RESUMEN
Cytokine Storm is a complex and heterogeneous state of life-threatening systemic inflammation and immunopathology. Autoinflammation is a mechanistic category of immune dysregulation wherein immunopathology originates due to poor regulation of innate immunity. The growing family of monogenic Systemic Autoinflammatory Diseases (SAIDs) has been a wellspring for pathogenic insights and proof-of-principle targeted therapeutic interventions. There is surprisingly little overlap between SAID and Cytokine Storm Syndromes, and there is a great deal to be inferred from those SAID that do, and do not, consistently lead to Cytokine Storm. This chapter will summarize how illustrations of the autoinflammatory paradigm have advanced the understanding of human inflammation, including the role of autoinflammation in familial HLH. Next, it will draw from monogenic SAID, both those with strong associations with cytokine storm and those without, to illustrate how the cytokine IL-18 links innate immune dysregulation and cytokine storm.
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Síndrome de Liberación de Citoquinas , Inmunidad Innata , Humanos , Síndrome de Liberación de Citoquinas/inmunología , Interleucina-18/inmunología , Interleucina-18/genética , Inflamación/inmunología , Enfermedades Autoinflamatorias Hereditarias/inmunología , Enfermedades Autoinflamatorias Hereditarias/genética , Animales , Citocinas/inmunología , Citocinas/metabolismoRESUMEN
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.
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Síndrome de Liberación de Citoquinas , Interleucina-1 , Humanos , Síndrome de Liberación de Citoquinas/inmunología , Síndrome de Liberación de Citoquinas/tratamiento farmacológico , Interleucina-1/antagonistas & inhibidores , Interleucina-1/inmunología , Interleucina-1/genética , Interleucina-1/metabolismo , Animales , Proteína Antagonista del Receptor de Interleucina 1/uso terapéutico , Proteína Antagonista del Receptor de Interleucina 1/genética , Proteínas de Unión al Calcio/genética , Interleucina-18/genética , Interleucina-18/inmunología , Síndrome de Activación Macrofágica/inmunología , Síndrome de Activación Macrofágica/tratamiento farmacológico , Síndrome de Activación Macrofágica/genética , Linfohistiocitosis Hemofagocítica/inmunología , Linfohistiocitosis Hemofagocítica/genética , Linfohistiocitosis Hemofagocítica/tratamiento farmacológico , Proteínas Adaptadoras de Señalización CARDRESUMEN
Introduction: Interleukin-18 (IL-18), a pro-inflammatory cytokine belonging to the IL-1 Family, is a key mediator ofautoinflammatory diseases associated with the development of macrophage activation syndrome (MAS).High levels of IL-18 correlate with MAS and COVID-19 severity and mortality, particularly in COVID-19patients with MAS. As an inflammation inducer, IL-18 binds its receptor IL-1 Receptor 5 (IL-1R5), leadingto the recruitment of the co-receptor, IL-1 Receptor 7 (IL-1R7). This heterotrimeric complex subsequentlyinitiates downstream signaling, resulting in local and systemic inflammation. Methods: We reported earlier the development of a novel humanized monoclonal anti-human IL-1R7 antibody whichspecifically blocks the activity of human IL-18 and its inflammatory signaling in human cell and wholeblood cultures. In the current study, we further explored the strategy of blocking IL-1R7 inhyperinflammation in vivo using animal models. Results: We first identified an anti-mouse IL-1R7 antibody that significantly suppressed mouse IL-18 andlipopolysaccharide (LPS)-induced IFNg production in mouse splenocyte and peritoneal cell cultures. Whenapplied in vivo, the antibody reduced Propionibacterium acnes and LPS-induced liver injury and protectedmice from tissue and systemic hyperinflammation. Importantly, anti-IL-1R7 significantly inhibited plasma,liver cell and spleen cell IFNg production. Also, anti-IL-1R7 downregulated plasma TNFa, IL-6, IL-1b,MIP-2 production and the production of the liver enzyme ALT. In parallel, anti-IL-1R7 suppressed LPSinducedinflammatory cell infiltration in lungs and inhibited the subsequent IFNg production andinflammation in mice when assessed using an acute lung injury model. Discussion: Altogether, our data suggest that blocking IL-1R7 represents a potential therapeutic strategy to specificallymodulate IL-18-mediated hyperinflammation, warranting further investigation of its clinical application intreating IL-18-mediated diseases, including MAS and COVID-19.
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Inflamación , Lipopolisacáridos , Animales , Ratones , Lipopolisacáridos/inmunología , Inflamación/inmunología , Humanos , Interleucina-18/metabolismo , Interleucina-18/inmunología , Modelos Animales de Enfermedad , COVID-19/inmunología , Ratones Endogámicos C57BL , Síndrome de Activación Macrofágica/inmunología , SARS-CoV-2/inmunologíaRESUMEN
Interleukin-1 (IL-1) family cytokines are key immunological regulators that achieve their signaling prowess after post-translational proteolytic processing. In this issue of Immunity, Dong et al. reveal the structural consequences of this process on proinflammatory IL-18, demonstrating that pro-IL-18 and mature IL-18 are structurally distinct.
