RESUMEN
Psoriasis is a chronic disorder characterized by a complex interplay between keratinocytes and inflammatory mediators. In a previous study, we evaluated diacerein's ability to diminish interleukin (IL)-1's proinflammatory effects on cultured primary human keratinocytes. In this study, we evaluated diacerein's ability to diminish the inflammatory effects of a cytokine mixture (CM) consisting of IL-17A, IL-22, oncostatin M, IL-1A, and tumor necrosis factor (TNF)-alpha on cultured primary human keratinocytes. These five cytokines have been previously shown to induce an in vivo-equivalent cell culture psoriasis model. We also evaluated diacerein's anti-inflammatory effects in comparison to and in combination with infliximab, a TNF-alpha inhibitor currently used in the treatment of psoriasis. We found 81 genes that were significantly (P < 0.05) dysregulated by CM compared to medium control. All three treatment groups (diacerein alone, infliximab alone, and diacerein plus infliximab) diminished the effects of CM on these genes, with the greatest effect seen with diacerein plus infliximab. Using enzyme-linked immunosorbent assay method on cell culture supernatant, we determined the protein concentration for five genes (IL-19, IL-6, CSF3, S100A8, and NAP-2) significantly (P < 0.05) upregulated by CM at the gene level. Diacerein alone diminished the effect of CM on the protein concentration of two genes, whereas diacerein plus infliximab diminished the effect of CM on the protein concentration of all the five genes. Based on these results, we conclude that diacerein alone or in combination with infliximab may have a therapeutic role in psoriasis by downregulating key inflammatory mediators.
Asunto(s)
Antraquinonas/farmacología , Mediadores de Inflamación/farmacología , Infliximab/farmacología , Queratinocitos/efectos de los fármacos , Humanos , Interleucina-17/antagonistas & inhibidores , Interleucina-17/genética , Interleucina-17/metabolismo , Interleucina-1alfa/antagonistas & inhibidores , Interleucina-1alfa/genética , Interleucina-1alfa/metabolismo , Interleucinas/antagonistas & inhibidores , Interleucinas/genética , Interleucinas/metabolismo , Queratinocitos/metabolismo , Oncostatina M/antagonistas & inhibidores , Oncostatina M/genética , Oncostatina M/metabolismo , Factor de Necrosis Tumoral alfa/antagonistas & inhibidores , Factor de Necrosis Tumoral alfa/genética , Factor de Necrosis Tumoral alfa/metabolismo , Interleucina-22RESUMEN
Rheumatoid arthritis (RA) is a chronic autoimmune disease characterized by synovial inflammation and joint destruction. Although great progress has been made in the treatment of RA with antagonists of pro-inflammatory cytokines such as TNF-α, IL-6 and IL-1, the disease remains refractory in some patients. Previous studies have found that small-molecule inflammatory mediators, such as prostaglandins, leukotrienes, reactive oxygen species, nitric oxide, lipoxins and platelet-activating factor, play a significant role in the development of RA. Such compounds help to induce, maintain or reduce inflammation and could therefore be potential therapeutic targets. In this review, we describe the roles of various classes of small-molecule inflammatory mediators in RA and discuss the effects of some drugs that modulate their activity. Many drugs targeting these mediators have demonstrated good efficacy in mouse models of RA but not in patients. However, it is clear that many small-molecule inflammatory mediators play key roles in the pathogenesis of RA, and a better understanding of the underlying molecular pathways may assist in the development of targeted therapies that are efficacious in RA patients.
Asunto(s)
Antirreumáticos/uso terapéutico , Artritis Reumatoide/tratamiento farmacológico , Artritis Reumatoide/patología , Mediadores de Inflamación/metabolismo , Humanos , Inflamación/tratamiento farmacológico , Inflamación/patología , Interleucina-1alfa/antagonistas & inhibidores , Interleucina-6/antagonistas & inhibidores , Leucotrienos/metabolismo , Lipoxinas/metabolismo , Óxido Nítrico/metabolismo , Factor de Activación Plaquetaria/metabolismo , Prostaglandinas/metabolismo , Especies Reactivas de Oxígeno/metabolismo , Factor de Necrosis Tumoral alfa/antagonistas & inhibidoresRESUMEN
Candida albicans is a commensal fungus that predominantly resides on mucosal surfaces and can cause lethal systemic infection when the host defense is compromised. Candidalysin is a cytolytic peptide toxin produced by C. albicans hyphae that is essential for mucosal tissue damage and is believed to contribute to the establishment of systemic infection and mortality. Candidalysin is also required for the epithelial innate response in which proinflammatory cytokines and chemokines are produced and neutrophil recruitment is initiated. It was recently reported that epidermal growth factor receptor (EGFR) was essential for the candidalysin-triggered epithelial response. The present study identified IL-1α as another component of candidalysin-mediated initial epithelial activation. We found that human oral epithelial cells released IL-1α rapidly after candidalysin exposure. Blockade of IL-1α/IL-1 receptor (IL-1R) signaling in candidalysin-exposed cells resulted in decreased phosphorylation of IκBα, decreased induction of IκBζ and decreased production of granulocyte-macrophage colony-stimulating factor and IL-8. Expression of c-Fos, which is induced downstream of EGFR signaling in candidalysin-treated cells, is less affected by IL-1R blockade. Inversely, blockade of EGFR signaling does not affect candidalysin-mediated phosphorylation of IκBα and induction of IκBζ, suggesting that independent signaling pathways contribute to the induction of NF-κB and c-Fos downstream of the candidalysin pore formation site. Consistently, antibody inhibition of both EGFR and IL-1R enhanced the suppressive effect of cytokine production in candidalysin-treated cells. Thus, we identified the immediate release of IL-1α and its synergistic role with EGFR ligands on the initial activation of oral epithelial cells in response to candidalysin.
