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1.
Proc Natl Acad Sci U S A ; 121(33): e2405644121, 2024 Aug 13.
Artigo em Inglês | MEDLINE | ID: mdl-39121163

RESUMO

Nuclear factor kappa B (NFκB) is a pathogenic factor in chronic lymphocytic leukemia (CLL) that is not addressed specifically by current therapies. NFκB is activated by inflammatory factors that stimulate toll-like receptors (TLRs) and receptors for interleukin-1 (IL-1) family members. IL-1 is considered a master regulator of inflammation, and IL-1 receptor signaling is inhibited by the IL-1 receptor antagonist anakinra. These considerations suggested that anakinra might have a role in the treatment of CLL. Consistent with this idea, anakinra inhibited spontaneous and TLR7-mediated activation of the canonical NFκB pathway in CLL cells in vitro. However, CLL cells exhibited only weak signaling responses to IL-1 itself, and anakinra was found to inhibit NFκB along with oxidative stress in an IL-1 receptor-independent manner. Anakinra was then administered with minimal toxicity to 11 previously untreated CLL patients in a phase I dose-escalation trial (NCT04691765). A stereotyped clinical response was observed in all patients. Anakinra lowered blood lymphocytes and lymph node sizes within the first month that were associated with downregulation of NFκB and oxidative stress in the leukemia cells. However, inhibition of NFκB was accompanied by upregulation of type 1 interferon (IFN) signaling, c-MYC-regulated genes and proteins, and loss of the initial clinical response. Anakinra increased IFN signaling and survival of CLL cells in vitro that were, respectively, phenocopied by mitochondrial antioxidants and reversed by IFN receptor blocking antibodies. These observations suggest that anakinra has activity in CLL and may be a useful adjunct for conventional therapies as long as compensatory IFN signaling is blocked at the same time.


Assuntos
Proteína Antagonista do Receptor de Interleucina 1 , Leucemia Linfocítica Crônica de Células B , NF-kappa B , Transdução de Sinais , Idoso , Feminino , Humanos , Masculino , Pessoa de Meia-Idade , Interferons/metabolismo , Proteína Antagonista do Receptor de Interleucina 1/farmacologia , Proteína Antagonista do Receptor de Interleucina 1/uso terapêutico , Leucemia Linfocítica Crônica de Células B/tratamento farmacológico , Leucemia Linfocítica Crônica de Células B/metabolismo , NF-kappa B/metabolismo , Estresse Oxidativo/efeitos dos fármacos , Receptores de Interleucina-1/metabolismo , Receptores de Interleucina-1/antagonistas & inibidores , Transdução de Sinais/efeitos dos fármacos , Receptor 7 Toll-Like/metabolismo , Receptor 7 Toll-Like/antagonistas & inibidores
2.
Adv Exp Med Biol ; 1448: 553-563, 2024.
Artigo em Inglês | MEDLINE | ID: mdl-39117838

RESUMO

Interleukin-1 is a prototypic proinflammatory cytokine that is elevated in cytokine storm syndromes (CSSs), such as secondary hemophagocytic lymphohistiocytosis (sHLH) and macrophage activation syndrome (MAS). IL-1 has many pleotropic and redundant roles in both innate and adaptive immune responses. Blockade of IL-1 with recombinant human interleukin-1 receptor antagonist has shown efficacy in treating CSS. Recently, an IL-1 family member, IL-18, has been demonstrated to be contributory to CSS in autoinflammatory conditions, such as in inflammasomopathies (e.g., NLRC4 mutations). Anecdotally, recombinant IL-18 binding protein can be of benefit in treating IL-18-driven CSS. Lastly, another IL-1 family member, IL-33, has been postulated to contribute to CSS in an animal model of disease. Targeting of IL-1 and related cytokines holds promise in treating a variety of CSS.


Assuntos
Síndrome da Liberação de Citocina , Interleucina-1 , Humanos , Síndrome da Liberação de Citocina/imunologia , Síndrome da Liberação de Citocina/tratamento farmacológico , Interleucina-1/antagonistas & inibidores , Interleucina-1/imunologia , Interleucina-1/genética , Interleucina-1/metabolismo , Animais , Proteína Antagonista do Receptor de Interleucina 1/uso terapêutico , Proteína Antagonista do Receptor de Interleucina 1/genética , Proteínas de Ligação ao Cálcio/genética , Interleucina-18/genética , Interleucina-18/imunologia , Síndrome de Ativação Macrofágica/imunologia , Síndrome de Ativação Macrofágica/tratamento farmacológico , Síndrome de Ativação Macrofágica/genética , Linfo-Histiocitose Hemofagocítica/imunologia , Linfo-Histiocitose Hemofagocítica/genética , Linfo-Histiocitose Hemofagocítica/tratamento farmacológico , Proteínas Adaptadoras de Sinalização CARD
3.
Chem Biodivers ; 21(2): e202301653, 2024 Feb.
Artigo em Inglês | MEDLINE | ID: mdl-38158718

RESUMO

Rheumatoid arthritis (RA) is an autoimmune disease characterized by aggressive cartilage and bone erosion. This work aimed to evaluate the metabolomic profile of Medicago sativa L. (MS) (alfalfa) seeds and explore its therapeutic impact against RA in rats. Arthritis was induced by complete Freund's adjuvant (CFA) and its severity was assessed by the arthritis index. Treatment with MS seeds butanol fraction and interlukin-1 receptor antagonist (IL-1RA) were evaluated through measuring interlukin-1 receptor (IL-1R) type 1 gene expression, interlukin-1 beta (IL-1ß), oxidative stress markers, C-reactive protein (CRP), tumor necrosis factor-alpha (TNF-α), prostaglandin E2 (PGE2), caspase-3 (Cas-3), intracellular adhesion molecule-1 (ICAM-1), DNA fragmentation, and chromosomal damage. Total phenolics/ flavonoids content in the ethyl acetate, butanol fraction and crude extract of MS seeds were estimated. The major identified compounds were Quercetin, Trans-taxifolin, Gallic acid, 7,4'-Dihydroxyflavone, Cinnamic acid, Kudzusaponin SA4, Isorhamnetin 3-O-beta-D-2'',3'',4''-triacetylglucopyranoside, Apigenin, 5,7,4'-Trihydroxy-3'-methoxyflavone, Desmethylxanthohumol, Pantothenic acid, Soyasapogenol E, Malvidin, Helilandin B, Stigmasterol, and Wairol. Treatment with MS seeds butanol fraction and IL-1RA enhanced all the biochemical parameters and the histopathological features of the ankle joint. In conclusion, Trans-taxifolin was isolated for the first time from the genus Medicago. MS butanol fraction seeds extract and IL-1 RA were considered as anti-rheumatic agents.