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Interleucina-18 , Transducción de Señal , Interleucina-18/metabolismo , Interleucina-18/inmunología , Humanos , Transducción de Señal/inmunología , Animales , Procesamiento Proteico-PostraduccionalRESUMEN
Herpes simplex keratitis (HSK) is a blinding disease caused by herpes simplex virus type 1 (HSV-1) infection, and rapid eradication of the virus from the affected cornea is imperative. Nod-like receptors (NLRs) are intracellular innate immune sensors closely associated with cell death, inflammation and immune responses. In this study, we investigated the role of NLRP12 in the antiviral immunology in HSK and the underlying mechanisms. We found that NLRP12 expression was significantly decreased in HSV-1-infected human corneal epithelial cells (HCE-Ts) and HSK mouse corneas. Overexpression of NLRP12 significantly reduced viral replication in infected HCE-Ts and functioned through inflammasome-mediated pyroptosis and downstream IL-18-IFN-γ axis. In HSK mouse models, overexpression of NLRP12 reduced viral replication in the cornea and alleviated HSK symptoms. This resulted from enhanced antiviral immune responses including the activation of specific immune cells in both the cornea and the draining lymph nodes. Specifically, the NLRP12-IL-18-IFN-γ axis regulated the interaction between infected corneal epithelial cells and macrophages. In conclusion, our study identified a role of NLRP12 in mediating pyroptosis and regulating antiviral immune responses. This novel finding opens the possibilities of NLRP12 as a viable target in the therapeutic strategies for HSV-1 infection.
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Herpesvirus Humano 1 , Interferón gamma , Interleucina-18 , Queratitis Herpética , Ratones Endogámicos C57BL , Piroptosis , Transducción de Señal , Animales , Queratitis Herpética/inmunología , Queratitis Herpética/virología , Humanos , Interleucina-18/metabolismo , Interleucina-18/inmunología , Interferón gamma/metabolismo , Interferón gamma/inmunología , Herpesvirus Humano 1/inmunología , Herpesvirus Humano 1/fisiología , Ratones , Córnea/virología , Córnea/inmunología , Córnea/patología , Femenino , Replicación Viral , Péptidos y Proteínas de Señalización Intracelular/metabolismo , Péptidos y Proteínas de Señalización Intracelular/genética , Modelos Animales de Enfermedad , Inflamasomas/metabolismo , Inflamasomas/inmunología , Inmunidad InnataRESUMEN
Background: An increased level of interleukin-17A and interleukin-18 in the serum and intestinal mucosa of celiac disease patients reflecting the severity of villous atrophy and inflammation was documented. Thus, the objective of this study was to evaluate the concentrations of salivary-17A, interleukin-1 beta, and interleukin-18 in patients with celiac disease who are on a gluten-free diet, both with and without periodontitis, and to compare these levels with those in healthy individuals. Methods: The study involved 23 participants with serologically confirmed celiac disease (CD) and 23 control subjects. The CD patients had been following a gluten-free diet (GFD) for a minimum of 1 year and had no other autoimmune disorders. The research involved collecting demographic data, conducting periodontal examinations, gathering unstimulated whole saliva, and performing enzyme-linked immunosorbent assays to measure salivary interleukin-17A, interleukin-1 beta, and interleukin-18 levels. Spearman's correlation analysis was utilized to explore the relationships between CD markers in patients on a GFD and their periodontal clinical findings. Results: The periodontal findings indicated significantly lower values in celiac disease patients adhering to a gluten-free diet compared to control subjects (p = 0.001). No significant differences were found in salivary IL-17A, IL-18, and IL-1B levels between celiac disease patients and control subjects. Nevertheless, the levels of all interleukins were elevated in periodontitis patients in both the celiac and control groups. The IL-1 Beta level was significantly higher in periodontitis patients compared to non-periodontitis patients in the control group (p = 0.035). Significant negative correlations were observed between serum IgA levels and plaque index (r = -0.460, p = 0.010), as well as gingival index (r = -0.396, p = 0.030) in CD patients on a gluten-free diet. Conclusion: Celiac disease patients on gluten-free diet exhibited better periodontal health compared to control subjects. However, increased levels of salivary IL-17A, IL-18 and IL-1B levels were associated with periodontitis. Additionally, serum IgA level was significantly inversely associated with periodontitis clinical manifestations and with salivary inflammatory mediators in CD patients on GFD.
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Enfermedad Celíaca , Interleucina-17 , Interleucina-18 , Periodontitis , Saliva , Adulto , Femenino , Humanos , Masculino , Persona de Mediana Edad , Adulto Joven , Biomarcadores/metabolismo , Estudios de Casos y Controles , Enfermedad Celíaca/inmunología , Dieta Sin Gluten , Interleucina-17/inmunología , Interleucina-18/inmunología , Interleucina-1beta/inmunología , Periodontitis/inmunología , Saliva/química , Saliva/inmunologíaRESUMEN
Background and Objectives: Systemic inflammatory response syndrome (SIRS) is one of the most significant complications after on-pump heart surgery procedures. High cytokine levels have been shown after open-heart surgeries and a genetic predisposition seems to be an important underlying modulatory characteristic for SIRS. To investigate the association between interleukin 18 -607 C/A, interleukin 18 -137 G/C and osteopontin 9250 C/T genetic polymorphisms and SIRS in on-pump CABG patients. Materials and Methods: Two hundred consecutive elective on-pump CABG patients were recruited prospectively to the study. Genomic DNA was extracted from whole blood and genotyping was determined by sequence specific PCR or PCR-RFLP methods for related polymorphisms. Results: SIRS incidence was 60.2%, 38.1%, 18.9% on postoperative day 1, 2 and 3, respectively, in the whole study population. The SIRS rate on the second postoperative day was 13% and 43.4%, respectively, in osteopontin 9250 C/T T allele non-carriers and carriers (p = 0.004). WBC (White Blood Cell) counts were higher on day 2 and 3 in osteopontin 9250 C/T T allele carriers compared to non-carriers (day 2; 12.7 ± 4 vs. 10.5 ± 2.4 (p = 0.015), day 3; 11.8 ± 4 vs. 9.1 ± 4.7 (p = 0.035)). The average ICU stay was 3.1 ± 7.4, 1.28 ± 0.97 for IL 18-137 G/C C allele carriers and non-carriers, respectively (p = 0.003), and in the IL 18-137 G/C C allele carriers, SIRS developed in 42.2% by the second postoperative day whereas the rate was 57.8% in non-carriers (p = 0.025). Conclusions: The current research revealed a possible link between osteopontin 9250 C/T and IL18-137 G/C genetic polymorphism and SIRS and morbidity in on-pump CABG patients.
