue in EAE mice. Individually cloned phages with this insert preferentially homed to EAE CNS after an intravenous injection. Similarly, systemically-administered fluorescence-labeled synthetic MS-1 peptide showed selective accumulation in the spinal cord of EAE mice. We suggest that peptide MS-1 might be useful for targeted drug delivery to CNS in EAE/MS.
Assuntos
Sistema Nervoso Central/metabolismo , Encefalomielite Autoimune Experimental/metabolismo , Peptídeos/metabolismo , Animais , Encéfalo/metabolismo , Biologia Computacional , Encefalomielite Autoimune Experimental/patologia , Sequenciamento de Nucleotídeos em Larga Escala , Inflamação/metabolismo , Camundongos , Camundongos Endogâmicos C57BL , Biblioteca de Peptídeos , Peptídeos/genética , Medula Espinal/metabolismoRESUMO
Observations in patients with autoimmune diseases and studies in animal models of autoimmunity have revealed that external environmental factors including exposure to microbes and the state of the host gut microbiota can influence susceptibility to autoimmunity and subsequent disease development. Mechanisms underlying these outcomes continue to be elucidated. These include deviation of the cytokine response and imbalance between pathogenic versus regulatory T cell subsets. Furthermore, specific commensal organisms are associated with enhanced severity of arthritis in susceptible individuals, while exposure to certain microbes or helminths can afford protection against this disease. In addition, the role of metabolites (e.g., short-chain fatty acids, tryptophan catabolites), produced either by the microbes themselves or from their action on dietary products, in modulation of arthritis is increasingly being realized. In this context, re-setting of the microbial dysbiosis in RA using prebiotics, probiotics, or fecal microbial transplant is emerging as a promising approach for the prevention and treatment of arthritis. It is hoped that advances in defining the interplay between gut microbiota, dietary products, and bioactive metabolites would help in the development of therapeutic regimen customized for the needs of individual patients in the near future.
Assuntos
Artrite Reumatoide/imunologia , Doenças Autoimunes/imunologia , Autoimunidade/imunologia , Microbioma Gastrointestinal/imunologia , Animais , Disbiose/imunologia , Humanos , Subpopulações de Linfócitos T/imunologiaRESUMO
OBJECTIVE AND DESIGN: Multiple sclerosis (MS) is a debilitating autoimmune disease involving immune dysregulation of the pathogenic T helper 17 (Th17) versus protective T regulatory (Treg) cell subsets, besides other cellular aberrations. Studies on the mechanisms underlying these changes have unraveled the involvement of mitogen-activated protein kinase (MAPK) pathway in the disease process. We describe here a gene expression- and bioinformatics-based study showing that celastrol, a natural triterpenoid, acting via MAPK pathway regulates the downstream genes encoding serum/glucocorticoid regulated kinase 1 (SGK1), which plays a vital role in Th17/Treg differentiation, and brain-derived neurotrophic factor (BDNF), which is a neurotrophic factor, thereby offering protection against experimental autoimmune encephalomyelitis (EAE) in mice. METHODS: We first tested the gene expression profile of splenocytes of EAE mice in response to the disease-related antigen, myelin oligodendrocyte glycoprotein (MOG), and then examined the effect of celastrol on that profile. RESULTS: Interestingly, celastrol reversed the expression of many MOG-induced genes involved in inflammation and immune pathology. The MAPK pathway involving p38MAPK and ERK was identified as one of the mediators of celastrol action. It involved suppression of SGK1 but upregulation of BDNF, which then contributed to protection against EAE. CONCLUSION: Our results not only provide novel insights into disease pathogenesis, but also offer promising therapeutic targets for MS.
Assuntos
Anti-Inflamatórios , Encefalomielite Autoimune Experimental/tratamento farmacológico , Fatores Imunológicos , Triterpenos , Animais , Anti-Inflamatórios/farmacologia , Anti-Inflamatórios/uso terapêutico , Fator Neurotrófico Derivado do Encéfalo/genética , Citocinas/genética , Encefalomielite Autoimune Experimental/genética , Encefalomielite Autoimune Experimental/imunologia , Regulação da Expressão Gênica/efeitos dos fármacos , Proteínas Imediatamente Precoces/genética , Proteínas Imediatamente Precoces/imunologia , Fatores Imunológicos/farmacologia , Fatores Imunológicos/uso terapêutico , Masculino , Camundongos Endogâmicos C57BL , Proteínas Quinases Ativadas por Mitógeno/imunologia , Glicoproteína Mielina-Oligodendrócito , Triterpenos Pentacíclicos , Proteínas Serina-Treonina Quinases/genética , Proteínas Serina-Treonina Quinases/imunologia , Baço/citologia , Linfócitos T/efeitos dos fármacos , Linfócitos T/imunologia , Triterpenos/farmacologia , Triterpenos/uso terapêuticoRESUMO
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.