Assuntos
Artrite Experimental , Artrite Reumatoide , Ratos , Animais , Extratos Vegetais/farmacologia , Extratos Vegetais/uso terapêutico , Medicago sativa/metabolismo , Anti-Inflamatórios/farmacologia , Fitoterapia , Mediadores da Inflamação/metabolismo , Mediadores da Inflamação/uso terapêutico , Proteína Antagonista do Receptor de Interleucina 1/metabolismo , Proteína Antagonista do Receptor de Interleucina 1/uso terapêutico , Artrite Experimental/tratamento farmacológico , Artrite Reumatoide/induzido quimicamente , Artrite Reumatoide/tratamento farmacológico , Interleucinas/metabolismo , Interleucinas/uso terapêutico , Fator de Necrose Tumoral alfa/metabolismo , Estresse Oxidativo , Butanóis , Citocinas/metabolismo
4.
Eur J Haematol ; 111(3): 458-476, 2023 Sep.
Artigo em Inglês | MEDLINE | ID: mdl-37344166

RESUMO

BACKGROUND: Haemophagocytic lymphohistiocytosis (HLH) or macrophage activation syndrome (MAS) has a potentially high mortality rate. Anakinra, an interleukin-1 receptor antagonist, is now recommended early in HLH/MAS, with intravenous (IV) use proposed in critically unwell patients. This systematic review establishes the literature relating to IV anakinra in secondary HLH/MAS (sHLH/MAS). METHODS: We screened Embase, PubMed, and Medline, including all reports of IV anakinra for HLH or MAS. We extracted age, HLH/MAS trigger, continuous infusion or bolus dosing, and survival. RESULTS: Twenty-nine case reports/series identified 87 patients (median age 22 years, range 22 months to 84 years), all with sHLH. Amongst identifiable triggers, 43% were systemic infection, 33% rheumatological, 9% oncological. Children had predominantly a rheumatological trigger (48%), whilst adults were more commonly infection-driven (50%). Overall, rheumatologically triggered disease showed greater survival (83.3%), particularly compared with oncological triggers (42.9%). Children had a greater survival, particularly under 10 years (83%, vs. adults, 63%). CONCLUSIONS: Despite IV anakinra recipients likely to be critically unwell, this cohort had similar disease triggers and survival compared to large historical cohorts, and enhances awareness of age and trigger-specific survival patterns. IV anakinra had a wide therapeutic dosing range and tolerability, regardless of trigger, demonstrating substantial utility in severe sHLH/MAS.


Assuntos
Linfo-Histiocitose Hemofagocítica , Síndrome de Ativação Macrofágica , Doenças Reumáticas , Sepse , Adulto , Criança , Humanos , Lactente , Linfo-Histiocitose Hemofagocítica/diagnóstico , Linfo-Histiocitose Hemofagocítica/tratamento farmacológico , Linfo-Histiocitose Hemofagocítica/etiologia , Síndrome de Ativação Macrofágica/diagnóstico , Síndrome de Ativação Macrofágica/tratamento farmacológico , Síndrome de Ativação Macrofágica/etiologia , Proteína Antagonista do Receptor de Interleucina 1/efeitos adversos , Sepse/complicações , Doenças Reumáticas/complicações , Doenças Reumáticas/tratamento farmacológico
5.
Int Endod J ; 56(1): 27-38, 2023 Jan.
Artigo em Inglês | MEDLINE | ID: mdl-36190353

RESUMO

AIMS: Lipopolysaccharides (LPS)-activated human dental pulp stem cells (hDPSCs) and macrophage co-cultures showed downregulated TNF-α secretion that is modulated by hDPSCs through IDO axis, whereas the secretory levels of IL-1ß remained unchanged. Therefore, sustained production of IL-1ß could contribute to progressive dental pulp inflammation. However, the role of interleukin-1 receptor antagonist (IL-1RA) in downregulating the secretion of IL-1ß and TNF-α in LPS-activated M0/M1/M2 macrophage and hDPSCs co-culture has not been studied yet. Therefore, the aim of the present study was to determine the immunomodulatory role of blocking IL-1 receptors in DPSCs macrophage co-culture activated with LPS. METHODOLOGY: Human monocytic cell line THP-1 was polarized to M0, M1 and M2 macrophages and co-cultured with hDPSCs. The viability of the co-cultured cells was assessed by apoptosis assay. Co-cultures were activated with LPS followed by the assessment of gene expression and protein levels of IL-1ß and TNF-α with and without IL-1RA blocking via qRT-PCR and cytokine flex assay by flow cytometry. Data from three separate experiments were analysed using one-way anova followed by Tukey's post hoc test and a p-value of <.05 was considered statistically significant. RESULTS: THP-1-derived M0, M1 and M2 macrophages co-cultured with hDPSCs showed spindle and round-shaped cells, with >90% viability when assessed by apoptosis assay. Inflammatory TNF-α and IL-1ß profiles in stimulated co-cultures showed upregulated IL-1ß, whereas TNF-α was downregulated (p < .05). Anti-inflammatory gene expression levels of IL-10 and TGF-ß were downregulated (p < .05). Blocking with IL-1RA resulted in a remarkable decrease in IL-1ß at the gene expression and protein production levels whilst TNF-α levels remained low (p < .05). Levels of anti-inflammatory cytokine IL-10 showed no significant difference. CONCLUSION: Blocking the IL-1 receptor in hDPSCs and macrophage (M0, M1, M2) co-cultures activated with LPS resulted in downregulation of inflammatory cytokines IL-1ß and TNF-α. These findings highlight the immunomodulatory effect of IL-1RA in inflammatory conditions of dental pulp infections.