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Puente de Arteria Coronaria , Interleucina-18 , Osteopontina , Síndrome de Respuesta Inflamatoria Sistémica , Anciano , Femenino , Humanos , Masculino , Persona de Mediana Edad , Puente de Arteria Coronaria/efectos adversos , Predisposición Genética a la Enfermedad , Genotipo , Interleucina-18/sangre , Interleucina-18/genética , Interleucina-18/inmunología , Osteopontina/sangre , Osteopontina/genética , Osteopontina/inmunología , Polimorfismo Genético , Polimorfismo de Nucleótido Simple , Complicaciones Posoperatorias/etiología , Complicaciones Posoperatorias/epidemiología , Estudios Prospectivos , Síndrome de Respuesta Inflamatoria Sistémica/genética , Síndrome de Respuesta Inflamatoria Sistémica/sangre , Síndrome de Respuesta Inflamatoria Sistémica/etiologíaRESUMEN
Natural killer cells (NK cells) are the front line of immune cells to combat pathogens and able to influence the subsequent adaptive immune responses. One of the factors contributing to pathogenesis in dengue hemorrhagic fever (DHF) disease is aberrant immune activation during early phase of infection. This study explored the profile of NK cells in dengue infected pediatric patients with different degrees of disease severity. DHF patients contained higher frequency of activated NK cells but lower ratio of CD56dim:CD56bright NK subsets. Activated NK cells exhibited alterations in several NK receptors. Interestingly, the frequencies of NKp30 expressing activated NK cells were more pronounced in dengue fever (DF) than in DHF pediatric patients. In vitro functional analysis indicated that degranulation of NK cells in responding to dengue infected dendritic cells (DCs) required cell-cell contact and type I IFNs. Meanwhile, Interferon gamma (IFN-γ) production initially required cell-cell contact and type I IFNs followed by Interleukin-12 (IL-12), Interleukin-15 (IL-15) and Interleukin-18 (IL-18) resulting in the amplification of IFN-γ producing NK cells over time. This study highlighted the complexity and the factors influencing NK cells responses to dengue virus. Degree of activation, phenotypes of activated cells and the crosstalk between NK cells and other immune cells, could modulate the outcome of NK cells function in the dengue disease.
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Células Dendríticas , Virus del Dengue , Interferón gamma , Interleucina-12 , Células Asesinas Naturales , Fenotipo , Células Asesinas Naturales/inmunología , Humanos , Niño , Interleucina-12/inmunología , Masculino , Femenino , Células Dendríticas/inmunología , Virus del Dengue/inmunología , Interferón gamma/inmunología , Interleucina-15/inmunología , Activación de Linfocitos , Interleucina-18/inmunología , Receptor 3 Gatillante de la Citotoxidad Natural/inmunología , Preescolar , Dengue/inmunología , Dengue/virología , Dengue Grave/inmunología , Dengue Grave/virología , Adolescente , Antígeno CD56/inmunología , Interferón Tipo I/inmunologíaRESUMEN
BACKGROUND: Numerous biological interventions and small molecules are used to treat Crohn's disease; however, the effectiveness of these treatments varies largely. Non-responsiveness to biological therapies is associated with interleukin (IL)-18 gene polymorphisms and high IL-18 expression has been implicated in the pathogenesis of Crohn's disease. AIMS: The aim of this study was to elucidate the expression of precursor and mature IL-18 in patients with Crohn's disease who exhibited varied responses to cytokine-targeted treatments and determine whether selective inhibition of mature IL-18 offers a novel therapeutic avenue. METHODS: We generated a monoclonal antibody that specifically recognizes the neoepitope of caspase-cleaved mature IL-18. Expression of precursor and mature IL-18 was analyzed in patients with Crohn's disease. Anti-mature IL-18 monoclonal antibodies were intraperitoneally administered in an acute colitis mouse model, and the disease activity index, body weight loss, tissue pathology, proinflammatory cytokine expression, goblet cell function, and microbiota composition were assessed. RESULTS: Precursor and mature IL-18 expression was upregulated and goblet cell function was impaired in patients with Crohn's disease who were unresponsive to biological therapies. Administration of anti-mature IL-18 antibodies ameliorated induced colitis by repairing goblet cell function and restoring the mucus layer. CONCLUSIONS: The newly developed monoclonal antibody holds promise as a therapeutic alternative for Crohn's disease.