Asunto(s)
Células Epiteliales/inmunología , Proteínas Fúngicas/toxicidad , Interleucina-1alfa/metabolismo , Mucosa Bucal/metabolismo , Proteínas Adaptadoras Transductoras de Señales/metabolismo , Candida albicans/inmunología , Línea Celular , Receptores ErbB/antagonistas & inhibidores , Receptores ErbB/metabolismo , Factor Estimulante de Colonias de Granulocitos y Macrófagos/metabolismo , Humanos , Proteínas I-kappa B/metabolismo , Inmunidad Innata/inmunología , Interleucina-1alfa/antagonistas & inhibidores , Interleucina-8/metabolismo , Mucosa Bucal/citología , Fosforilación , Receptores de Interleucina-1/antagonistas & inhibidores , Receptores de Interleucina-1/metabolismo , Transducción de Señal/fisiologíaRESUMEN
OBJECTIVE: Most guidelines recommend the use of nonsteroidal anti-inflammatory drugs (NSAIDs), duloxetine, and tramadol for the nonoperative treatment of osteoarthritis (OA), but the use of them is limited by the tolerability and safety concerns. Lutikizumab is a novel anti-IL-1α/ß dual variable domain immunoglobulin that can simultaneously bind and inhibit IL-1α and IL-1ß to relieve the pain and dysfunction symptoms. We conducted this network meta-analysis to comprehensively compare the clinical efficacy and safety of lutikizumab with other drugs recommended by guidelines. METHODS: We conducted a Bayesian network and conventional meta-analyses to compare the efficacy and safety of lutikizumab with other traditional drugs. All eligible randomized clinical trials, in PubMed, CNKI, EMBASE, and Web of Science databases, from January 2000 to January 2020, were included. The Cochrane risk of the bias assessment tool was used for quality assessment. Pain relief, function improvement, and risk of adverse effects (AEs) were compared in this study. RESULTS: 24 articles with 11858 patients were included. Duloxetine (DUL) had the largest effect for pain relief (4.76, 95% CI [2.35 to 7.17]), and selective cox-2 inhibitors (SCI) were the most efficacious treatment for physical function improvement (SMD 3.94, 95% CI [2.48 to 5.40]). Lutikizumab showed no benefit compared with placebo for both pain relief (SMD 1.11, 95% CI [-2.29 to 4.52]) and function improvement (SMD 0.992, 95% CI [-0.433 to 4.25]). Lutikizumab and all other drugs are of favorable tolerance for patients in the treatment of OA compared with placebo. CONCLUSIONS: Lutikizumab, the new anti-Interleukin-1α/ß dual variable domain immunoglobulin, showed no improvement in pain or function when compared with placebo. Selective cox-2 inhibitors and duloxetine remain the most effective and safest treatment for OA. More high-quality trials are still needed to reconfirm the findings of this study.
Asunto(s)
Antiinflamatorios no Esteroideos/uso terapéutico , Inmunoglobulinas/uso terapéutico , Osteoartritis/tratamiento farmacológico , Antiinflamatorios no Esteroideos/efectos adversos , Antiinflamatorios no Esteroideos/farmacología , Teorema de Bayes , Celecoxib/uso terapéutico , Inhibidores de la Ciclooxigenasa 2/efectos adversos , Inhibidores de la Ciclooxigenasa 2/uso terapéutico , Humanos , Inmunoglobulinas/efectos adversos , Inmunoglobulinas/farmacología , Interleucina-1alfa/antagonistas & inhibidores , Interleucina-1beta/antagonistas & inhibidores , Dolor/tratamiento farmacológico , Dolor/etiología , Resultado del TratamientoRESUMEN
Secukinumab is a novel IL-17A inhibitor that has been confirmed to be effective for treating PsA and RA. Several studies have demonstrated that secukinumab also provides benefits for AS patients. Thus, we performed a meta-analysis of RCTs to evaluate the short-term efficacy and safety of secukinumab for the management of AS. The PubMed, Medline, Embase, Web of Science, and Cochrane Library databases were searched for RCTs published prior to March 2020 on the treatment of AS with secukinumab. The primary outcome was the ASAS20 response, and the secondary outcomes included the ASAS40 response, ASAS5/6 response, SF-36 PCS score, ASQoL score, and AEs. Dichotomous data were expressed as pooled RRs with 95% CIs, while continuous data were expressed as pooled MDs with 95% CIs. Subgroup analysis was conducted based on whether the AS patients previously underwent treatment with TNFi. A total of 4 RCTs with 1166 patients were included in our meta-analysis. At week 16, secukinumab 150 mg yielded significant improvements in the clinical response and patient-reported outcomes for AS patients. There was no increased risk of AEs. Consistent results were detected in the meta-analysis of secukinumab 75 mg versus a placebo. Furthermore, no significant difference was detected between the secukinumab 75 mg group and secukinumab 150 mg group. We concluded that secukinumab is effective for treating AS and generally well tolerated by AS patients in the short term, regardless of whether they previously underwent TNFi treatment. The superiority of secukinumab 150 mg over secukinumab 75 mg seems to be limited, since no significant difference in any endpoint was detected between the two groups.
