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1.
Adv Exp Med Biol ; 1240: 95-110, 2020.
Artigo em Inglês | MEDLINE | ID: mdl-32060891

RESUMO

The ability of the immune system to prevent or control the growth of tumor cells is critically dependent on inflammatory processes that lead to the activation, expansion, and recruitment of antitumor effector cells into the tumor microenvironment (TME). These processes are orchestrated by soluble cytokines produced in tissues that alarm local immune surveillance cells (such as dendritic cells, DCs) to mobilize protective antitumor immune populations (B cells, T cells). The interleukin (IL)-36 family of pro-inflammatory cytokines plays an important role in multiple disease processes, ranging from an instigator of autoimmune psoriasis to an initiator of therapeutic immune responses against tumor cells. This chapter will focus on the biologic role of immunomodulatory IL-36 family cytokines in the cancer setting and their potential utility in the design of effective interventional therapies. (127 words).


Assuntos
Interleucina-1/imunologia , Interleucina-1/metabolismo , Neoplasias/imunologia , Microambiente Tumoral , Animais , Células Dendríticas/imunologia , Humanos , Linfócitos T/imunologia
2.
Adv Exp Med Biol ; 1240: 1-23, 2020.
Artigo em Inglês | MEDLINE | ID: mdl-32060884

RESUMO

Interleukin 1 (IL-1) has long been known for its pleiotropic effects on inflammation that plays a complex, and sometimes contrasting, role in different stages of cancer development. As a major proinflammatory cytokine, IL-1ß is mainly expressed by innate immune cells. IL-1α, however, is expressed by various cell types under physiological and pathological conditions. IL-1R1 is the main receptor for both ligands and is expressed by various cell types, including innate and adaptive immune cell types, epithelial cells, endothelial cells, adipocytes, chondrocytes, fibroblasts, etc. IL-1 and IL-1R1 receptor interaction leads to a set of common signaling pathways, mainly the NF-kB and MAP kinase pathways, as a result of complex positive and negative regulations. The variety of cell types with IL-1R1 expression dictates the role of IL-1 signaling at different stages of cancer, which under certain circumstances leads to contrasting roles in tumor development. Recent availability of IL-1R1 conditional knockout mouse model has made it possible to dissect the role of IL-1/IL-1R1 signaling transduction in different cell types within the tumor microenvironment. This chapter will focus on the role of IL-1/IL-1R1 in different cell types within the tumor microenvironment and discuss the potential of targeting this pathway in cancer therapy.


Assuntos
Interleucina-1/imunologia , Interleucina-1/metabolismo , Transdução de Sinais , Microambiente Tumoral , Animais , Humanos , Mediadores da Inflamação/imunologia , Mediadores da Inflamação/metabolismo , Interleucina-1/antagonistas & inibidores , Camundongos Knockout , Neoplasias/tratamento farmacológico , Neoplasias/imunologia , Neoplasias/metabolismo , Transdução de Sinais/efeitos dos fármacos , Transdução de Sinais/imunologia , Microambiente Tumoral/efeitos dos fármacos , Microambiente Tumoral/imunologia
3.
Chem Pharm Bull (Tokyo) ; 68(2): 133-139, 2020.
Artigo em Inglês | MEDLINE | ID: mdl-32009080

RESUMO

C1q/tumor necrosis factor (TNF)-related protein 12 (CTRP12) is a secretory protein that participates in the regulation of glucose and lipid metabolism in obesity and diabetes. Its role in cardiovascular disease, particularly sepsis-induced cardiac injury, is unclear. Here, we stimulated cardiomyocytes with lipopolysaccharide (LPS) to establish an in vitro cardiomyocyte injury model and CTRP12 was overexpressed with an adenovirus delivery system. Overexpression of CTRP12 reduced the transcription and release of pro-inflammatory cytokines from LPS-stimulated cardiomyocytes, including TNFα, interleukin-1 (IL-1), and IL-6. Reactive oxygen species (ROS) level increased and the oxidation/redox system was disturbed in LPS-stimulated cardiomyocytes, as evident from the decrease in superoxide dismutase activity and an increase in reduced nicotinamide adenine dinucleotide phosphate (NADPH) oxidase activity and malondialdehyde level. CTRP12 overexpression decreased the increasing level of ROS and ameliorated the unbalance in the oxidation/redox system in LPS-stimulated cardiomyocytes. The viability of cardiomyocytes decreased after LPS stimulation, and the cells underwent apoptosis. CTRP12-overexpressing cardiomyocytes showed a decrease in the number of terminal deoxynucleotidyl transferase-mediated deoxyuridine triphosphate nick-end labeling (TUNEL)-positive cells, and the ratio of B cell lymphoma (Bcl)-1/Bax in these cells was recovered. In comparison with the control group, LPS-stimulated cardiomyocytes showed reduced expression of nuclear factor E2-related factor 2 (NRF2), while CTRP12-overexpressing cardiomyocytes showed elevated NRF2 expression. Small-interfering RNA-mediated silencing of NRF2 expression in cardiomyocytes resulted in the inhibition of the protective effects of CTRP12. Thus, CTRP12 ameliorated injury in LPS-stimulated cardiomyocytes in an NRF2-dependent manner.