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Anticuerpos Monoclonales , Enfermedad de Crohn , Células Caliciformes , Interleucina-18 , Interleucina-18/metabolismo , Interleucina-18/inmunología , Animales , Células Caliciformes/inmunología , Células Caliciformes/patología , Células Caliciformes/efectos de los fármacos , Humanos , Anticuerpos Monoclonales/farmacología , Anticuerpos Monoclonales/uso terapéutico , Ratones , Enfermedad de Crohn/inmunología , Enfermedad de Crohn/tratamiento farmacológico , Femenino , Masculino , Modelos Animales de Enfermedad , Colitis/inmunología , Colitis/tratamiento farmacológico , Adulto , Ratones Endogámicos C57BLRESUMEN
Allergic asthma (AA) is closely associated with the polarization of T helper (Th)2 and Th17 cells. Interleukin (IL)-18 acts as an inducer of Th2 and Th17 cell responses. However, expressions of IL-18 and IL-18 receptor alpha (IL-18Rα) in blood Th2 and Th17 cells of patients with AA remain unclear. We therefore investigated their expressions in Th2 and Th17 cells using flow cytometric analysis, quantitative real-time PCR (qPCR), and murine AA model. We observed increased proportions of Th2, Th17, IL-18+, IL-18+ Th2, and IL-18+ Th17 cells in blood CD4+ T cells of patients with AA. Additionally, house dust mite seemed to upregulate further IL-18 expression in Th2 and Th17, and upregulate IL-18Rα expression in CD4+ T, Th2, and Th17 cells of AA patients. It was also found that the plasma levels of IL-4, IL-17A, and IL-18 in AA patients were elevated, and they were correlated between each other. In ovalbumin (OVA)-induced asthma mouse (AM), we observed that the percentages of blood CD4+ T, Th2, and Th17 cells were increased. Moreover, OVA-induced AM expressed higher level of IL-18Rα in blood Th2 cells, which was downregulated by IL-18. Increased IL-18Rα expression was also observed in blood Th2 cells of OVA-induced FcεRIα-/- mice. Collectively, our findings suggest the involvement of Th2 cells in AA by expressing excessive IL-18 and IL-18Rα in response to allergen, and that IL-18 and IL-18Rα expressing Th2 cells are likely to be the potential targets for AA therapy.
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Alérgenos , Asma , Interleucina-18 , Células Th17 , Células Th2 , Humanos , Interleucina-18/inmunología , Interleucina-18/sangre , Asma/inmunología , Asma/sangre , Animales , Células Th2/inmunología , Ratones , Femenino , Células Th17/inmunología , Masculino , Adulto , Alérgenos/inmunología , Persona de Mediana Edad , Regulación hacia Arriba/inmunología , Subunidad alfa del Receptor de Interleucina-18/inmunología , Subunidad alfa del Receptor de Interleucina-18/genética , Ovalbúmina/inmunología , Receptores de Interleucina-18/inmunología , Ratones Endogámicos BALB C , Modelos Animales de Enfermedad , Pyroglyphidae/inmunología , Adulto JovenRESUMEN
ABSTRACT: Multiple myeloma is a plasma cell malignancy that is currently incurable with conventional therapies. Following the success of CD19-targeted chimeric antigen receptor (CAR) T cells in leukemia and lymphoma, CAR T cells targeting B-cell maturation antigen (BCMA) more recently demonstrated impressive activity in relapsed and refractory myeloma patients. However, BCMA-directed therapy can fail due to weak expression of BCMA on myeloma cells, suggesting that novel approaches to better address this antigen-low disease may improve patient outcomes. We hypothesized that engineered secretion of the proinflammatory cytokine interleukin-18 (IL-18) and multiantigen targeting could improve CAR T-cell activity against BCMA-low myeloma. In a syngeneic murine model of myeloma, CAR T cells targeting the myeloma-associated antigens BCMA and B-cell activating factor receptor (BAFF-R) failed to eliminate myeloma when these antigens were weakly expressed, whereas IL-18-secreting CAR T cells targeting these antigens promoted myeloma clearance. IL-18-secreting CAR T cells developed an effector-like T-cell phenotype, promoted interferon-gamma production, reprogrammed the myeloma bone marrow microenvironment through type-I/II interferon signaling, and activated macrophages to mediate antimyeloma activity. Simultaneous targeting of weakly-expressed BCMA and BAFF-R with dual-CAR T cells enhanced T-cell:target-cell avidity, increased overall CAR signal strength, and stimulated antimyeloma activity. Dual-antigen targeting augmented CAR T-cell secretion of engineered IL-18 and facilitated elimination of larger myeloma burdens in vivo. Our results demonstrate that combination of engineered IL-18 secretion and multiantigen targeting can eliminate myeloma with weak antigen expression through distinct mechanisms.
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Antígeno de Maduración de Linfocitos B , Inmunoterapia Adoptiva , Interleucina-18 , Mieloma Múltiple , Animales , Mieloma Múltiple/inmunología , Mieloma Múltiple/terapia , Mieloma Múltiple/patología , Ratones , Interleucina-18/inmunología , Inmunoterapia Adoptiva/métodos , Antígeno de Maduración de Linfocitos B/inmunología , Humanos , Receptores Quiméricos de Antígenos/inmunología , Modelos Animales de Enfermedad , Antígenos de Neoplasias/inmunología , Linfocitos T/inmunología , Linfocitos T/metabolismo , Línea Celular TumoralRESUMEN
Cytokines mediate cell-cell communication in the immune system and represent important therapeutic targets1-3. A myriad of studies have highlighted their central role in immune function4-13, yet we lack a global view of the cellular responses of each immune cell type to each cytokine. To address this gap, we created the Immune Dictionary, a compendium of single-cell transcriptomic profiles of more than 17 immune cell types in response to each of 86 cytokines (>1,400 cytokine-cell type combinations) in mouse lymph nodes in vivo. A cytokine-centric view of the dictionary revealed that most cytokines induce highly cell-type-specific responses. For example, the inflammatory cytokine interleukin-1ß induces distinct gene programmes in almost every cell type. A cell-type-centric view of the dictionary identified more than 66 cytokine-driven cellular polarization states across immune cell types, including previously uncharacterized states such as an interleukin-18-induced polyfunctional natural killer cell state. Based on this dictionary, we developed companion software, Immune Response Enrichment Analysis, for assessing cytokine activities and immune cell polarization from gene expression data, and applied it to reveal cytokine networks in tumours following immune checkpoint blockade therapy. Our dictionary generates new hypotheses for cytokine functions, illuminates pleiotropic effects of cytokines, expands our knowledge of activation states of each immune cell type, and provides a framework to deduce the roles of specific cytokines and cell-cell communication networks in any immune response.