Asunto(s)
Anticuerpos Monoclonales Humanizados/farmacología , Espondilitis Anquilosante/tratamiento farmacológico , Anticuerpos Monoclonales , Antirreumáticos/farmacología , Humanos , Interleucina-1alfa/antagonistas & inhibidores , Seguridad del Paciente , Calidad de Vida , Ensayos Clínicos Controlados Aleatorios como Asunto , Inducción de Remisión , Índice de Severidad de la Enfermedad , Encuestas y Cuestionarios , Resultado del TratamientoRESUMEN
Recurrent pericarditis (RP) occurs in 15% to 30% of patients following a first episode, despite standard treatment with nonsteroidal anti-inflammatory drugs, colchicine, and corticosteroids; many patients become dependent on corticosteroids. Rilonacept (KPL-914), an interleukin-1α and ß inhibitor, is in development for the treatment of RP. RHAPSODY, a double-blind, placebo-controlled, randomized-withdrawal (RW) pivotal Phase 3 trial (NCT03737110), enrolls patients 12 years or older presenting with at least a third pericarditis episode, pericarditis pain score ≥4 (11-point numeric rating scale [NRS]), and C-reactive protein ≥1 mg/dL at screening. After a subcutaneous loading dose (adults, 320 mg; children, 4.4 mg/kg), all patients receive blinded weekly subcutaneous rilonacept (adults, 160 mg; children, 2.2 mg/kg) during the run-in period. Patients must taper and discontinue concomitant pericarditis medications during the blinded run-in period and achieve clinical response (C-reactive protein ≤0.5 mg/dL and weekly average NRS ≤2.0 during the 7 days prior to and including the day of randomization) by end of the run-in (while on rilonacept monotherapy) to be randomized to either continued rilonacept or placebo in the RW period. Primary efficacy end point was time to adjudicated pericarditis recurrence during the RW period; secondary efficacy end points were proportion of patients maintaining clinical response, percentage of days with NRS ≤2, and percentage of patients with no-to-minimal pericarditis symptoms at week 16 of the RW period. Safety evaluations include adverse event monitoring, physical examinations, and laboratory tests. The RHAPSODY trial will evaluate the efficacy and safety of rilonacept in the treatment of RP to improve outcomes and patient health-related quality of life.
Asunto(s)
Monitoreo de Drogas/métodos , Pericarditis , Calidad de Vida , Proteínas Recombinantes de Fusión , Prevención Secundaria/métodos , Adolescente , Adulto , Antiinflamatorios/administración & dosificación , Antiinflamatorios/efectos adversos , Ensayos Clínicos Fase III como Asunto , Método Doble Ciego , Esquema de Medicación , Femenino , Humanos , Inyecciones Subcutáneas , Interleucina-1alfa/antagonistas & inhibidores , Interleucina-1beta/antagonistas & inhibidores , Masculino , Pericarditis/diagnóstico , Pericarditis/tratamiento farmacológico , Pericarditis/fisiopatología , Pericarditis/psicología , Ensayos Clínicos Controlados Aleatorios como Asunto , Proteínas Recombinantes de Fusión/administración & dosificación , Proteínas Recombinantes de Fusión/efectos adversosAsunto(s)
Anticuerpos Monoclonales/farmacología , Anticuerpos Neutralizantes/farmacología , Interleucina-1alfa/antagonistas & inhibidores , Accidente Cerebrovascular Isquémico/etiología , Accidente Cerebrovascular Isquémico/metabolismo , Animales , Infarto Encefálico/etiología , Infarto Encefálico/metabolismo , Infarto Encefálico/patología , Manejo de la Enfermedad , Modelos Animales de Enfermedad , Susceptibilidad a Enfermedades , Endotelinas/metabolismo , Accidente Cerebrovascular Isquémico/diagnóstico , Accidente Cerebrovascular Isquémico/terapia , Masculino , RatonesRESUMEN
The objective of this study was to evaluate the safety and efficacy of bermekimab, an IL-1α inhibitor, in the treatment of hidradenitis suppurativa (HS). This study was a phase II, multicenter, open-label study of two dose cohorts of bermekimab in patients with moderate-to-severe HS who are naïve to or have failed prior anti-TNF therapy. Patients with HS (n = 42) were divided into groups A and B based on whether or not they had previously failed an anti-TNF therapy. In group A (n = 24), bermekimab was administered subcutaneously at a dose of 400 mg weekly (13 doses) in patients who had previously failed anti-TNF therapy; in group B (n = 18), bermekimab was administered subcutaneously at a dose of 400 mg weekly (13 doses) in patients who were anti-TNF naïve. Bermekimab, previously found to be effective in treating HS, was evaluated using a subcutaneous formulation in patients with HS naïve to or having failed anti-TNF therapy. There were no bermekimab-related adverse events with the exception of injection site reactions. Bermekimab was effective despite treatment history, with 61% and 63% of patients naïve to and having failed anti-TNF therapy, respectively, achieving HS clinical response after 12 weeks of treatment. A significant reduction in abscesses and inflammatory nodules of 60% (P < 0.004) and 46% (P < 0.001) was seen in anti-TNF naïve and anti-TNF failure groups, respectively. Clinically and statistically significant reduction was seen in patients experiencing pain, with the Visual Analogue Scale pain score reducing by 64% (P < 0.001) and 54% (P < 0.001) in the anti-TNF naïve and anti-TNF failure groups, respectively. IL-1α is emerging as an important clinical target for skin disease, and bermekimab may represent a new therapeutic option for treating moderate-to-severe HS.
