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AIMS: Although the cannabinoid CB1 receptor has been implicated in atherosclerosis, its cell-specific effects in this disease are not well understood. To address this, we generated a transgenic mouse model to study the role of myeloid CB1 signaling in atherosclerosis. METHODS AND RESULTS: Here, we report that male mice with myeloid-specific Cnr1 deficiency on atherogenic background developed smaller lesions and necrotic cores than controls, while only minor genotype differences were observed in females. Male Cnr1 deficient mice showed reduced arterial monocyte recruitment and macrophage proliferation with less inflammatory phenotype. The sex-specific differences in proliferation were dependent on estrogen receptor (ER)α-estradiol signaling. Kinase activity profiling identified a CB1-dependent regulation of p53 and cyclin-dependent kinases. Transcriptomic profiling further revealed chromatin modifications, mRNA processing and mitochondrial respiration among the key processes affected by CB1 signaling, which was supported by metabolic flux assays. Chronic administration of the peripherally-restricted CB1 antagonist JD5037 inhibited plaque progression and macrophage proliferation, but only in male mice. Finally, CNR1 expression was detectable in human carotid endarterectomy plaques and inversely correlated with proliferation, oxidative metabolism and inflammatory markers, suggesting a possible implication of CB1-dependent regulation in human pathophysiology. CONCLUSION: Impaired macrophage CB1 signaling is atheroprotective by limiting their arterial recruitment, proliferation and inflammatory reprogramming in male mice. The importance of macrophage CB1 signaling appears to be sex-dependent.
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Food antigens are closely related to progression of inflammatory bowel disease; however, details of how they induce intestinal immune responses and causes intestinal inflammation is not yet clear. The present study aimed to examine the effects of oral collagen on the intestinal mucosa, and elucidate the mechanism of food antigen-induced enteritis. Here, we provide evidence that Aspirin (a mucosal-damaging agent) and type II collagen (CII; a food antigen) acted synergistically to disrupt the intestinal mucosal barrier, and increase intestinal permeability, which resulted in a large amount of CII entered into the lamina propria, where it interacted with the intestinal immune system, promoted intestinal inflammation, and shaped innate and adaptive immune reactions into Th1-dominant. The underlying mechanism of the CII-induced intestinal inflammation may associate with higher levels of Th1, TLR2 and TLR4, and lower levels of Th2 in the intestine of Aspirin + CII treated rats. The study indicate that compromised integrity of the intestinal barrier appears to be a prerequisite for CII-induced intestinal inflammation. The synergistic effect of food antigens and mucosal barrier injury is an important cause of intestinal inflammation. This new understanding the role of food antigen on intestinal inflammation will provide us with a new strategy for treatment and prevention of intestinal inflammation.
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Aspirina/toxicidad , Colitis/inducido químicamente , Colágeno Tipo II/toxicidad , Inflamación/patología , Mucosa Intestinal/patología , Células TH1/inmunología , Receptor Toll-Like 2/inmunología , Animales , Antiinflamatorios no Esteroideos/toxicidad , Colitis/patología , Modelos Animales de Enfermedad , Femenino , Inflamación/inducido químicamente , Inflamación/inmunología , Inflamación/metabolismo , Mucosa Intestinal/efectos de los fármacos , Mucosa Intestinal/inmunología , Mucosa Intestinal/metabolismo , Ratas , Ratas Wistar , Receptor Toll-Like 4/inmunologíaRESUMEN
It has been universally acknowledged that interleukin37 (IL37) has an immunosuppressive effect on various inflammatory disorders. However, whether IL37 participates in the acute inflammation associated with coronary heart disease (CHD) has not yet been clarified. In the present study, the association between the serum levels of IL37 and the clinical indexes of CHD were analysed. In addition, the antiinflammatory effects of IL37 on peripheral blood mononuclear cells (PBMCs) were studied in CHD patients. PBMCs from 46 healthy controls (HCs) and 92 CHD patients were cultured in vitro and stimulated using the recombinant IL37 protein. The protein levels, as well as the mRNA expression of inflammatory cytokines (TNFα, IL1ß, IL6, and IL17) were analysed by enzymelinked immunosorbent assay (ELISA) and realtime polymerase chain reaction (RTPCR). Spearman's correlation test was performed to examine the association between the serum level of IL37 and the levels of proinflammatory cytokines, certain clinical indexes, and disease activity during CHD. Compared to the HCs, the CHD patients, especially those with acute myocardial infarction, exhibited higher levels of IL37 in their PBMCs and sera. Serum levels of IL37 were associated with the levels of IL17, IL6, and TNFα, and clinical indexes such as the left ventricular ejection fraction (LVEF), aminoNterminal proplasma brain natriuretic peptide (NTproBNP) levels, and cardiac troponin T (cTnT) levels in CHD patients. Compared to the HC group, the production of inflammatory cytokines such as IL17, IL6, TNFα, and IL1ß increased in the PBMCs of CHD patients and significantly decreased after the stimulation of the cells with recombinant IL37. The IL37 levels in CHD patients were high, and were correlated with the levels of CHDrelated proinflammatory cytokines and disease activity. Notably, the expression of CHDrelated proinflammatory cytokines in the PBMCs of CHD patients decreased following the stimulation of the cells with recombinant IL37, indicating that IL37 exerts antiinflammatory effects during CHD.