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Citocinas , Inmunidad , Análisis de la Célula Individual , Animales , Ratones , Comunicación Celular/efectos de los fármacos , Citocinas/inmunología , Perfilación de la Expresión Génica , Regulación de la Expresión Génica , Inhibidores de Puntos de Control Inmunológico/farmacología , Inhibidores de Puntos de Control Inmunológico/uso terapéutico , Inmunidad/efectos de los fármacos , Interleucina-18/inmunología , Interleucina-1beta/inmunología , Células Asesinas Naturales/inmunología , Ganglios Linfáticos/citología , Ganglios Linfáticos/inmunología , Neoplasias/inmunología , Neoplasias/terapia , Transducción de Señal/efectos de los fármacos , Programas InformáticosRESUMEN
BACKGROUND: Antitumor necrosis factor (TNF)-α antibodies have improved the outcome of inflammatory bowel disease (IBD); but half of patients remain unresponsive to treatment. Interleukin-18 (IL-18) gene polymorphism is associated with resistance to anti-TNF-α antibodies, but therapies targeting IL-18 have not been clinically applied. Only the mature protein is biologically active, and we aimed to investigate whether specific inhibition of mature IL-18 using a monoclonal antibody (mAb) against a neoepitope of caspase-cleaved mature IL-18 could be an innovative treatment for IBD. METHODS: The expression of precursor and mature IL-18 in patients with UC was examined. Colitis was induced in C57/BL6 mice by administering dextran sulfate sodium (DSS), followed by injection with anti-IL-18 neoepitope mAb. Colon tissues were collected and subjected to histological analysis, immunohistochemistry, immunoblotting, and quantitative polymerase chain reaction. Colon epithelial permeability and microbiota composition were analyzed. RESULTS: Mature IL-18 expression was elevated in colon tissues of patients with active ulcerative colitis. Administration of anti-IL-18 neoepitope mAb ameliorated acute and chronic DSS-induced colitis; reduced interferon-γ, TNF-α, and chemokine (CXC motif) ligand-2 production and epithelial cell permeability; promoted goblet cell function; and altered the intestinal microbiome composition. The suppressive effect of anti-IL-18 neoepitope mAb was superior to that of anti-whole IL-18 mAb. Furthermore, combination therapy with anti-TNF-α Ab suppressed acute and chronic colitis additively by suppressing cytokine expressions and reducing cell permeability by upregulating claudin1 and occludin expression. CONCLUSIONS: Anti-IL-18 neoepitope mAb ameliorates acute and chronic colitis, suggesting that this mAb will be an innovative therapeutic option for IBD.
We investigate a novel monoclonal antibody that specifically recognizes a neoepitope of caspase-cleaved IL-18 and alleviates dextran sulfate sodium-induced colitis by suppressing the secretion of inflammatory cytokines, improving intestinal epithelial permeability, promoting goblet cell function, and regulating intestinal microbiota.
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Anticuerpos Monoclonales , Sulfato de Dextran , Interleucina-18 , Mucosa Intestinal , Ratones Endogámicos C57BL , Animales , Femenino , Humanos , Masculino , Ratones , Anticuerpos Monoclonales/farmacología , Anticuerpos Monoclonales/uso terapéutico , Colitis Ulcerosa/tratamiento farmacológico , Colitis Ulcerosa/inmunología , Colon/patología , Colon/metabolismo , Colon/inmunología , Modelos Animales de Enfermedad , Interleucina-18/metabolismo , Interleucina-18/inmunología , Mucosa Intestinal/inmunología , Mucosa Intestinal/efectos de los fármacos , Mucosa Intestinal/metabolismoRESUMEN
Inflammasomes are multiprotein signaling complexes that activate the innate immune system. Canonical inflammasomes recruit and activate caspase-1, which then cleaves and activates IL-1ß and IL-18, as well as gasdermin D (GSDMD) to induce pyroptosis. In contrast, non-canonical inflammasomes, caspases-4/-5 (CASP4/5) in humans and caspase-11 (CASP11) in mice, are known to cleave GSDMD, but their role in direct processing of other substrates besides GSDMD has remained unknown. Here, we show that CASP4/5 but not CASP11 can directly cleave and activate IL-18. However, CASP4/5/11 can all cleave IL-1ß to generate a 27-kDa fragment that deactivates IL-1ß signaling. Mechanistically, we demonstrate that the sequence identity of the tetrapeptide sequence adjacent to the caspase cleavage site regulates IL-18 and IL-1ß recruitment and activation. Altogether, we have identified new substrates of the non-canonical inflammasomes and reveal key mechanistic details regulating inflammation that may aid in developing new therapeutics for immune-related disorders.