Assuntos
Proteína Antagonista do Receptor de Interleucina 1 , Lipopolissacarídeos , Humanos , Proteína Antagonista do Receptor de Interleucina 1/farmacologia , Lipopolissacarídeos/farmacologia , Técnicas de Cocultura , Interleucina-10 , Fator de Necrose Tumoral alfa , Polpa Dentária , Macrófagos , Anti-Inflamatórios , Células-Tronco
6.
J Allergy Clin Immunol ; 149(1): 358-368, 2022 01.
Artigo em Inglês | MEDLINE | ID: mdl-33974929

RESUMO

BACKGROUND: IgG4-related disease (IgG4-RD) is a fibroinflammatory condition involving loss of B-cell tolerance and production of autoantibodies. However, the relevant targets and role of these aberrant humoral immune responses are not defined. OBJECTIVE: Our aim was to identify novel autoantibodies and autoantigen targets that promote pathogenic responses in IgG4-RD. METHODS: We sequenced plasmablast antibody repertoires in patients with IgG4-RD. Representative mAbs were expressed and their specificities characterized by using cytokine microarrays. The role of anti-IL-1 receptor antagonist (IL-1RA) autoantibodies was investigated by using in vitro assays. RESULTS: We identified strong reactivity against human IL-1RA by using a clonally expanded plasmablast-derived mAb from a patient with IgG4-RD. Plasma from patients with IgG4-RD exhibited elevated levels of reactivity against IL-1RA compared with plasma from the controls and neutralized IL-1RA activity, resulting in inflammatory and fibrotic mediator production in vitro. IL-1RA was detected in lesional tissues from patients with IgG4-RD. Patients with anti-IL-1RA autoantibodies of the IgG4 subclass had greater numbers of organs affected than did those without anti-IL-1RA autoantibodies. Peptide analyses identified IL-1RA epitopes targeted by anti-IL-1RA antibodies at sites near the IL-1RA/IL-1R interface. Serum from patients with systemic lupus erythematosus (SLE) and rheumatoid arthritis (RA) also had elevated levels of anti-IL-1RA autoantibodies compared with those of the controls. CONCLUSION: A subset of patients with IgG4-RD have anti-IL-1RA autoantibodies, which promote proinflammatory and profibrotic meditator production via IL-1RA neutralization. These findings support a novel immunologic mechanism underlying the pathogenesis of IgG4-RD. Anti-IL-1RA autoantibodies are also present in a subset of patients with SLE and RA, suggesting a potential common pathway in multiple autoimmune diseases.


Assuntos
Anticorpos Neutralizantes/sangue , Autoanticorpos/sangue , Fibrose/imunologia , Imunoglobulina G/imunologia , Receptores de Interleucina-1/antagonistas & inibidores , Adolescente , Adulto , Idoso , Idoso de 80 Anos ou mais , Artrite Reumatoide/sangue , Artrite Reumatoide/imunologia , Autoantígenos , Criança , Pré-Escolar , Feminino , Fibrose/sangue , Humanos , Imunoglobulina G/sangue , Lúpus Eritematoso Sistêmico/sangue , Lúpus Eritematoso Sistêmico/imunologia , Masculino , Pessoa de Meia-Idade , Esclerose Múltipla/sangue , Esclerose Múltipla/imunologia , Receptores de Interleucina-1/imunologia , Adulto Jovem
7.
J Clin Immunol ; 42(6): 1330-1341, 2022 08.
Artigo em Inglês | MEDLINE | ID: mdl-35699824

RESUMO

PURPOSE: A recent phase II open-label study of the interleukin 1 (IL-1) receptor antagonist (IL-1Ra) anakinra in treating IVIG-resistant Kawasaki disease (KD) patients reported promising results. Here, we aimed to characterize the immunological impact of IL-1 blockade in this unique study population. METHODS: Patients' and control sera and supernatants of cells (whole blood, neutrophils, coronary artery endothelial cells) stimulated with recombinant IL-1ß were analyzed for single or multiple marker (n = 22) expression by ELISA or multiplexed bead array assay. Data were analyzed using unsupervised hierarchical clustering, multiple correlation, and multi-comparison statistics and were compared to retrospective analyses of KD transcriptomics. RESULTS: Inflammation in IVIG-resistant KD (n = 16) is hallmarked by over-expression of innate immune mediators (particularly IL-6 > CXCL10 > S100A12 > IL-1Ra). Those as well as levels of immune or endothelial cell activation markers (sICAM-1, sVCAM-1) declined most significantly in course of anakinra treatment. Prior as well as following IL-1R blockade, over-expression of leucine-rich-α2-glycoprotein 1 (LRG1) associated best with remnant inflammatory activity and the necessity to escalate anakinra dosage and separated inflammatory KD patients from sJIA-MAS (n = 13) and MIS-C (n = 4). Protein as well as retrospective gene expression analyses indicated tight association of LRG1 with IL-1ß signaling and neutrophilia, while particularly neutrophil stimulation with recombinant IL-1ß resulted in concentration-dependent LRG1 release. CONCLUSION: Our study identifies LRG1 as known trigger of endothelial activation and cardiac re-modeling to associate with IL-1ß signaling in KD. Besides a potential patho-mechanistic implication of these findings, our data suggest blood leukocyte and neutrophil counts to best predict response to IL-1Ra treatment in IVIG-resistant KD.