Assuntos
Artrite Reumatoide/sangue , Doenças Autoimunes/sangue , MicroRNAs/sangue , Animais , Artrite Reumatoide/tratamento farmacológico , Artrite Reumatoide/genética , Doenças Autoimunes/tratamento farmacológico , Doenças Autoimunes/genética , Células Cultivadas , Masculino , Medicina Tradicional Chinesa , Triterpenos Pentacíclicos , Ratos , Triterpenos/uso terapêuticoRESUMO
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.
Assuntos
Encefalomielite Autoimune Experimental/genética , Encefalomielite Autoimune Experimental/metabolismo , MicroRNAs/genética , MicroRNAs/metabolismo , Animais , Biomarcadores/metabolismo , Diferenciação Celular/genética , Diferenciação Celular/fisiologia , Humanos , Esclerose Múltipla/genética , Esclerose Múltipla/metabolismo , Transdução de Sinais/genética , Transdução de Sinais/fisiologiaRESUMO
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.
Assuntos
Anti-Inflamatórios/uso terapêutico , Artrite/tratamento farmacológico , Artrite/imunologia , Doenças Autoimunes/tratamento farmacológico , Produtos Biológicos/uso terapêutico , Animais , Anti-Inflamatórios/farmacologia , Artrite/etiologia , Artrite Reumatoide/tratamento farmacológico , Artrite Reumatoide/etiologia , Artrite Reumatoide/patologia , Doenças Autoimunes/etiologia , Produtos Biológicos/farmacologia , Biomarcadores , Modelos Animais de Doenças , Portadores de Fármacos , Sistemas de Liberação de Medicamentos , Avaliação Pré-Clínica de Medicamentos , Humanos , Mediadores da Inflamação/metabolismo , Microbiota , Terapia de Alvo Molecular , Nanopartículas/química , Preparações de Plantas/farmacologia , Preparações de Plantas/uso terapêuticoRESUMO
Pro-inflammatory cytokines promote autoimmune inflammation and tissue damage, while anti-inflammatory cytokines help resolve inflammation and facilitate tissue repair. Over the past few decades, this general feature of cytokine-mediated events has offered a broad framework to comprehend the pathogenesis of autoimmune and other immune-mediated diseases, and to successfully develop therapeutic approaches for diseases such as rheumatoid arthritis (RA). Anti-tumor necrosis factor-α (TNF-α) therapy is a testimony in support of this endeavor. However, many patients with RA fail to respond to this or other biologics, and some patients may suffer unexpected aggravation of arthritic inflammation or other autoimmune effects. These observations combined with rapid advancements in immunology in regard to newer cytokines and T cell subsets have enforced a re-evaluation of the perceived pathogenic attribute of the pro-inflammatory cytokines. Studies conducted by others and us in experimental models of arthritis involving direct administration of IFN-γ or TNF-α; in vivo neutralization of the cytokine; the use of animals deficient in the cytokine or its receptor; and the impact of the cytokine or anti-cytokine therapy on defined T cell subsets have revealed paradoxical anti-inflammatory and immunoregulatory attributes of these two cytokines. Similar studies in other models of autoimmunity as well as limited studies in arthritis patients have also unveiled the disease-protective effects of these pro-inflammatory cytokines. A major mechanism in this regard is the altered balance between the pathogenic T helper 17 (Th17) and protective T regulatory (Treg) cells in favor of the latter. However, it is essential to consider that this aspect of the pro-inflammatory cytokines is context-dependent such that the dose and timing of intervention, the experimental model of the disease under study, and the differences in individual responsiveness can influence the final outcomes. Nevertheless, the realization that pro-inflammatory cytokines can also be immunoregulatory offers a new perspective in fully understanding the pathogenesis of autoimmune diseases and in designing better therapies for controlling them.