Asunto(s)
Anticuerpos Monoclonales Humanizados/administración & dosificación , Hidradenitis Supurativa/tratamiento farmacológico , Reacción en el Punto de Inyección/epidemiología , Interleucina-1alfa/antagonistas & inhibidores , Dolor/tratamiento farmacológico , Adulto , Anticuerpos Monoclonales Humanizados/efectos adversos , Relación Dosis-Respuesta a Droga , Esquema de Medicación , Femenino , Hidradenitis Supurativa/complicaciones , Hidradenitis Supurativa/diagnóstico , Hidradenitis Supurativa/inmunología , Humanos , Reacción en el Punto de Inyección/etiología , Inyecciones Subcutáneas , Interleucina-1alfa/inmunología , Masculino , Persona de Mediana Edad , Dolor/diagnóstico , Dolor/inmunología , Dimensión del Dolor , Calidad de Vida , Índice de Severidad de la Enfermedad , Resultado del TratamientoRESUMEN
The inflammatory effects of IL-1α/ß are controlled by IL-1R antagonist (IL-1Ra). One IL-1Ra isoform is secreted, whereas three other isoforms (intracellular IL-1Ra [icIL-1Ra] 1, 2, and 3) are supposed to remain intracellular because of the absence of a signal peptide. In contrast to the well-characterized function of the secreted isoform, the biological role of the intracellular isoforms remains largely unclear. icIL-1Ra1 represents the major isoform in keratinocytes. We created icIL-1Ra1-/- mice and investigated the role of icIL-1Ra1 in Aldara (5% imiquimod)-induced psoriasis-like skin inflammation. Naive icIL-1Ra1-/- mice bred habitually and exhibited a normal phenotype. icIL-1Ra1 deficiency aggravated Aldara-induced skin inflammation, as demonstrated by increased ear thickness and increased mRNA levels of key proinflammatory cytokines. No intracellular effect of icIL-1Ra1 could be detected in isolated keratinocytes using RNA-sequencing analysis; however, Aldara treatment led to caspase 1/11-, caspase 8-, and RIPK3-independent keratinocyte cell death accompanied by the release of both icIL-1Ra1 and IL-1α. Furthermore, blocking IL-1α attenuated the clinical severity of Aldara-induced ear thickening in icIL-1Ra1-/- mice. Our data suggest that upon keratinocyte damage icIL-1Ra1 acts extracellularly as an antagonist of the alarmin IL-1α to immediately counteract its inflammatory effects.
Asunto(s)
Alarminas/antagonistas & inhibidores , Apoptosis/inmunología , Proteína Antagonista del Receptor de Interleucina 1/metabolismo , Interleucina-1alfa/antagonistas & inhibidores , Psoriasis/inmunología , Alarminas/inmunología , Alarminas/metabolismo , Animales , Modelos Animales de Enfermedad , Femenino , Humanos , Imiquimod/inmunología , Proteína Antagonista del Receptor de Interleucina 1/inmunología , Interleucina-1alfa/inmunología , Interleucina-1alfa/metabolismo , Queratinocitos/metabolismo , Masculino , Ratones , Ratones Noqueados , Isoformas de Proteínas/inmunología , Isoformas de Proteínas/metabolismo , Psoriasis/diagnóstico , Psoriasis/patología , Índice de Severidad de la Enfermedad , Transducción de Señal/inmunología , Piel/citología , Piel/inmunología , Piel/patologíaAsunto(s)
Interleucina-1alfa/antagonistas & inhibidores , Interleucina-1beta/antagonistas & inhibidores , Enfermedad del Hígado Graso no Alcohólico/tratamiento farmacológico , Animales , Humanos , Interleucina-1alfa/metabolismo , Interleucina-1beta/metabolismo , Enfermedad del Hígado Graso no Alcohólico/fisiopatologíaRESUMEN
Ex vivo culture of mouse and human skin causes an inflammatory response characterized by production of multiple cytokines. We used ex vivo culture of mouse tail skin specimens to investigate mechanisms of this skin culture-induced inflammatory response. Multiplex assays revealed production of interleukin 1 alpha (IL-1α), interleukin 1 beta (IL-1ß), interleukin 6 (IL-6), chemokine C-X-C motif ligand 1 (CXCL1), granulocyte colony-stimulating factor (G-CSF) and granulocyte-macrophage colony-stimulating factor (GM-CSF) during skin culture, and quantitative PCR revealed transcripts for these proteins were also increased. Ex vivo cultures of skin from myeloid differentiation primary response 88 deficient mice (Myd88-/- ) demonstrated significantly reduced expression of transcripts for the aforementioned cytokines. The same result was observed with skin from interleukin 1 receptor type 1 deficient mice (Il1r1-/- ). These data suggested the IL-1R1/MyD88 axis is required for the skin culture-induced inflammatory response and led us to investigate the role of IL-1α and IL-1ß (the ligands for IL-1R1) in this process. Addition of IL-1α neutralizing antibody to skin cultures significantly reduced expression of Cxcl1, Il6 and Csf3. IL-1ß neutralization did not reduce levels of these transcripts. These studies suggest that IL-1α promotes the skin the culture-induced inflammatory response.