Assuntos
Síndrome de Linfonodos Mucocutâneos , Biomarcadores , Criança , Células Endoteliais/metabolismo , Glicoproteínas/metabolismo , Glicoproteínas/uso terapêutico , Humanos , Imunoglobulinas Intravenosas/uso terapêutico , Proteína Antagonista do Receptor de Interleucina 1/uso terapêutico , Interleucina-1beta , Interleucina-6/metabolismo , Leucina/uso terapêutico , Síndrome de Linfonodos Mucocutâneos/complicações , Síndrome de Linfonodos Mucocutâneos/tratamento farmacológico , Estudos Retrospectivos , Proteína S100A12
8.
Cytokine ; 153: 155851, 2022 05.
Artigo em Inglês | MEDLINE | ID: mdl-35272075

RESUMO

INTRODUCTION: The IL-1 receptor antagonist (IL-1Ra or IL-1RN) is a member of the IL-1 superfamily that functions as a competitive antagonist of the cell surface IL-1 receptor, thereby regulating various immune and inflammatory responses related to IL-1. IL-1 induces tumor growth and metastasis, while IL-1RN inhibits the secretion of IL-1α and IL-6 in cancer cells. Interleukin-4 (IL-4) is a potent anti-inflammatory cytokine, can be secreted by many types of immune cells. In this study, it was aimed to reveal the effects of IL-1RN and IL-4 VNTR polymorphisms on disease development and survival in patients with multiple myeloma (MM). MATERIAL AND METHODS: In this study, 244 patients diagnosed with MM in hematology clinic between January 2010 and January 2021, and 179 healthy individuals were included. The genotypes of the IL-1RN VNTR polymorphism were statistically compared before treatment between patients having undergone stem cell transplantation and healthy controls, as were the genotypes of IL-4 VNTR polymorphism. Additionally, the statistically significant effects of these genotypes on survival were examined. RESULTS: In the statistical analysis of the distribution of IL-1RN VNTR gene variants, 1/3 and 1/4 genotypes were found to be significantly higher in patients with MM compared to the healthy controls (p = 0.035). There was no significant difference between the MM patient group and the healthy controls in terms of IL-4 VNTR genotype distribution. PFS of patients with IL-1RN VNTR non-2-allele carrier genotypes was significantly shorter, but no significant effect was found on OS (p = 0.03, p = 0.786, respectively). Patients with IL-1RN VNTR non-2-allele carrier genotypes had 1.718-fold increased risk of shorter PFS. CONCLUSIONS: In conclusion, with this study, the effects of IL-1RN VNTR and IL-4 VNTR polymorphisms on MM were evaluated for the first time in the literature. This study will shed light on ones on cytokine-MM relationship and epigenetic mechanisms.


Assuntos
Interleucina-4 , Mieloma Múltiplo , Predisposição Genética para Doença , Genótipo , Humanos , Proteína Antagonista do Receptor de Interleucina 1/genética , Interleucina-1/genética , Interleucina-4/genética , Repetições Minissatélites/genética , Mieloma Múltiplo/genética , Polimorfismo Genético/genética , Receptores de Interleucina-1/genética
9.
J Neuroinflammation ; 18(1): 15, 2021 Jan 06.
Artigo em Inglês | MEDLINE | ID: mdl-33407641

RESUMO

BACKGROUND: The acute phase response (APR) to CNS insults contributes to the overall magnitude and nature of the systemic inflammatory response. Aspects of this response are thought to drive secondary inflammatory pathology at the lesion site, and suppression of the APR can therefore afford some neuroprotection. In this study, we examined the APR in a mouse model of traumatic spinal cord injury (SCI), along with its relationship to neutrophil recruitment during the immediate aftermath of the insult. We specifically investigated the effect of IL-1 receptor antagonist (IL-1RA) administration on the APR and leukocyte recruitment to the injured spinal cord. METHODS: Adult female C57BL/6 mice underwent either a 70kD contusive SCI, or sham surgery, and tissue was collected at 2, 6, 12, and 24 hours post-operation. For IL-1RA experiments, SCI mice received two intraperitoneal injections of human IL-1RA (100mg/kg), or saline as control, immediately following, and 5 hours after impact, and animals were sacrificed 6 hours later. Blood, spleen, liver and spinal cord were collected to study markers of central and peripheral inflammation by flow cytometry, immunohistochemistry and qPCR. Results were analysed by two-way ANOVA or student's t-test, as appropriate. RESULTS: SCI induced a robust APR, hallmarked by elevated hepatic expression of pro-inflammatory marker genes and a significantly increased neutrophil presence in the blood, liver and spleen of these animals, as early as 2 hours after injury. This peripheral response preceded significant neutrophil infiltration of the spinal cord, which peaked 24 hours post-SCI. Although expression of IL-1RA was also induced in the liver following SCI, its response was delayed compared to IL-1ß. Exogenous administration of IL-1RA during this putative therapeutic window was able to suppress the hepatic APR, as evidenced by a reduction in CXCL1 and SAA-2 expression as well as a significant decrease in neutrophil infiltration in both the liver and the injured spinal cord itself. CONCLUSIONS: Our data indicate that peripheral administration of IL-1RA can attenuate the APR which in turn reduces immune cell infiltration at the spinal cord lesion site. We propose IL-1RA treatment as a viable therapeutic strategy to minimise the harmful effects of SCI-induced inflammation.


Assuntos
Reação de Fase Aguda/imunologia , Reação de Fase Aguda/prevenção & controle , Proteína Antagonista do Receptor de Interleucina 1/administração & dosagem , Traumatismos da Medula Espinal/tratamento farmacológico , Traumatismos da Medula Espinal/imunologia , Reação de Fase Aguda/metabolismo , Animais , Feminino , Humanos , Imunidade Celular/efeitos dos fármacos , Imunidade Celular/fisiologia , Inflamação/imunologia , Inflamação/metabolismo , Inflamação/prevenção & controle , Injeções Intraperitoneais , Camundongos , Camundongos Endogâmicos C57BL , Traumatismos da Medula Espinal/metabolismo , Vértebras Torácicas/lesões , Resultado do Tratamento
10.
Cell Immunol ; 361: 104281, 2021 03.
Artigo em Inglês | MEDLINE | ID: mdl-33453508

RESUMO

Dendritic cells (DCs) mature upon an inflammatory trigger. However, an inflammatory trigger can lead to a semi-mature phenotype, allowing DCs to evoke tolerance and expedite the resolution of inflammation. This duality likely involves context-dependent modulation of inflammatory signaling. Human α1-antitrypsin (hAAT) promotes semimature DCs. We examined changes in a wide spectrum of signaling cascades in stimulated murine bone marrow-derived cells with hAAT. Upon stimulation by IL-1ß+IFNγ, hAAT-treated cells depicted an attenuated calcium flux. Disrupting PKA or NF-κB pathways revoked only some hAAT-mediated outcomes. hAAT-treated cells exhibited a distict pattern of kinase phosphorylation. hAAT-mediated increase in Treg cells in-vitro required intact inflammatory signaling pathways. Taken together, hAAT appears to require a stimulated microenvironment to promote inflammatory resolution, setting it aside from classical anti-inflammatory agents. Further studies are required to identify the specific molecules targeted by hAAT that mediate these and other outcomes.