Assuntos
Artrite Reumatoide/imunologia , Doenças Autoimunes/imunologia , Citocinas/imunologia , Imunomodulação , Animais , Doenças Autoimunes/tratamento farmacológico , Doenças Autoimunes/fisiopatologia , Humanos , Inflamação/imunologia , Interferon gama/administração & dosagem , Interferon gama/imunologia , Interferon gama/uso terapêutico , Camundongos , Receptores Tipo II do Fator de Necrose Tumoral/imunologia , Subpopulações de Linfócitos T , Linfócitos T Reguladores/imunologia , Células Th17/imunologia , Fator de Necrose Tumoral alfa/imunologia , Fator de Necrose Tumoral alfa/uso terapêuticoRESUMO
Elevated production of arachidonic acid (AA)-derived pro-inflammatory eicosanoids due to the concerted action of secretory phospholipase A2 group IIA (sPLA2IIA), 5-lipoxygenase (5-LOX) and cyclooxygenase-2 (COX-2) is a common feature of many inflammatory disorders. Hence, modulation of the bioactivity of these 3 enzymes is an important strategy to control inflammation. However, the failure of drugs specific for an individual enzyme (sPLA2IIA-, 5-LOX- or COX-2) and the success of 5-LOX/COX-2 dual inhibitors in effectively controlling inflammation in clinical trials prompted us to evaluate a common inhibitor for sPLA2IIA, 5-LOX and COX-2 enzymes. Celastrol, a quinone methide triterpene, was selected in this regard through molecular docking studies. We provide the first evidence for celastrol's ability to inhibit the catalytic activity of sPLA2IIA, 5-LOX and COX-2 enzymes. Celastrol significantly inhibited the catalytic activity of sPLA2IIA (IC50=6µM) in vitro, which is independent of substrate and calcium concentration. In addition, celastrol inhibited the catalytic activities of 5-LOX (IC50=5µM) and COX-2 (IC50=20µM) in vitro; sPLA2IIA-induced edema and carrageenan-induced edema in mice; and lipopolysaccharide-stimulated production of PGE2 in human neutrophils. Thus, celastrol modulates inflammatory responses by targeting multiple enzymes of AA pathway.
Assuntos
Araquidonato 5-Lipoxigenase/metabolismo , Ácido Araquidônico/metabolismo , Catálise/efeitos dos fármacos , Ciclo-Oxigenase 2/metabolismo , Fosfolipases A2 do Grupo II/metabolismo , Inflamação/tratamento farmacológico , Triterpenos/farmacologia , Animais , Cálcio/metabolismo , Inibidores de Ciclo-Oxigenase 2/farmacologia , Dinoprostona/metabolismo , Edema/metabolismo , Humanos , Inflamação/metabolismo , Lipopolissacarídeos/farmacologia , Inibidores de Lipoxigenase/farmacologia , Masculino , Camundongos , Simulação de Acoplamento Molecular , Neutrófilos/efeitos dos fármacos , Neutrófilos/metabolismo , Triterpenos PentacíclicosRESUMO
Celastrol, a triterpenoid derived from traditional Chinese medicinal plants, has anti-inflammatory, antioxidant, and anticancer activities. Celastrol has shown preventive/therapeutic effects in experimental models of several chronic diseases. These include, chronic inflammatory and autoimmune diseases (e.g., rheumatoid arthritis, multiple sclerosis, systemic lupus erythematosus, inflammatory bowel disease, and psoriasis), neurodegenerative disorders (e.g., Alzheimer's disease, Parkinson's disease, and Amyotrophic lateral sclerosis), atherosclerosis, obesity, Type 2 diabetes, and cancer. Celastrol modulates intricate cellular pathways and networks associated with disease pathology, and it interrupts or redirects the aberrant cellular and molecular events so as to limit disease progression and facilitate recovery, where feasible. The major cell signaling pathways modulated by celastrol include the NF-kB pathway, MAPK pathway, JAK/STAT pathway, PI3K/Akt/mTOR pathway, and antioxidant defense mechanisms. Furthermore, celastrol modulates cell proliferation, apoptosis, proteasome activity, heat-shock protein response, innate and adaptive immune responses, angiogenesis, and bone remodeling. Current understanding of the mechanisms of action of celastrol and information about its disease-modulating activities in experimental models have set the stage for testing celastrol in clinical studies as a therapeutic agent for several chronic human diseases.