Asunto(s)
Inflamación/genética , Interleucina-1alfa/genética , Piel/fisiopatología , Animales , Anticuerpos Neutralizantes/farmacología , Quimiocina CXCL1/genética , Quimiocina CXCL1/metabolismo , Inflamación/metabolismo , Inflamación/patología , Interleucina-1alfa/antagonistas & inhibidores , Interleucina-1alfa/metabolismo , Interleucina-1beta/antagonistas & inhibidores , Interleucina-1beta/genética , Interleucina-1beta/metabolismo , Interleucina-6/genética , Interleucina-6/metabolismo , Ratones , Ratones Noqueados , Factor 88 de Diferenciación Mieloide/genética , Piel/patología , Técnicas de Cultivo de TejidosRESUMEN
El desenlace de la infección por SARS-CoV-2 (COVID-19) afecta fundamentalmente al campo pulmonar, ocasionando un cuadro de SÍNDROME DE DISTRÉS RESPIRATORIO AGUDO (SDRA). Este proceso es un cuadro inflamatorio, protagonizado por una cascada de citocinas bajo el amparo del INFLAMOSOMA NLRP3, responsable principal de la destrucción alveolar. De entre todas las citocinas que se desencadenan en este cuadro destaca la IL beta. ANAKINRA es un potente fármaco biológico, capaz de bloquear esta IL 1 beta. Proponemos su uso, de cara a controlar el SDRA secundario a la infección por COVID-19
The outcome of the SARS-CoV-2 (COVID-19) infection fundamentally affects the lung field, causing ACUTE RESPIRATORY DISTRESS SYNDROME (ARDS). This process is an inflammatory picture, involving an NLRP3 INFLAMOSOME-triggered cytokine storm, the main player in alveolar destruction. IL-1 beta stands out among the cytokines that are triggered in this picture. ANAKINRA is a potent biological drug, capable of blocking this IL 1 beta. We propose its use in controlling ARDS secondary to COVID-19 infection
Asunto(s)
Humanos , Síndrome Respiratorio Agudo Grave/tratamiento farmacológico , Infecciones por Coronavirus/complicaciones , Coronavirus Relacionado al Síndrome Respiratorio Agudo Severo/patogenicidad , Neumonía Viral/tratamiento farmacológico , Interleucina-1alfa/antagonistas & inhibidores , Interleucina-1beta/antagonistas & inhibidores , Proteína con Dominio Pirina 3 de la Familia NLR/inmunología , Inflamasomas/inmunología , Terapia Biológica/métodos , Interleucina-1alfa/inmunología , Interleucina-1beta/inmunologíaRESUMEN
BACKGROUND: Diaper dermatitis (DD) is the most common acute inflammatory skin disease. It has a serious effect on children's and families' quality of life. We aimed to screen and evaluate the efficacy of different formulas for relieving the diaper dermatitis symptoms by developing a kind of diaper dermatitis-like reconstructed human skin equivalent in vitro. MATERIALS AND METHOD: We developed the human skin equivalent for diaper dermatitis with 0.2% Sodium lauryl sulfate (SLS). The diaper dermatitis-like human skin equivalent was characterized by high level of inflammation, such as overexpression of interleukin-1α (IL-1α), and impaired skin barrier. Four formulas with potential of anti-inflammation and promotion of skin barrier function were topically applied on the diaper dermatitis-like human skin equivalent surface. The afterward protection efficacy was evaluated by endpoints of IL-1α, tissue viability, and skin barrier function. RESULTS: The chemical irritant induced high release of IL-1α, impaired tissue viability, and skin barrier function. The cream prepared with potential of anti-inflammation and skin protection could effectively decrease and relive the impact of irritant with decreased level of IL-1α and the higher tissue viability than the placebo exposure. CONCLUSION: The results showed that diaper dermatitis-like human skin equivalent induced by SLS can mimic the skin irritation response of the diaper rash.