Assuntos
Células Dendríticas/metabolismo , Transdução de Sinais/efeitos dos fármacos , alfa 1-Antitripsina/farmacologia , Animais , Medula Óssea/metabolismo , Células da Medula Óssea/metabolismo , Cálcio/metabolismo , Células Cultivadas , Tolerância Imunológica/imunologia , Inflamação/metabolismo , Interleucina-1/imunologia , Camundongos , Camundongos Endogâmicos C57BL , NF-kappa B/metabolismo , Receptores CCR7/imunologia , Receptores CCR7/metabolismo , Receptores de Interleucina-1/antagonistas & inibidores , Receptores de Interleucina-1/imunologia , Transdução de Sinais/imunologia , Linfócitos T Reguladores/imunologia , alfa 1-Antitripsina/metabolismo
11.
Biomarkers ; 26(8): 788-807, 2021 Dec.
Artigo em Inglês | MEDLINE | ID: mdl-34704882

RESUMO

CONTEXT: Rheumatoid arthritis (RA) is a chronic, progressive autoimmune disease characterized by aggressive and systematic polyarthritis. OBJECTIVE: The present study aimed to isolate and identify the phenolic constituents in Brassica oleracea L. (Brassicaceae) seeds methanolic extract and evaluates its effect against rheumatoid arthritis in rats referring to the new therapy; interleukin-1 receptor antagonist (IL-1RA). MATERIALS AND METHODS: The GC/MS profiling of the plant was determined. Arthritis induction was done using complete Freund's adjuvant. Arthritis severity was assessed by percentage of edema and arthritis index. IL-1 receptor type I gene expression, interleukin-1ß (IL-1ß), oxidative stress markers, protein content, inflammatory mediators, prostaglandin-E2 (PGE2), genetic abnormalities and the histopathological features of ankle joint were evaluated. RESULTS: For the first time twelve phenolic compounds had been isolated from the seeds extract. Treatment with extract and IL-1RA improved the tested parameters by variable degrees. CONCLUSIONS: RA is an irreversible disease, where its severity increases with the time of induction. Brassica oleracea L. seeds extract is considered as a promising anti-arthritis agent. IL-1 RA may be considered as an unusual therapeutic agent for RA disease. More studies are needed to consider the seeds extract as a nutraceutical agent and to recommend IL-1RA as a new RA drug.


Assuntos
Artrite Experimental/prevenção & controle , Artrite Reumatoide/prevenção & controle , Brassica/química , Mediadores da Inflamação/metabolismo , Compostos Fitoquímicos/farmacologia , Receptores Tipo I de Interleucina-1/antagonistas & inibidores , Sementes/química , Animais , Artrite Experimental/induzido quimicamente , Artrite Experimental/metabolismo , Artrite Reumatoide/genética , Artrite Reumatoide/metabolismo , Biomarcadores/sangue , Adjuvante de Freund , Regulação da Expressão Gênica/efeitos dos fármacos , Humanos , Proteína Antagonista do Receptor de Interleucina 1/metabolismo , Interleucina-1beta/metabolismo , Masculino , Estrutura Molecular , Estresse Oxidativo/efeitos dos fármacos , Compostos Fitoquímicos/química , Fitoterapia/métodos , Extratos Vegetais/química , Extratos Vegetais/farmacologia , Ratos Wistar , Receptores Tipo I de Interleucina-1/genética , Receptores Tipo I de Interleucina-1/metabolismo , Transdução de Sinais/efeitos dos fármacos
12.
Int J Mol Sci ; 22(12)2021 Jun 11.
Artigo em Inglês | MEDLINE | ID: mdl-34208064

RESUMO

Febrile Infection-Related Epilepsy Syndrome (FIRES) is a unique catastrophic epilepsy syndrome, and the development of drug-resistant epilepsy (DRE) is inevitable. Recently, anakinra, an interleukin-1 receptor antagonist (IL-1RA), has been increasingly used to treat DRE due to its potent anticonvulsant activity. We here summarized its effects in 38 patients (32 patients with FIRES and six with DRE). Of the 22 patients with FIRES, 16 (73%) had at least short-term seizure control 1 week after starting anakinra, while the remaining six suspected anakinra-refractory cases were male and had poor prognoses. Due to the small sample size, an explanation for anakinra refractoriness was not evident. In all DRE patients, seizures disappeared or improved, and cognitive function improved in five of the six patients following treatment. Patients showed no serious side effects, although drug reactions with eosinophilia and systemic symptoms, cytopenia, and infections were observed. Thus, anakinra has led to a marked improvement in some cases, and functional deficiency of IL-1RA was indicated, supporting a direct mechanism for its therapeutic effect. This review first discusses the effectiveness of anakinra for intractable epileptic syndromes. Anakinra could become a new tool for intractable epilepsy treatment. However, it does not currently have a solid evidence base.