Assuntos
Triterpenos/uso terapêutico , Inibidores da Angiogênese/farmacologia , Animais , Antineoplásicos Fitogênicos/farmacologia , Doenças Autoimunes/tratamento farmacológico , Doença Crônica , Humanos , Inflamação/tratamento farmacológico , Triterpenos Pentacíclicos , Transdução de Sinais/efeitos dos fármacos , Triterpenos/farmacologiaRESUMO
Inflammation is an integral component of autoimmune arthritis. The balance of pathogenic T helper 17 (Th17) and protective T regulatory (Treg) cells can influence disease severity, and its resetting offers an attractive approach to control autoimmunity. We determined the frequency of Th17 and Treg in the joints of rats with adjuvant arthritis (AA), a model of rheumatoid arthritis (RA). We also investigated the impact of Celastrol, a bioactive compound from the traditional Chinese medicine Celastrus that can suppress AA, on Th17/Treg balance in the joints. Celastrol treatment reduced Th17 cells but increased Treg in the joints, and it inhibited Th17 differentiation but promoted Treg differentiation in vitro by blocking the activation of pSTAT3. Furthermore, Celastrol limited the production of Th17-differentiating cytokines and chemokines (CCL3, CCL5). Thus, Celastrol suppressed arthritis in part by altering Th17/Treg ratio in inflamed joints, and it should be tested as a potential adjunct/alternative for RA therapy.
Assuntos
Artrite Experimental/imunologia , Artrite Reumatoide , Diferenciação Celular/efeitos dos fármacos , Quimiotaxia/efeitos dos fármacos , Medicamentos de Ervas Chinesas/farmacologia , Linfócitos T Reguladores/efeitos dos fármacos , Células Th17/efeitos dos fármacos , Triterpenos/farmacologia , Animais , Doenças Autoimunes/imunologia , Quimiotaxia/imunologia , Modelos Animais de Doenças , Inflamação/imunologia , Triterpenos Pentacíclicos , Ratos , Linfócitos T Reguladores/imunologia , Células Th17/imunologiaRESUMO
Cytokines serve as key mediators of inflammation and tissue damage in a variety of immune-mediated disorders. The induction, progression, and resolution of inflammation in such disorders are characterized by a dynamic balance between both the pro-inflammatory and anti-inflammatory cytokines as well as the pathogenic and protective T cell subsets. Over the past two decades, the roles of the interleukin-17 (IL-17) /IL-23 axis and the T helper 17 (Th17)/ T regulatory (Treg) cell balance in the pathogenesis of autoimmunity and other inflammatory diseases have extensively been analyzed, and their significance validated. However, these studies, coupled with others devoted to well-established Th1/Th2 cytokines, have unraveled some challenging issues including the dual action of cytokines and the plasticity of T cell subsets. Nevertheless, major positive advances have also been made regarding cytokines and T cell subsets as therapeutic targets/agents. In this special issue, "Cytokines in Immune Pathology and Therapy," leading experts have shared their research work and perspectives on the roles of cytokines in the development and control of immune-mediated diseases. An outline of 14 articles in the first volume is presented here. The second volume will follow soon.
Assuntos
Doenças Autoimunes/imunologia , Autoimunidade , Citocinas/imunologia , Doenças do Sistema Imunitário/imunologia , Subpopulações de Linfócitos T/imunologia , Progressão da Doença , Humanos , Inflamação/imunologia , Interleucina-17 , Interleucina-23/imunologia , Linfócitos T Reguladores/imunologia , Células Th1/imunologia , Células Th17/imunologiaRESUMO
Both genetic and environmental factors contribute to the pathogenesis of inflammatory and autoimmune diseases. The association of specific major histocompatibility complex (MHC) alleles with susceptibility to particular autoimmune diseases is well known, although the mechanistic aspects of this link are not fully unraveled yet. Furthermore, the prevalence of many autoimmune diseases is much higher in females than in males. Intensive efforts are currently being directed to defining the role of sex hormones, the hypothalamicpituitaryadrenal (HPA) axis, and other modifying factors in this sexual dimorphism. Among the environmental factors, emerging understanding of the interplay between the gut microbiota and the immune system has opened up a new frontier of biomedical research with a renewed perspective of host-environment interactions. In addition, besides specific T helper subsets and their cytokine products, the roles of the scavenger receptors, the inflammasome, the newer cytokines of the IL-1 (e.g., IL-33, IL-37) and IL-12 (e.g., IL-27, IL-35) families, and the soluble mediators produced by adipocytes (adipokines) (e.g., leptin, adiponectin) in the pathogenesis of inflammation, autoimmunity, and metabolic disorders are increasingly being realized. In this special issue, "Cytokines in Immune Pathology and Therapy," second volume, leading experts have shared their research work and perspectives on the above-mentioned cytokines and other modulators of inflammation and autoimmunity. An outline of 15 articles in volume 2 is presented here. Volume 1 of this special issue containing 14 articles was published recently.