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Enfermedad Coronaria/sangre , Interleucina-1/sangre , Leucocitos Mononucleares/metabolismo , Anciano , Enfermedad Coronaria/patología , Enfermedad Coronaria/prevención & control , Femenino , Humanos , Inflamación/sangre , Inflamación/patología , Inflamación/prevención & control , Interleucina-1/farmacología , Leucocitos Mononucleares/patología , Masculino , Persona de Mediana Edad , Proteínas Recombinantes/farmacologíaRESUMEN
IL-10 is an immunosuppressive cytokine produced and sensed by many immune cells and exerts a protective role in autoimmune diseases. However, the underlying mechanism by which IL-10 contributes to prevent the arthritic inflammation in macrophages is poorly understood. Herein we report on a novel anti-arthritic property of IL-10 through the inhibition of IL-33 signaling by macrophages during collagen-induced arthritis (CIA) development. We show that IL-33 expression rather than its receptor (ST2) is positively correlated with IL-10 level in active RA. IL-10 deficiency in mice leads to significant upregulation of IL-33 expression and aggravates the progression of CIA, while exogenous IL-10 treatment effectively diminishes IL-33 production in IL-10 knockout (IL-10-/-) CIA mice. We demonstrate further that the inhibitory effect of IL-10 in suppressing IL-33 production requires STAT3 activation in macrophages. Furthermore, IL-33 stimulated proinflammatory genes are notably increased in IL-10-/- CIA mice, whereas macrophages treated with recombinant IL-10 exhibit decreased IL-33 amplified inflammation and inhibited IL-33 activated NF-κB signaling pathway. Our findings indicate that IL-10 act as a negative regulator of IL-33/ST2 signaling pathways in vivo, suggesting a potential therapeutic role of IL-10 in autoimmune diseases.
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Artritis Reumatoide/metabolismo , Proteína 1 Similar al Receptor de Interleucina-1/metabolismo , Interleucina-10/metabolismo , Interleucina-33/metabolismo , Macrófagos/metabolismo , Animales , Artritis Reumatoide/patología , Femenino , Humanos , Inflamación/metabolismo , Inflamación/patología , Interleucina-10/deficiencia , Macrófagos/patología , Masculino , Ratones Endogámicos C57BL , Ratones Endogámicos DBA , Ratones Noqueados , Persona de Mediana EdadRESUMEN
BACKGROUND: Interleukin-37 (IL-37) has been known to play an immunosuppressive role in various inflammatory disorders, but whether it participates in the regulation of pathogenesis of ankylosing spondylitis (AS) has not been investigated. Here, we examined the serum levels of IL-37 and its clinical association in AS, and explored the anti-inflammatory effects of IL-37 on peripheral blood mononuclear cells (PBMCs) from AS patients. METHODS: The mRNA levels of IL-37, TNF-α, IL-6, IL-17, and IL-23 in PBMCs and their serum concentrations from 46 AS patients were examined by real-time polymerase chain reaction (RT-PCR) and enzyme-linked immunoassay (ELISA), respectively. The correlations between serum IL-37 levels with disease activity, laboratory values and pro-inflammatory cytokines in AS were analyzed by Spearman correlation test. PBMCs from 46 AS patients were stimulated with recombinant IL-37 protein, expressions of TNF-α, IL-6, IL-17 and IL-23 were determined by RT-PCR and ELISA. RESULTS: Compared to healthy controls (HC), AS patients and active AS patients showed higher levels of IL-37 in PBMCs and serum respectively. Strikingly, serum IL-37 levels were higher in AS patients with osteoporosis than those without. Serum levels of IL-37 were correlated with laboratory values as well as TNF-α, IL-6 and IL-17, but not IL-23 in patients with AS. The productions of pro-inflammatory cytokines such as TNF-α, IL-6, IL-17, IL-23 in PBMCs from AS patients were obviously attenuated after recombinant IL-37 stimulation, but not in the HC. CONCLUSION: The higher levels of IL-37 were found in AS patients, which were correlated with disease activity and AS related pro-inflammatory cytokines. More importantly, IL-37 inhibits the expressions of the pro-inflammatory cytokines from PBMCs in AS patients, indicating the potential anti-inflammatory role of IL-37 in AS.