Assuntos
Encéfalo/patologia , Epilepsia Resistente a Medicamentos/tratamento farmacológico , Inflamação/tratamento farmacológico , Proteína Antagonista do Receptor de Interleucina 1/uso terapêutico , Humanos , Inflamação/patologia , Proteína Antagonista do Receptor de Interleucina 1/administração & dosagem
13.
Int J Mol Sci ; 22(15)2021 Jul 27.
Artigo em Inglês | MEDLINE | ID: mdl-34360771

RESUMO

Inflammation plays a central role in the pathogenesis of knee PTOA after knee trauma. While a comprehensive therapy capable of preventing or delaying post-traumatic osteoarthritis (PTOA) progression after knee joint injury does not yet clinically exist, current literature suggests that certain aspects of early post-traumatic pathology of the knee joint may be prevented or delayed by anti-inflammatory therapeutic interventions. We discuss multifaceted therapeutic approaches that may be capable of effectively reducing the continuous cycle of inflammation and concomitant processes that lead to cartilage degradation as well as those that can simultaneously promote intrinsic repair processes. Within this context, we focus on early disease prevention, the optimal timeframe of treatment and possible long-lasting sustained delivery local modes of treatments that could prevent knee joint-associated PTOA symptoms. Specifically, we identify anti-inflammatory candidates that are not only anti-inflammatory but also anti-degenerative, anti-apoptotic and pro-regenerative.


Assuntos
Anti-Inflamatórios/uso terapêutico , Traumatismos do Joelho , Osteoartrite do Joelho , Animais , Cartilagem Articular/metabolismo , Cartilagem Articular/patologia , Humanos , Traumatismos do Joelho/complicações , Traumatismos do Joelho/tratamento farmacológico , Traumatismos do Joelho/metabolismo , Traumatismos do Joelho/patologia , Articulação do Joelho/metabolismo , Articulação do Joelho/patologia , Osteoartrite do Joelho/tratamento farmacológico , Osteoartrite do Joelho/etiologia , Osteoartrite do Joelho/metabolismo , Osteoartrite do Joelho/patologia
14.
J Allergy Clin Immunol ; 143(3): 1077-1086.e10, 2019 03.
Artigo em Inglês | MEDLINE | ID: mdl-30529452

RESUMO

BACKGROUND: Long-term follow-up of allergen-specific B cells in terms of immunoglobulin isotype expression, plasmablast differentiation, and regulatory B (Breg) cell development during allergen-specific immunotherapy (AIT) has not been reported. OBJECTIVE: Allergen-specific B-cell responses during 2 years of house dust mite AIT were compared between responder and nonresponder patients. METHODS: B cells specific for Der p 1 were detected by using the fluorochrome-labeled allergen method. The frequency of IgA-, IgG1- and IgG4-switched Der p 1-specific B cells, plasmablasts, and IL-10- and IL-1 receptor antagonist (IL-1RA)-producing Breg cells were investigated and correlated to clinical response to AIT. RESULTS: Sixteen of 25 patients completed the 2-year study. Eleven responder patients showed a successful response to AIT, as measured by a decrease in symptom-medication scores from 13.23 ± 0.28 to 2.45 ± 0.24 (P = .001) and a decrease in skin prick test reactivity to house dust mite from 7.0 ± 1.3 to 2.7 ± 0.5 mm (P = .001). IgG4+ and IgA+ Der p 1-specific B cells showed a significant increase after AIT, with a significantly greater frequency in responders compared with nonresponders in the IgG4+ but not the IgA+ fraction. The frequency of plasmablasts and IL-10- and/or IL-1RA-producing Breg cells was greater among responders compared with nonresponders after 2 years. The increased frequency of Der p 1-specific IgG4+ B cells, plasmablasts, and IL-10+ and dual-positive IL-10+IL-1RA+ Breg cells significantly correlated with improved clinical symptoms over the course of AIT. CONCLUSION: Allergen-specific B cells in patients responding to AIT are characterized by increased numbers of IgA- and IgG4-expressing Der p 1-specific B cells, plasmablasts, and IL-10+ and/or IL-1RA+ Breg cells.


Assuntos
Alérgenos/imunologia , Antígenos de Dermatophagoides/imunologia , Proteínas de Artrópodes/imunologia , Linfócitos B/imunologia , Cisteína Endopeptidases/imunologia , Dessensibilização Imunológica , Hipersensibilidade/terapia , Tolerância Imunológica , Adolescente , Adulto , Feminino , Humanos , Hipersensibilidade/imunologia , Masculino , Pessoa de Meia-Idade , Adulto Jovem
15.
Rheumatology (Oxford) ; 58(Suppl 6): vi9-vi22, 2019 11 01.
Artigo em Inglês | MEDLINE | ID: mdl-31769856

RESUMO

Systemic juvenile idiopathic arthritis and adult-onset Still's disease are rare autoinflammatory disorders with common features, supporting the recognition of these being one disease-Still's disease-with different ages of onset. Anakinra was recently approved by the European Medicines Agency for Still's disease. In this review we discuss the reasoning for considering Still's disease as one disease and present anakinra efficacy and safety based on the available literature. The analysis of 27 studies showed that response to anakinra in Still's disease was remarkable, with clinically inactive disease or the equivalent reported for 23-100% of patients. Glucocorticoid reduction and/or stoppage was reported universally across the studies. In studies on paediatric patients where anakinra was used early or as first-line treatment, clinically inactive disease and successful anakinra tapering/stopping occurred in >50% of patients. Overall, current data support targeted therapy with anakinra in Still's disease since it improves clinical outcome, especially if initiated early in the disease course.


Assuntos
Antirreumáticos/uso terapêutico , Artrite Juvenil/tratamento farmacológico , Proteína Antagonista do Receptor de Interleucina 1/uso terapêutico , Doença de Still de Início Tardio/tratamento farmacológico , Adulto , Artrite Juvenil/diagnóstico , Criança , Relação Dose-Resposta a Droga , Esquema de Medicação , Aprovação de Drogas , Feminino , Humanos , Proteína Antagonista do Receptor de Interleucina 1/efeitos adversos , Masculino , Segurança do Paciente , Índice de Gravidade de Doença , Resultado do Tratamento
16.
Cytokine ; 123: 154772, 2019 11.
Artigo em Inglês | MEDLINE | ID: mdl-31299415