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Caspasas , Interleucina-18 , Interleucina-1beta , Caspasas/genética , Caspasas/inmunología , Interleucina-18/química , Interleucina-18/genética , Interleucina-18/inmunología , Interleucina-1beta/química , Interleucina-1beta/genética , Interleucina-1beta/inmunología , Células RAW 264.7 , Células HEK293 , Células HeLa , Células THP-1 , Humanos , Inflamasomas/inmunología , Transducción de Señal/genética , Proteolisis , Unión Proteica , Multimerización de Proteína , Infecciones por Salmonella/enzimología , Infecciones por Salmonella/inmunologíaRESUMEN
Background: The inflammatory response plays a critical role in postoperative nosocomial infections, which are the most common postoperative complications causing adverse events and poor postoperative outcomes. This study aimed to explore the ability of early inflammation-related factor levels to predict the occurrence of nosocomial infections after abdominal surgery. Methods: The study included 146 patients with open abdominal surgery (a nosocomial infection group (NI group, n=42) and a no-nosocomial infection group (NNI group, n=104)). After 1:1 matching, the patients were divided into a matching nosocomial infection group (M-NI group, n=25) and a matching no-nosocomial infection group (M-NNI group, n=25). Serum levels of interleukin (IL)-6, IL-8, IL-10, IL-12, IL-18, macrophage migration inhibitory factor (MIF), and monocyte chemotactic protein (MCP-1) were tested at three time points (pre-operation, 0-hour post-operation (POD1) and 24-hour post-operation (POD2)). The area under the receiver operating characteristic curve (AUC-ROC) was used to test the predictive abilities. Results: There were significant differences in the levels of IL-6, IL-12, and IL-18 between the M-NI and M-NNI groups (p < 0.05), but not in the levels of other inflammatory factors. MIF, IL-8, and MCP-1 levels were higher in the M-NI group than in the M-NNI group at POD2 (p < 0.05). In the ROC analysis, the AUC for prediction of nosocomial infection using a combination of IL-6 and IL-18 at POD1 was 0.9616, while the AUCs for IL-6 alone and IL-12 alone were 0.8584 and 0.8256, respectively. Conclusions: The combination of the levels of inflammatory factors, IL-6 and IL-18, at the 0-hour postoperative time point, significantly improved the predictive ability to the development of postoperative infection during perioperative period. Our study suggests the importance of monitoring postoperative inflammatory markers.
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Infección Hospitalaria , Interleucina-18 , Interleucina-6 , Proteínas Quimioatrayentes de Monocitos , Humanos , Interleucina-10 , Interleucina-12 , Interleucina-18/sangre , Interleucina-18/inmunología , Interleucina-6/sangre , Interleucina-6/inmunología , Interleucina-8 , Factores Inhibidores de la Migración de Macrófagos , Complicaciones Posoperatorias/diagnóstico , Complicaciones Posoperatorias/etiología , Complicaciones Posoperatorias/inmunología , Biomarcadores/sangre , Abdomen/cirugía , Infección Hospitalaria/sangre , Infección Hospitalaria/inmunologíaRESUMEN
Nontuberculous mycobacteria (NTM) cause pulmonary disease in individuals without obvious immunodeficiency. This study was initiated to gain insight into the immunological factors that predispose persons to NTM pulmonary disease (NTMPD). Blood was obtained from 15 pairs of NTMPD patients and their healthy household contacts. Peripheral blood mononuclear cells (PBMCs) were stimulated with the Mycobacterium avium complex (MAC). A total of 34 cytokines and chemokines were evaluated in plasma and PBMC culture supernatants using multiplex immunoassays, and gene expression in the PBMCs was determined using real-time PCR. PBMCs from NTMPD patients produced significantly less interleukin-1ß (IL-1ß), IL-18, IL-1α, and IL-10 than PBMCs from their healthy household contacts in response to MAC. Although plasma RANTES levels were high in NTMPD patients, they had no effect on IL-1ß production by macrophages infected with MAC. Toll-like receptor 2 (TLR2) and TWIK2 (a two-pore domain K+ channel) were impaired in response to MAC in PBMCs of NTMPD patients. A TLR2 inhibitor decreased all four cytokines, whereas a two-pore domain K+ channel inhibitor decreased the production of IL-1ß, IL-18, and IL-1α, but not IL-10, by MAC-stimulated PBMCs and monocytes. The ratio of monocytes was reduced in whole blood of NTMPD patients compared with that of healthy household contacts. A reduced monocyte ratio might contribute to the attenuated production of IL-1 family cytokines by PBMCs of NTMPD patients in response to MAC stimulations. Collectively, our findings suggest that the attenuated IL-1 response may increase susceptibility to NTM pulmonary infection through multiple factors, including impaired expression of the TLR2 and TWIK2 and reduced monocyte ratio. IMPORTANCE Upon MAC stimulation, the production of IL-1 family cytokines and IL-10 by PBMCs of NTMPD patients was attenuated compared with that of healthy household contacts. Upon MAC stimulation, the expression of TLR2 and TWIK2 (one of the two-pore domain K+ channels) was attenuated in PBMCs of NTMPD patients compared with that of healthy household contacts. The production of IL-1 family cytokines by MAC-stimulated PBMCs and MAC-infected monocytes of healthy donors was reduced by a TLR2 inhibitor and two-pore domain K+ channel inhibitor. The ratio of monocytes was reduced in whole blood of NTMPD patients compared with that of healthy household contacts. Collectively, our data suggest that defects in the expression of TLR2 and TWIK2 in human PBMCs or monocytes and reduced monocyte ratio are involved in the reduced production of IL-1 family cytokines, and it may increase susceptibility to NTM pulmonary infection.