Assuntos
Imunidade Adaptativa/imunologia , Autoimunidade/imunologia , Citocinas/metabolismo , Imunidade Inata/imunologia , Inflamação/imunologia , Doenças Autoimunes/imunologia , Feminino , Humanos , Fatores Imunológicos/imunologia , Mediadores da Inflamação/imunologia , Complexo Principal de Histocompatibilidade/genética , Complexo Principal de Histocompatibilidade/imunologia , Masculino , Microbiota/imunologia , Fatores SexuaisRESUMO
The T helper (Th) cell subsets are characterized by the type of cytokines produced and the master transcription factor expressed. Th1 cells participate in cell-mediated immunity, whereas Th2 cells promote humoral immunity. Furthermore, the two subsets can control each other. Thereby, Th1-Th2 balance offered a key paradigm in understanding the induction and regulation of immune pathology in autoimmune and other diseases. However, over the past decade, Th17 cells producing interleukin-17 (IL-17) have emerged as the major pathogenic T cell subset in many pathological conditions that were previously attributed to Th1 cells. In addition, the role of CD4+CD25+T regulatory cells (Treg) in controlling the activity of Th17 and other T cell subsets has increasingly been realized. Thereby, examination of the Th17/Treg balance in the course of autoimmune diseases has significantly advanced our understanding of the pathogenesis of these disorders. The differentiation of Th17 and Treg cells from naïve T cells is inter-related and controlled in part by the cytokine milieu. For example, transforming growth factor ß (TGFß) is required for Treg induction, whereas the same cytokine in the presence of IL-6 (or IL-1) promotes the differentiation of Th17. Furthermore, IL-23 plays a role in the maintenance of Th17. Accordingly, novel therapeutic approaches are being developed to target IL-23/IL-17 as well as to modulate the Th17/Treg balance in favor of immune regulation to control autoimmunity.
Assuntos
Artrite Reumatoide/imunologia , Artrite/imunologia , Doenças Autoimunes/imunologia , Interleucina-17/imunologia , Interleucina-23/imunologia , Linfócitos T Reguladores/imunologia , Células Th17/imunologia , Animais , Artrite/fisiopatologia , Artrite/terapia , Artrite Experimental/imunologia , Artrite Experimental/fisiopatologia , Artrite Reumatoide/fisiopatologia , Artrite Reumatoide/terapia , Doenças Autoimunes/fisiopatologia , Doenças Autoimunes/terapia , Humanos , Interleucina-17/metabolismo , Interleucina-23/metabolismo , Linfócitos T Reguladores/patologia , Equilíbrio Th1-Th2 , Células Th17/patologiaRESUMO
Rheumatoid arthritis (RA) is a chronic autoimmune disorder affecting the synovial joints. The currently available drugs for RA are effective only in a proportion of patients and their prolonged use is associated with severe adverse effects. Thus, new anti-arthritic agents are being sought. We tested Pristimerin, a naturally occurring triterpenoid, for its therapeutic activity against rat adjuvant arthritis. Pristimerin effectively inhibited both arthritic inflammation and cartilage and bone damage in the joints. Pristimerin-treated rats exhibited a reduction in the pro-inflammatory cytokines (IL-6, IL-17, IL-18, and IL-23) and the IL-6/IL-17-associated transcription factors (pSTAT3 and ROR-γt), coupled with an increase in the immunomodulatory cytokine IL-10. Also increased was IFN-γ, which can inhibit IL-17 response. In addition, the Th17/Treg ratio was altered in favor of immune suppression and the RANKL/OPG ratio was skewed towards anti-osteoclastogenesis. This is the first report on testing Pristimerin in arthritis. We suggest further evaluation of Pristimerin in RA patients.