Asunto(s)
Antiinflamatorios/farmacología , Dermatitis del Pañal , Modelos Biológicos , Crema para la Piel/farmacología , Piel , Células Cultivadas , Cosméticos , Dermatitis Atópica , Dermatitis del Pañal/patología , Dermatitis del Pañal/fisiopatología , Humanos , Interleucina-1alfa/antagonistas & inhibidores , Interleucina-1alfa/metabolismo , Queratinocitos/efectos de los fármacos , Sustancias Protectoras/farmacología , Piel/efectos de los fármacos , Piel/fisiopatología , Dodecil Sulfato de SodioRESUMEN
After cutaneous injury, keratinocytes secrete paracrine factors that regulate wound cell functions; dysregulation of this signaling can lead to wound pathologies. Previously, we established that keratinocyte integrin α3ß1 promotes wound angiogenesis through paracrine stimulation of endothelial cells. We hypothesize here that α3ß1-dependent paracrine signaling from keratinocytes regulates the differentiation state of myofibroblasts. We report that epidermal α3-knockout mice exhibit more wound myofibroblasts and fewer cyclooxygenase 2 (Cox-2)-positive dermal cells than controls. We also found that conditioned medium from α3-expressing mouse keratinocytes (MKα3+), but not from α3-null MK cells (MKα3-), induces expression of Cox-2 in fibroblasts in a time- and dose-dependent manner and that this induction is mediated by IL-1α. Compared with MKα3- cells, MKα3+ cells secrete more IL-1α and less IL-1RA, a natural IL-1 receptor antagonist. Treatment with an IL-1α neutralizing antibody, recombinant IL-1RA, or IL-1 receptor-targeting small interfering RNA suppresses MKα3+ conditioned medium-dependent induction of Cox-2 expression in fibroblasts. Finally, active recombinant IL-1α is sufficient to induce Cox-2 in fibroblasts and to inhibit transforming growth factor-ß-induced α-SMA expression. Our findings support a role for keratinocyte integrin α3ß1 in controlling the secretion of IL-1α, a paracrine factor that regulates the wound myofibroblast phenotype.
Asunto(s)
Integrina alfa3beta1/metabolismo , Interleucina-1alfa/metabolismo , Queratinocitos/metabolismo , Miofibroblastos/fisiología , Comunicación Paracrina/fisiología , Actinas/metabolismo , Animales , Diferenciación Celular/efectos de los fármacos , Diferenciación Celular/inmunología , Línea Celular , Medios de Cultivo Condicionados/metabolismo , Ciclooxigenasa 2/metabolismo , Epidermis/inmunología , Epidermis/metabolismo , Humanos , Integrina alfa3/genética , Integrina alfa3/metabolismo , Integrina alfa3beta1/inmunología , Proteína Antagonista del Receptor de Interleucina 1/metabolismo , Interleucina-1alfa/antagonistas & inhibidores , Interleucina-1alfa/inmunología , Queratinocitos/inmunología , Ratones , Ratones Noqueados , Comunicación Paracrina/efectos de los fármacos , Repitelización/inmunología , Receptores de Interleucina-1/antagonistas & inhibidores , Receptores de Interleucina-1/genética , Receptores de Interleucina-1/metabolismo , Proteínas Recombinantes/metabolismo , Piel/citología , Piel/inmunología , Piel/lesionesRESUMEN
AIMS: Targeting interleukin-1 (IL-1) represents a novel therapeutic approach to atherosclerosis. CANTOS demonstrated the benefits of IL-1ß neutralization in patients post-myocardial infarction with residual inflammatory risk. Yet, some mouse data have shown a prominent role of IL-1α rather than IL-1ß in atherosclerosis, or even a deleterious effect of IL-1 on outward arterial remodelling in atherosclerosis-susceptible mice. To shed light on these disparate results, this study investigated the effect of neutralizing IL-1α or/and IL-1ß isoforms starting either early in atherogenesis or later in ApoE-/- mice with established atheroma. METHODS AND RESULTS: The neutralization of IL-1α or of both IL-1 isoforms impaired outward remodelling during early atherogenesis as assessed by micro-computed tomographic and histologic assessment. In contrast, the neutralization of IL-1ß did not impair outward remodelling either during early atherogenesis or in mice with established lesions. Interleukin-1ß inhibition promoted a slant of blood monocytes towards a less inflammatory state during atherogenesis, reduced the size of established atheromata, and increased plasma levels of IL-10 without limiting outward remodelling of brachiocephalic arteries. CONCLUSION: This study established a pivotal role for IL-1α in the remodelling of arteries during early experimental atherogenesis, whereas IL-1ß drives inflammation during atherogenesis and the evolution of advanced atheroma in mice.