RESUMO

The NLRP3 inflammasome, IL-1ß release and pyroptosis (cell lysis) have recently been proposed to be essential for the progression of urinary tract infection (UTI) and elimination of intracellular bacterial niches. However, the effects of IL-1R antagonist (IL-1RA) on immune responses during UTI, except for its ability to disrupt IL-1ß signalling, are not well understood. The aim of this study was to investigate the role of IL-1RA in UPEC colonization of bladder epithelial cells and the subsequent host inflammatory response. Human bladder epithelial cells (5637) and CRISPR/Cas9 generated NLRP3 and caspase-1 knockdown cells and IL-1RA knockout cells were stimulated with the UPEC isolate CFT073. The results showed that the UPEC virulence factor α-hemolysin is essential for IL-1RA release, and that the inflammasome-associated proteins caspase-1 and NLRP3 affect the release of IL-1RA. IL-1RA deficient cells showed a reduced adherence and invasion by CFT073 compared to wild-type cells, suggesting that IL-1RA may oppose mechanisms that protects against bacterial colonization. A targeted protein analysis of inflammation-related proteins showed that the basal expression of 23 proteins and the UPEC-induced expression of 10 proteins were significantly altered in IL-1RA deficient bladder epithelial cells compared to Cas9 control cells. This suggests that IL-1RA has a broad effect on the inflammatory response in bladder epithelial cells.


Assuntos
Células Epiteliais/imunologia , Infecções por Escherichia coli/imunologia , Inflamassomos/imunologia , Proteína Antagonista do Receptor de Interleucina 1/imunologia , Bexiga Urinária/imunologia , Infecções Urinárias/imunologia , Escherichia coli Uropatogênica/imunologia , Linhagem Celular , Células Epiteliais/microbiologia , Infecções por Escherichia coli/patologia , Humanos , Bexiga Urinária/microbiologia , Bexiga Urinária/patologia , Infecções Urinárias/microbiologia , Infecções Urinárias/patologia
17.
Clin Transplant ; 33(10): e13699, 2019 10.
Artigo em Inglês | MEDLINE | ID: mdl-31437316

RESUMO

Heart transplant (HTx) recipients are at increased risk of pericardial disease. Idiopathic recurrent pericarditis has not been previously described following HTx. We describe a 35-year-old male who was admitted with pericarditis and moderate pericardial effusion 10 months after HTx. Two weeks before his admission, his prednisone had been tapered off. A thorough infectious workup and endomyocardial biopsy was unrevealing. He was started on colchicine with the addition of tapering prednisone regimen of 40 mg daily due to unresolved pain. Over the next several years, he had three recurrent episodes of pericarditis requiring re-initiation of prednisone with extensive investigations negative for rejection, autoimmune, and infectious causes. Cardiac MRI confirmed pericardial inflammation. Due to his recurrent course and inability to wean off prednisone, anakinra, an IL-1 receptor antagonist, was started at 100 mg sc daily. This allowed successful discontinuation of prednisone. He is now 34 months post-transplant without recurrence on anakinra and colchicine maintenance. Due to the overlap between idiopathic recurrent pericarditis and auto-inflammatory diseases, there is growing evidence for utilizing IL-1 receptor antagonists in this condition. While pericarditis is common in the HTx population, this is the first report of successful use of an IL-1 receptor blocker for pericarditis in this population.


Assuntos
Antirreumáticos/uso terapêutico , Cardiomiopatias/cirurgia , Transplante de Coração/efeitos adversos , Proteína Antagonista do Receptor de Interleucina 1/uso terapêutico , Pericardite/tratamento farmacológico , Receptores de Interleucina-1/antagonistas & inibidores , Adulto , Cardiomiopatias/patologia , Humanos , Masculino , Pericardite/etiologia , Pericardite/patologia , Prognóstico
18.
Epilepsy Behav ; 101(Pt B): 106275, 2019 12.
Artigo em Inglês | MEDLINE | ID: mdl-31171434

RESUMO

Preclinical studies in immature and adult rodents and clinical observations show that neuroinflammation and oxidative stress are rapid onset phenomena occurring in the brain during status epilepticus and persisting thereafter. Notably, both neuroinflammation and oxidative stress contribute to the acute and long-term sequelae of status epilepticus thus representing potential druggable targets. Antiinflammatory drugs that interfere with the IL-1ß pathway, such as anakinra, can control benzodiazepine-refractory status epilepticus in animals, and there is recent proof-of-concept evidence for therapeutic effects in children with Febrile infection related epilepsy syndrome (FIRES). Inhibitors of monoacylglycerol lipase and P2X7 receptor antagonists are also promising antiinflammatory drug candidates for rapidly aborting de novo status epilepticus and provide neuroprotection. Antiinflammatory and antioxidant drugs administered to rodents during status epilepticus and transiently thereafter, prevent long-term sequelae such as cognitive deficits and seizure progression in animals developing epilepsy. Some drugs are already in medical use and are well-tolerated, therefore, they may be considered for treating status epilepticus and its neurological consequences. Finally, markers of neuroinflammation and oxidative stress are measureable in peripheral blood and by neuroimaging, which offers an opportunity for developing prognostic and predictive mechanistic biomarkers in people exposed to status epilepticus. This article is part of the Special Issue "Proceedings of the 7th London-Innsbruck Colloquium on Status Epilepticus and Acute Seizures.


Assuntos
Anti-Inflamatórios/uso terapêutico , Espécies Reativas de Oxigênio/metabolismo , Estado Epiléptico/tratamento farmacológico , Estado Epiléptico/metabolismo , Animais , Anti-Inflamatórios/farmacologia , Biomarcadores/sangue , Biomarcadores/metabolismo , Encéfalo/efeitos dos fármacos , Encéfalo/metabolismo , Humanos , Inflamação/tratamento farmacológico , Inflamação/metabolismo , Interleucina-1beta/antagonistas & inibidores , Interleucina-1beta/metabolismo , Estresse Oxidativo/efeitos dos fármacos , Estresse Oxidativo/fisiologia , Antagonistas do Receptor Purinérgico P2X/farmacologia , Antagonistas do Receptor Purinérgico P2X/uso terapêutico , Espécies Reativas de Oxigênio/antagonistas & inibidores , Convulsões/tratamento farmacológico , Convulsões/metabolismo
19.
J Neurosci ; 37(43): 10278-10289, 2017 10 25.
Artigo em Inglês | MEDLINE | ID: mdl-28924012