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Interleucina-1/sangre , Espondilitis Anquilosante/sangre , Adulto , Estudios de Casos y Controles , Femenino , Humanos , Mediadores de Inflamación/metabolismo , Interleucina-1/genética , Leucocitos Mononucleares/metabolismo , Masculino , Osteoporosis/sangre , Osteoporosis/complicaciones , ARN Mensajero/genética , ARN Mensajero/metabolismo , Proteínas Recombinantes/metabolismo , Espondilitis Anquilosante/complicaciones , Espondilitis Anquilosante/genéticaRESUMEN
BACKGROUND: Interleukin-37 (IL-37), a member of IL-1 family, is primarily an anti-inflammatory cytokine, which reduces systemic and local inflammation. However, the expression and role of IL-37 in Graves' disease (GD) remains unknown. This study aims to measure the levels of serum and peripheral blood mononuclear cells (PBMCs) IL-37 in patients with Graves' disease and to examine its association with disease activity. Furthermore, we investigate the effect of IL-37 on proinflammatory cytokines involved in the pathogenesis of GD. METHODS: The expressions of IL-37, TNF-α, IL-6, and IL-17 mRNA in peripheral blood mononuclear cells (PBMCs) of 40 patients with Graves' disease were determined by real-time reverse transcription-polymerase chain reaction (RT-PCR), and the levels of IL-37, TNF-α, IL-6, and IL-17 in serum were detected by enzyme-linked immunoassay (ELISA). The correlation of serum IL-37 levels with cytokines and disease activity in Graves' disease patients were investigated. The expressions of cytokines TNF-α, IL-6, and IL-17 in PBMCs under recombinant IL-37 stimulation were determined by RT-PCR and ELISA respectively. RESULTS: The levels of IL-37, TNF-α, IL-6, and IL-17 in PBMCs and serum were significantly increased in patients with GD compared with healthy controls (HC). Serum IL-37 were closely correlated with TNF-α, IL-6, IL-17, thyrotropin (TSH), free thyroxine (FT4),free triiodothyronine (FT3) and thyrotropin receptor antibody (TRAB). GD patients with active disease showed higher IL-37 mRNA and serum protein levels compared with those with inactive disease as well as HC. Moreover, IL-37 suppressed the production of IL-6, IL-17 and TNF-α in PBMCs of patients with GD. CONCLUSIONS: Increased level of IL-37 in patients with GD are associated with TNF-α, IL-6, IL-17 and disease activity, and it plays a protective role against inflammatory effect in GD by inhibiting the production of proinflammatory cytokines. Thus, IL-37 may provide a novel research target for the pathogenesis and therapy of GD.
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Citocinas/metabolismo , Expresión Génica , Enfermedad de Graves/genética , Enfermedad de Graves/metabolismo , Mediadores de Inflamación/metabolismo , Interleucina-1/genética , Leucocitos Mononucleares/metabolismo , Adulto , Estudios de Casos y Controles , Citocinas/sangre , Citocinas/genética , Femenino , Regulación de la Expresión Génica , Enfermedad de Graves/diagnóstico , Humanos , Interleucina-1/sangre , Interleucina-1/metabolismo , Masculino , Persona de Mediana Edad , ARN Mensajero/genética , ARN Mensajero/metabolismo , Adulto JovenRESUMEN
INTRODUCTION: Our objective in the present study was to determine the signaling pathway of interleukin 10 (IL-10) for modulating IL-17 expression in macrophages and the importance of this mediation in collagen-induced arthritis (CIA). METHODS: IL-10-knockout (IL-10â»/â») mice and wild-type (WT) mice were immunized with chicken type II collagen (CII) to induce arthritis. The expression levels of IL-17 and retinoid-related orphan receptor γt (RORγt) in macrophages and joint tissues of IL-10â»/â» and WT mice were analyzed by enzyme-linked immunosorbent assay, quantitative RT-PCR (qRT-PCR) and Western blotting. The F4/80 macrophages and positive IL-17-producing macrophages in synovial tissues of the mice were determined by immunohistochemistry. The populations of classically activated macrophage (M1) and alternatively activated macrophage (M2) phenotypes were analyzed by flow cytometry. The expression of genes associated with M1 and M2 markers was analyzed by qRT-PCR. RESULTS: Compared to WT mice, IL-10â»/â» mice had exacerbated CIA development, which was associated with increased production of T helper 17 cell (Th17)/Th1 proinflammatory cytokines and CII-specific immunoglobulin G2a antibody after CII immunization. Macrophages in IL-10â»/â» mice had increased amounts of IL-17 and RORγt compared with the amounts in WT mice with CIA. Immunofluorescence microscopy showed that the number of IL-17-producing macrophages in synovial tissues was significantly higher in IL-10â»/â» mice than in WT mice. IL-10 deficiency might promote macrophage polarization toward the proinflammatory M1 phenotype, which contributes to the rheumatoid arthritis inflammation response. CONCLUSION: IL-10 inhibits IL-17 and RORγt expression in macrophages and suppresses macrophages toward the proinflammatory M1 phenotype, which is important for the role of IL-10 in mediating the pathogenesis of CIA.