Asunto(s)
Aterosclerosis/metabolismo , Interleucina-1alfa/metabolismo , Interleucina-1beta/metabolismo , Animales , Arteritis/metabolismo , Modelos Animales de Enfermedad , Interleucina-1alfa/antagonistas & inhibidores , Interleucina-1alfa/sangre , Interleucina-1beta/antagonistas & inhibidores , Interleucina-1beta/sangre , Masculino , Ratones , Ratones Noqueados , Monocitos/metabolismo , Placa Aterosclerótica/metabolismoRESUMEN
OBJECTIVE: To assess the efficacy and safety of the anti-interleukin-1α/ß (anti-IL-1α/ß) dual variable domain immunoglobulin lutikizumab (ABT-981) in patients with knee osteoarthritis (OA) and evidence of synovitis. METHODS: Patients (n = 350; 347 analyzed) with Kellgren/Lawrence grade 2-3 knee OA and synovitis (determined by magnetic resonance imaging [MRI] or ultrasound) were randomized to receive placebo or lutikizumab 25, 100, or 200 mg subcutaneously every 2 weeks for 50 weeks. The coprimary end points were change from baseline in Western Ontario and McMaster Universities Osteoarthritis Index (WOMAC) pain score at week 16 and change from baseline in MRI-assessed synovitis at week 26. RESULTS: The WOMAC pain score at week 16 had improved significantly versus placebo with lutikizumab 100 mg (P = 0.050) but not with the 25 mg or 200 mg doses. Beyond week 16, the WOMAC pain score was reduced in all groups but was not significantly different between lutikizumab-treated and placebo-treated patients. Changes from baseline in MRI-assessed synovitis at week 26 and other key symptom- and most structure-related end points at weeks 26 and 52 were not significantly different between the lutikizumab and placebo groups. Injection site reactions, neutropenia, and discontinuations due to neutropenia were more frequent with lutikizumab versus placebo. Reductions in neutrophil and high-sensitivity C-reactive protein levels plateaued with lutikizumab 100 mg, with further reductions not observed with the 200 mg dose. Immunogenic response to lutikizumab did not meaningfully affect systemic lutikizumab concentrations. CONCLUSION: The limited improvement in the WOMAC pain score and the lack of synovitis improvement with lutikizumab, together with published results from trials of other IL-1 inhibitors, suggest that IL-1 inhibition is not an effective analgesic/antiinflammatory therapy in most patients with knee OA and associated synovitis.
Asunto(s)
Inmunoglobulinas/uso terapéutico , Osteoartritis de la Rodilla/tratamiento farmacológico , Sinovitis/tratamiento farmacológico , Anciano , Proteína C-Reactiva/inmunología , Método Doble Ciego , Femenino , Humanos , Reacción en el Punto de Inyección/etiología , Interleucina-1alfa/antagonistas & inhibidores , Interleucina-1beta/antagonistas & inhibidores , Masculino , Persona de Mediana Edad , Neutropenia/inducido químicamente , Neutrófilos , Osteoartritis de la Rodilla/complicaciones , Osteoartritis de la Rodilla/diagnóstico por imagen , Osteoartritis de la Rodilla/inmunología , Sinovitis/diagnóstico por imagen , Sinovitis/etiología , Sinovitis/inmunología , Resultado del TratamientoRESUMEN
OBJECTIVE: Gangliosides, ubiquitously existing membrane components that modulate transmembrane signaling and mediate cell-to-cell and cell-to-matrix interactions, are key molecules of inflammatory and neurological disorders. However, the functions of gangliosides in the cartilage degradation process remain unclear. We investigated the functional role of gangliosides in cartilage metabolism related to osteoarthritis (OA) pathogenesis. DESIGN: We generated knockout (KO) mice by targeting the ß1, 4-N-acetylgalactosaminyltransferase (GalNAcT) gene, which encodes an enzyme of major gangliosides synthesis, and the GD3 synthase (GD3S) gene, which encodes an enzyme of partial gangliosides synthesis. In vivo OA and in vitro cartilage degradation models were used to evaluate the effect of gangliosides on the cartilage degradation process. RESULTS: The GalNAcT and GD3S KO mice developed and grew normally; nevertheless, OA changes in these mice were enhanced with aging. The GalNAcT KO mice showed significantly enhanced OA progression compared to GD3S mice in vivo. Both GalNAcT and GD3S KO mice showed severe IL-1α-induced cartilage degradation ex vivo. Phosphorylation of MAPKs was enhanced in both GalNAcT and GD3S KOs after IL-1α stimulation. Gangliosides modulated by GalNAcT or GD3S rescued an increase of MMP-13 induced by IL-1α in mice lacking GalNAcT or GD3S after exogenous replenishment in vitro. CONCLUSION: These data show that the deletion of gangliosides in mice enhanced OA development. Moreover, the gangliosides modulated by GalNAcT are important for cartilage metabolism, suggesting that GalNAcT is a potential target molecule for the development of novel OA treatments.