RESUMO

Creutzfeldt-Jakob disease (CJD) is a neurodegenerative disorder caused by prion protein (PrP) misfolding, clinically recognized by cognitive and motor deficits, electroencephalographic abnormalities, and seizures. Its neurophysiological bases are not known. To assess the potential involvement of NMDA receptor (NMDAR) dysfunction, we analyzed NMDA-dependent synaptic plasticity in hippocampal slices from Tg(CJD) mice, which model a genetic form of CJD. Because PrP depletion may result in functional upregulation of NMDARs, we also analyzed PrP knock-out (KO) mice. Long-term potentiation (LTP) at the Schaffer collateral-commissural synapses in the CA1 area of ∼100-d-old Tg(CJD) mice was comparable to that of wild-type (WT) controls, but there was an inversion of metaplasticity, with increased GluN2B phosphorylation, which is indicative of enhanced NMDAR activation. Similar but less marked changes were seen in PrP KO mice. At ∼300 d of age, the magnitude of LTP increased in Tg(CJD) mice but decreased in PrP KO mice, indicating divergent changes in hippocampal synaptic responsiveness. Tg(CJD) but not PrP KO mice were intrinsically more susceptible than WT controls to focal hippocampal seizures induced by kainic acid. IL-1ß-positive astrocytes increased in the Tg(CJD) hippocampus, and blocking IL-1 receptor signaling restored normal synaptic responses and reduced seizure susceptibility. These results indicate that alterations in NMDA-dependent glutamatergic transmission in Tg(CJD) mice do not depend solely on PrP functional loss. Moreover, astrocytic IL-1ß plays a role in the enhanced synaptic responsiveness and seizure susceptibility, suggesting that targeting IL-1ß signaling may offer a novel symptomatic treatment for CJD.SIGNIFICANCE STATEMENT Dementia and myoclonic jerks develop in individuals with Creutzfeldt-Jakob disease (CJD), an incurable brain disorder caused by alterations in prion protein structure. These individuals are prone to seizures and have high brain levels of the inflammatory cytokine IL-1ß. Here we show that blocking IL-1ß receptors with anakinra, the human recombinant form of the endogenous IL-1 receptor antagonist used to treat rheumatoid arthritis, normalizes hippocampal neurotransmission and reduces seizure susceptibility in a CJD mouse model. These results link neuroinflammation to defective neurotransmission and the enhanced susceptibility to seizures in CJD and raise the possibility that targeting IL-1ß with clinically available drugs may be beneficial for symptomatic treatment of the disease.


Assuntos
Síndrome de Creutzfeldt-Jakob/tratamento farmacológico , Modelos Animais de Doenças , Proteína Antagonista do Receptor de Interleucina 1/uso terapêutico , Interleucina-1beta/antagonistas & inibidores , Receptores de N-Metil-D-Aspartato/antagonistas & inibidores , Convulsões/tratamento farmacológico , Animais , Síndrome de Creutzfeldt-Jakob/metabolismo , Suscetibilidade a Doenças , Feminino , Hipocampo/efeitos dos fármacos , Hipocampo/metabolismo , Humanos , Proteína Antagonista do Receptor de Interleucina 1/farmacologia , Interleucina-1beta/metabolismo , Masculino , Camundongos , Camundongos Endogâmicos C57BL , Camundongos Knockout , Camundongos Transgênicos , N-Metilaspartato/antagonistas & inibidores , N-Metilaspartato/metabolismo , Plasticidade Neuronal/efeitos dos fármacos , Plasticidade Neuronal/fisiologia , Distribuição Aleatória , Receptores de N-Metil-D-Aspartato/metabolismo , Convulsões/metabolismo , Transdução de Sinais/efeitos dos fármacos , Transdução de Sinais/fisiologia , Transmissão Sináptica/efeitos dos fármacos , Transmissão Sináptica/fisiologia
20.
Neurobiol Dis ; 114: 24-30, 2018 06.
Artigo em Inglês | MEDLINE | ID: mdl-29477641

RESUMO

Pro-inflammatory mechanisms have recently emerged as an important component of early Alzheimer's disease (AD) pathogenesis. A particularly attractive therapeutic strategy is to selectively prevent the disruptive effects of activation of the innate immune system in the brain at an early transitional stage by reducing the production or directly neutralizing pro-inflammatory cytokines, in particular IL-1ß and TNF-α. Here we tested their in vivo effects on synaptic plasticity deficits, which provide sensitive and robust measures of synaptic failure, in a rat model of AD amyloidosis. Using electrophysiological techniques we longitudinally studied the effects of the NLRP3 inflammasome inhibitor Mcc950, the IL-1 receptor antagonist (anakinra) and an anti-TNF-α agent (etanercept) in awake freely moving transgenic rats overexpressing AD associated ß-amyloid precursor protein at a pre-plaque stage of amyloidosis. Repeated treatment with Mcc950 reversibly abrogated the inhibition of long-term potentiation. The IL-1 receptor antagonist and etanercept also had a similar beneficial effect on the deficit in synaptic plasticity. Our findings support the clinical development of Mcc950 and clinically available IL-1- and TNF-α-neutralizing agents in early AD.


Assuntos
Doença de Alzheimer/fisiopatologia , Amiloidose/fisiopatologia , Proteína 3 que Contém Domínio de Pirina da Família NLR/fisiologia , Plasticidade Neuronal/fisiologia , Doença de Alzheimer/tratamento farmacológico , Doença de Alzheimer/genética , Amiloidose/tratamento farmacológico , Amiloidose/genética , Animais , Anti-Inflamatórios não Esteroides/farmacologia , Anti-Inflamatórios não Esteroides/uso terapêutico , Etanercepte/farmacologia , Etanercepte/uso terapêutico , Humanos , Proteína Antagonista do Receptor de Interleucina 1/farmacologia , Proteína Antagonista do Receptor de Interleucina 1/uso terapêutico , Masculino , Proteína 3 que Contém Domínio de Pirina da Família NLR/agonistas , Proteína 3 que Contém Domínio de Pirina da Família NLR/antagonistas & inibidores , Plasticidade Neuronal/efeitos dos fármacos , Ratos , Ratos Transgênicos
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