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Citocinas , Enfermedades Pulmonares , Infecciones por Mycobacterium no Tuberculosas , Neumonía Bacteriana , Humanos , Interleucina-18/inmunología , Leucocitos Mononucleares , Enfermedades Pulmonares/inmunología , Monocitos/inmunología , Complejo Mycobacterium avium , Infecciones por Mycobacterium no Tuberculosas/inmunología , Receptor Toll-Like 2/inmunología , Neumonía Bacteriana/inmunología , Citocinas/inmunologíaRESUMEN
Interleukin-18 (IL-18) is a potent pro-inflammatory cytokine involved in host defense against infections and regulates the innate and acquired immune response. IL-18 is produced by both hematopoietic and non-hematopoietic cells, including monocytes, macrophages, keratinocytes and mesenchymal cell. IL-18 could potentially induce inflammatory and cytotoxic immune cell activities leading to autoimmunity. Its elevated levels have been reported in the blood of patients with some immune-related diseases, including rheumatoid arthritis, systemic lupus erythematosus, type I diabetes mellitus, atopic dermatitis, psoriasis, and inflammatory bowel disease. In the present review, we aimed to summarize the biological properties of IL-18 and its pathological role in different autoimmune diseases. We also reported some monoclonal antibodies and drugs targeting IL-18. Most of these monoclonal antibodies and drugs have only produced partial effectiveness or complete ineffectiveness in vitro, in vivo and human studies. The ineffectiveness of these drugs targeting IL-18 may be largely due to the loophole caused by the involvement of other cytokines and proteins in the signaling pathway of many inflammatory diseases besides the involvement of IL-18. Combination drug therapies, that focus on IL-18 inhibition, in addition to other cytokines, are highly recommended to be considered as an important area of research that needs to be explored.
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Enfermedades Autoinmunes , Inmunidad , Inflamación , Interleucina-18 , Anticuerpos Monoclonales , Enfermedades Autoinmunes/inmunología , Citocinas , Humanos , Inflamación/inmunología , Interleucina-18/inmunologíaRESUMEN
Sepsis serves as a leading cause of admission to and death of patients in the intensive care unit (ICU) and is described as a systemic inflammatory response syndrome caused by abnormal host response to infection. Adiposederived mesenchymal stem cells (ADSCs) have exhibited reliable and promising clinical application potential in multiple disorders. However, the function and the mechanism of ADSCs in sepsis remain elusive. In the present study, the crucial inhibitory effect of ADSCderived hydroxycarboxylic acid receptor 1 (HCAR1) on sepsis was identified. Reverse transcription quantitativePCR determined that the mRNA expression of HCAR1 was reduced while the mRNA expression of Tolllike receptor 4 (TLR4), major histocompatibility complex class II (MHC II), NODlike receptor family pyrin domain containing 3 (NLRP3), and the levels of interleukin1ß (IL1ß), tumor necrosis factorα (TNFα), interleukin10 (IL10), and interleukin18 (IL18) were enhanced in the peripheral blood of patients with sepsis. The expression of HCAR1 was negatively correlated with TLR4 (r=0.666), MHC II (r=0.587), and NLRP3 (r=0.621) expression and the expression of TLR4 was positively correlated with NLRP3 (r=0.641), IL1ß (r=0.666), TNFα (r=0.606), and IL18 (r=0.624) levels in the samples. Receiver operating characteristic (ROC) curve analysis revealed that the area under the ROC curve (AUC) of HCAR1, TLR4, MHC II and NLRP3 mRNA expression was 0.830, 0.853, 0.735 and 0.945, respectively, in which NLRP3 exhibited the highest diagnostic value, and the AUC values of IL1ß, IL18, TNFα, and IL10 were 0.751, 0.841, 0.924 and 0.729, respectively, in which TNFα exhibited the highest diagnostic value. A sepsis rat model was established by injecting lipopolysaccharide (LPS) and the rats were randomly divided into 5 groups, including a normal control group (NC group; n=6), a sepsis model group (LPS group; n=6), an ADSC transplantation group (L + M group; n=6), a combined HCAR1 receptor agonist group [L + HCAR1 inducer (Gi) + M group; n=6], and a combined HCAR1 receptor inhibitor group [L + HCAR1 blocker (Gk) + M group; n=6]. Hematoxylin and eosin staining determined that ADSCs attenuated the lung injury of septic rats and ADSCderived HCAR1 enhanced the effect of ADSCs. The expression of HCAR1, TLR4, MHC II, NLRP3, IL1ß, IL18 and TNFα levels were suppressed by ADSCs and the effect was further induced by ADSCderived HCAR1. However, ADSCderived HCAR1 induced the levels of antiinflammatory factor IL10. The negative correlation of HCAR1 expression with TLR4, MHC II, and NLRP3 expression in the peripheral blood and lung tissues of the rats was then identified. It is thus concluded that ADSCderived HCAR1 regulates immune response in the attenuation of sepsis. ADSCderived HCAR1 may be a promising therapeutic strategy for sepsis.