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Artritis Reumatoide/inmunología , Interleucina-10/inmunología , Interleucina-17/inmunología , Macrófagos/inmunología , Miembro 3 del Grupo F de la Subfamilia 1 de Receptores Nucleares/inmunología , Animales , Artritis Experimental/inmunología , Western Blotting , Ensayo de Inmunoadsorción Enzimática , Citometría de Flujo , Inmunohistoquímica , Masculino , Ratones , Ratones Endogámicos C57BL , Ratones Noqueados , Microscopía Confocal , Microscopía Fluorescente , Reacción en Cadena en Tiempo Real de la Polimerasa , Transducción de Señal/inmunologíaRESUMEN
BACKGROUND: Interleukin-37 (IL-37), a new member of IL-1 family cytokine, is recently identified as a natural inhibitor of innate immunity. This study aimed to measure the peripheral blood mononuclear cells (PBMCs) and serum levels of IL-37 in patients with systemic lupus erythematosus (SLE) and to investigate its role in SLE, including its correlation with disease activity, organ disorder and the regulation of inflammatory cytokines. METHODS: The expressions of IL-37 mRNAs in PBMCs and serum IL-37 levels in 66 SLE patients were measured by real-time polymerase chain reaction (RT-PCR) and enzyme-linked immunosorbent assay (ELISA). SLE patients PBMCs were stimulated with recombinant IL-37, levels of cytokines TNF-α, IL-1ß, IL-6 and IL-10 were detected by RT-PCR and ELISA. RESULTS: IL-37 mRNAs and serum protein levels were higher in patients with SLE compared with healthy controls. Patients with active disease showed higher IL-37 mRNAs and serum protein levels compared with those with inactive disease as well as healthy controls. Serum IL-37 levels correlated with SLEDAI and inversely with C3 and C4. Serum IL-37 levels were higher in SLE patients with renal involvement compared with those without renal disease. In vitro, IL-37 inhibited the production of TNF-α, IL-1ß and IL-6 in PBMCs of patients with SLE, whereas the production of IL-10 was unaffected. CONCLUSIONS: IL-37 associated with SLE disease activity, especially related with SLE renal disease activity. IL-37 is an important cytokine in the control of SLE pathogenesis by suppressing the production of inflammatory cytokines. Thus, IL-37 may provide a novel research target for the pathogenesis and therapy of SLE.
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Citocinas/sangre , Progresión de la Enfermedad , Mediadores de Inflamación/sangre , Interleucina-1/sangre , Leucocitos Mononucleares/metabolismo , Lupus Eritematoso Sistémico/sangre , Lupus Eritematoso Sistémico/patología , Adolescente , Adulto , Proteínas Sanguíneas/metabolismo , Estudios de Casos y Controles , Citocinas/biosíntesis , Demografía , Femenino , Regulación de la Expresión Génica/efectos de los fármacos , Humanos , Interleucina-1/genética , Riñón/efectos de los fármacos , Riñón/patología , Leucocitos Mononucleares/efectos de los fármacos , Lupus Eritematoso Sistémico/genética , Lupus Eritematoso Sistémico/inmunología , Masculino , Persona de Mediana Edad , ARN Mensajero/genética , ARN Mensajero/metabolismo , Proteínas Recombinantes de Fusión/farmacología , Adulto JovenRESUMEN
To gain further insights into the molecular basis of Sulforaphane (SF) mediated retinal pigment epithelial (RPE) 19 cell against oxidative stress, we investigated the effects of SF on the regulation of gene expression on a global scale and tested whether SF can endow RPE cells with the ability to resist apoptosis. The data revealed that after exposure to H2O2, RPE 19 cell viability was increased in the cells pretreated with SF compared to the cell not treated with SF. Microarray analysis revealed significant changes in the expression of 69 genes in RPE 19 cells after 6 hours of SF treatment. Based on the functional relevance, eight of the SF-responsive genes, that belong to antioxidant redox system, and inflammatory responsive factors were validated. The up-regulating translation of thioredoxin-1 (Trx1) and the nuclear translocation of Nuclear factor-like2 (Nrf2) were demonstrated by immunoblot analysis in SF treated RPE cells. Our data indicate that SF increases the ability of RPE 19 cell against oxidative stress through up-regulating antioxidative enzymes and down-regulating inflammatory mediators and chemokines. The results suggest that the antioxidant, SF, may be a valuable supplement for preventing and retarding the development of Age Related Macular Degeneration.