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Artritis Experimental/metabolismo , Cartílago Articular/metabolismo , Gangliósidos/fisiología , Osteoartritis/metabolismo , Envejecimiento/fisiología , Animales , Artritis Experimental/patología , Cartílago Articular/efectos de los fármacos , Cartílago Articular/patología , Células Cultivadas , Condrocitos/efectos de los fármacos , Condrocitos/metabolismo , Progresión de la Enfermedad , Gangliósidos/deficiencia , Gangliósidos/farmacología , Eliminación de Gen , Crecimiento/genética , Interleucina-1alfa/antagonistas & inhibidores , Interleucina-1alfa/farmacología , Sistema de Señalización de MAP Quinasas/efectos de los fármacos , Sistema de Señalización de MAP Quinasas/fisiología , Masculino , Metaloproteinasa 13 de la Matriz/biosíntesis , Ratones Noqueados , N-Acetilgalactosaminiltransferasas/deficiencia , N-Acetilgalactosaminiltransferasas/genética , N-Acetilgalactosaminiltransferasas/fisiología , Óxido Nítrico/metabolismo , Osteoartritis/patología , Sialiltransferasas/deficiencia , Sialiltransferasas/genética , Sialiltransferasas/fisiología , Técnicas de Cultivo de Tejidos , Regulación hacia Arriba/fisiología , Polipéptido N-AcetilgalactosaminiltransferasaAsunto(s)
Alarminas/inmunología , Interleucina-1alfa/inmunología , Espacio Intracelular/inmunología , Neoplasias/inmunología , Alarminas/antagonistas & inhibidores , Alarminas/metabolismo , Animales , Anticuerpos Neutralizantes/inmunología , Anticuerpos Neutralizantes/uso terapéutico , Humanos , Interleucina-1alfa/antagonistas & inhibidores , Interleucina-1alfa/metabolismo , Espacio Intracelular/efectos de los fármacos , Espacio Intracelular/metabolismo , Neoplasias/tratamiento farmacológico , Neoplasias/metabolismo , Resultado del Tratamiento , Microambiente Tumoral/efectos de los fármacos , Microambiente Tumoral/inmunologíaRESUMEN
BACKGROUND: Currently while, topical minoxidil and oral finasteride are the only medications approved in androgenetic alopecia (AGA), the cause oriented treatment and immunsupressive treatment are being performed in telogen effluvium (TE) and alopecia areata (AA) respectively. Considering the inflammatory factors in the pathogenesis of these three nonscarring alopecia forms, we have formulated a mixture for topical usage composed of six different herbal extracts (HE) which have already known antiinflammatory and antioxidant features. MATERIALS AND METHODS: In addition to performing the phytochemical analysis of HE, we detected the gene expression level of IL-1α, the crucial hair loss mediator, for the putative efficacy in nonscarring alopecia. Cell proliferation assay was performed by XTT reagent. After determination of non-cytotoxic concentration, HaCaT cells were treated with HE. RNA isolations were carried out from both non-treated and treated cell groups by using TRI-reagent. Gene expressions of IL-1α and as control GAPDH were determined by RT-qPCR analysis. RESULTS: Results were represented as "IL-1α/GAPDH Fold Change". HE solution caused statistically significant downregulation of IL-1α gene expressions (p<0.0001), compared to untreated control cells. HE treatment ended up with 0.1900 fold change for IL-1α. CONCLUSION: IL-1α is a direct growth inhibitory agent in hair follicles and an important actor in the pathogenesis of AGA , TE, and AA. Considering together the vitamins, flavonoids, and trace elements identified in the phytochemical analyses and downregulation of IL-1α in HaCaT cells, our HE may be an auxiliary agent in the therapy of these three nonscarring alopecia forms.
Asunto(s)
Alopecia , Regulación hacia Abajo/efectos de los fármacos , Interleucina-1alfa , Extractos Vegetales , Administración Tópica , Alopecia/tratamiento farmacológico , Alopecia/genética , Alopecia/inmunología , Células Cultivadas , Flavonoides/administración & dosificación , Perfilación de la Expresión Génica/métodos , Preparaciones para el Cabello/química , Preparaciones para el Cabello/farmacología , Humanos , Interleucina-1alfa/antagonistas & inhibidores , Interleucina-1alfa/genética , Queratinocitos/efectos de los fármacos , Fitoterapia/métodos , Extractos Vegetales/química , Extractos Vegetales/farmacología , Oligoelementos/administración & dosificación , Vitaminas/administración & dosificaciónRESUMEN
PURPOSE OF REVIEW: Cachexia is defined as ongoing loss of skeletal muscle mass, with or without depletion of adipose tissue and is a common syndrome in cancer patients, affecting 50% of those diagnosed. Cachexia, which cannot be fully reversed and causes significant functional impairment is caused by various mechanisms such as an altered energy balance and disruption of homeostatic control by the central nervous system. This central nervous system deregulation involves hypothalamic pituitary adrenal (HPA) axis stimulation, which can be triggered by IL-1R1 engagement on neuronal processes and endothelium in the microvasculature of the hypothalamus. This review will explore current evidence regarding both the importance of IL-1α in the various components of cancer cachexia and its potential as a therapeutic target. RECENT FINDINGS: IL-1α, which signals through IL-1R1, has been identified as a key agonist in the IL-1 pathway. As such, IL-1α has been explored as a therapeutic target in cancer cachexia, leading to the development of bermekimab, a mAb which neutralizes IL-1α. With a limited array of medication currently available to treat cancer cachexia, bermekimab represents a possible therapy. SUMMARY: IL-1α is a key mediator in cachexia development and targeting this may be a viable therapeutic target.