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Tejido Adiposo , Células Madre Mesenquimatosas , Receptores Acoplados a Proteínas G , Sepsis , Tejido Adiposo/citología , Tejido Adiposo/inmunología , Animales , Inmunidad , Interleucina-10/inmunología , Interleucina-18/inmunología , Lipopolisacáridos/farmacología , Células Madre Mesenquimatosas/citología , Células Madre Mesenquimatosas/inmunología , Proteína con Dominio Pirina 3 de la Familia NLR/genética , Proteína con Dominio Pirina 3 de la Familia NLR/inmunología , ARN Mensajero/metabolismo , Ratas , Receptores Acoplados a Proteínas G/inmunología , Sepsis/metabolismo , Receptor Toll-Like 4/genética , Receptor Toll-Like 4/inmunología , Factor de Necrosis Tumoral alfa/genética , Factor de Necrosis Tumoral alfa/inmunologíaRESUMEN
The exact immunological mechanisms of post infectious bronchiolitis obliterans (PIBO) in childhood are not fully known. It has been shown that the inflammasome and IL-18 pathway play important roles in the pathogenesis of lung fibrosis. We aimed to investigate the role of caspase-1, IL-18, and IL-18 components in PIBO. From January to May 2020, children with PIBO, children with history of influenza infection without PIBO, and healthy children were asked to participate in the study in three pediatric pulmonology centers. Serum caspase-1, IL-18, IL-18BP, IL-18R, and INF-γ levels were measured by ELISA and compared between the 3 groups. There were 21 children in the PIBO group, 16 children in the influenza group, and 39 children in the healthy control group. No differences in terms of age and gender between the 3 groups were found. IL-18 and IL-18BP levels were higher in the healthy control group (p = 0.018, p = 0.005, respectively). IL-18R was higher in the PIBO group (p = 0.001) and caspase-1 was higher in the PIBO and influenza group than the healthy control group (p = 0.002). IFN-γ levels did not differ between the 3 groups. IL-18BP/IL-18 was higher in the influenza group than the PIBO group and the healthy control group (p = 0.003). CONCLUSIONS: Caspase-1 level was increased in patients with PIBO which suggests that inflammasome activation may have a role in fibrosis; however, IL-18 level was found to be low. Mediators other than IL-18 may be involved in the inflammatory pathway in PIBO. Further immunological studies investigating inflammasome pathway are needed for PIBO with chronic inflammation. WHAT IS KNOWN: ⢠Post infectious bronchiolitis obliterans (PIBO) is a rare, severe chronic lung disease during childhood which is associated with inflammation and fibrosis which lead to partial or complete luminal obstruction especially in small airways. ⢠The exact immunological mechanisms of PIBO in childhood are not fully known. WHAT IS NEW: ⢠Inflammasome activation persists even years after acute infection and may play a role in fibrosis in PIBO. ⢠Mediators other than IL-18 may be involved in these inflammatory pathway.
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Bronquiolitis Obliterante , Caspasa 1 , Interleucina-18 , Bronquiolitis Obliterante/sangre , Bronquiolitis Obliterante/etiología , Bronquiolitis Obliterante/genética , Bronquiolitis Obliterante/inmunología , Estudios de Casos y Controles , Caspasa 1/sangre , Caspasa 1/genética , Caspasa 1/inmunología , Niño , Fibrosis/sangre , Fibrosis/genética , Fibrosis/inmunología , Humanos , Inflamasomas/inmunología , Inflamación/sangre , Inflamación/genética , Inflamación/inmunología , Gripe Humana/sangre , Gripe Humana/complicaciones , Gripe Humana/genética , Gripe Humana/inmunología , Péptidos y Proteínas de Señalización Intercelular/sangre , Péptidos y Proteínas de Señalización Intercelular/genética , Péptidos y Proteínas de Señalización Intercelular/inmunología , Interleucina-18/sangre , Interleucina-18/genética , Interleucina-18/inmunologíaRESUMEN
Atherosclerosis is associated with a haemostatic imbalance characterized by excessive activation of pro-inflammatory and pro-coagulant pathways. Non-vitamin K antagonists oral anticoagulant (NOACs) may reduce the incidence of cardiovascular events, cerebral ischemia, thromboembolic events and atherosclerosis. Chronic inflammation, vascular proliferation and the development of atherosclerosis is also influenced by 25-hydroxycholesterol (25-OHC). The aim of the study was to assess the effect of rivaroxaban and dabigatran on the messenger RNA (mRNA) expression of anti-inflammatory cytokines transforming growth factor ß (TGF-ß), interleukin (IL)-37, IL-35 as well as of pro-inflammatory cytokines IL-18 and IL-23, in endothelial cells damaged by 25-OHC. Human umbilical vascular endothelial cells (HUVECs) were treated with 25-OHC (10 µg/mL), rivaroxaban (100, 500 ng/mL), dabigatran (100, 500 ng/mL), 25-OHC + rivaroxaban, and 25-OHC + dabigatran. The mRNA expression of TGF-ß, IL-37, IL-35 subunits EBI3 and p35, IL-18, and IL-23 was analysed using real-time polymerase chain reaction (PCR). The results showed that 25-OHC decreased TGF-ß and IL-37 mRNA expression and increased EBI3, p35, IL-18, IL-23 mRNA expression in endothelial cell as compared to an untreated control (P < .05). Messenger RNA expression of TGF-ß and IL-37 significantly increased following stimulation with rivaroxaban and dabigatran as compared to an untreated control (P < .01). In HUVECs pre-treated with oxysterol, rivaroxaban and dabigatran increased mRNA expression of TGF-ß, IL-37 and decreased mRNA expression of EBI3, p35, IL-23 and IL-18 as compared to 25-OHC (P < .01). Our finding suggests that both rivaroxaban and dabigatran inhibit the inflammatory activation caused by oxysterol in vitro.