Assuntos
Inflamação/genética , Lipopolissacarídeos/imunologia , Miócitos Cardíacos/imunologia , Regulação para Cima , Adenoviridae/genética , Animais , Linhagem Celular , Células Cultivadas , Regulação para Baixo , Técnicas de Transferência de Genes , Inflamação/imunologia , Inflamação/patologia , Interleucina-1/genética , Interleucina-1/imunologia , Interleucina-6/genética , Interleucina-6/imunologia , Miócitos Cardíacos/metabolismo , Miócitos Cardíacos/patologia , Ratos , Ratos Sprague-Dawley , Fator de Necrose Tumoral alfa/genética , Fator de Necrose Tumoral alfa/imunologia
4.
Adv Exp Med Biol ; 1209: 109-123, 2019.
Artigo em Inglês | MEDLINE | ID: mdl-31728867

RESUMO

Inflammasome is a molecular platform that mediates the activation of caspases, maturation of interleukin-1 (IL-1) family members, and leads to inflammatory cell death called pyroptosis. It is vital for innate immune responses, providing protection against infectious agents, sterile environmental insults, and host cell damages. Aberrant activation of inflammasome is closely correlated with numerous hereditary and acquired inflammatory disorders. Therefore, a better understanding of how inflammasome is regulated may provide more promising therapeutics for controlling inflammasome-associated diseases. In recent years, it becomes apparent that autophagy, a cellular machinery essential for the recycling of intracellular components and maintenance of cellular homeostasis, acts as a key player in the activation and regulation of inflammasome, and ameliorates symptoms of inflammasome-related diseases. This review will discuss the recent insights into inflammasome activation and regulation mediated by autophagy.


Assuntos
Autofagia , Inflamassomos , Autofagia/imunologia , Caspases/metabolismo , Ativação Enzimática , Humanos , Imunidade Inata/imunologia , Inflamassomos/imunologia , Interleucina-1/imunologia , Piroptose/imunologia
5.
Nat Commun ; 10(1): 4700, 2019 10 16.
Artigo em Inglês | MEDLINE | ID: mdl-31619669

RESUMO

The functions of the IL-36 cytokines remain poorly understood. We report a previously unrecognized mechanism whereby IL-36 promotes innate antiviral immunity in mouse and human models of herpes simplex virus-1 (HSV-1) infections. HSV-1 actively suppresses production of type I interferon (IFN); our data reveal that IL-36 overcomes this immune evasion strategy by increasing cellular sensitivity to IFN. IL-36ß deficient mice display impaired IFN responses and poorly restrict viral replication in skin keratinocytes. In mouse and human keratinocytes IL-36 elicits an antiviral state driven by STAT1 and STAT2 via enhanced expression of IFNAR1 and IFNAR2 subunits of the type I IFN receptor. The degree of IFN regulatory factor 1 (IRF1) involvement is species dependent, with IRF1 playing a more prominent role in human cells. Similar mechanisms are activated by IL-1. Overall, IL-36 acts as an antiviral cytokine by potentiating type I IFN signaling and thereby upholds immune responses to viruses that limit the production of IFNs.


Assuntos
Herpes Simples/imunologia , Interferon Tipo I/imunologia , Interleucina-1/imunologia , Receptor de Interferon alfa e beta/genética , Animais , Modelos Animais de Doenças , Herpesvirus Humano 1 , Humanos , Evasão da Resposta Imune , Fator Regulador 1 de Interferon/imunologia , Interleucina-1/genética , Queratinócitos , Camundongos , Camundongos Knockout , Receptor de Interferon alfa e beta/metabolismo , Fator de Transcrição STAT1/imunologia , Fator de Transcrição STAT2/imunologia , Regulação para Cima
6.
Chin Med Sci J ; 34(3): 199-204, 2019 Sep 30.
Artigo em Inglês | MEDLINE | ID: mdl-31601303

RESUMO

Objective Psoriasis is an immune-mediated inflammatory disease. Despite advances in the study of its pathogenesis, the exact development mechanism of psoriasis remains to be fully elucidated. Hyperproliferative epidermis plays a crucial role in psoriasis. This study aimed to investigate the effects of interleukin-36ß (IL-36ß) on keratinocyte dysfunction in vitro. Methods Human keratinocyte cell lines, HaCaT cells, were treated with 0 (control), 50 or 100 ng/ml IL-36ß respectively for 24 h. Cell viability was determined with a cell counting kit-8 assay. Flow cytometry was used to assess the effects of IL-36ß on apoptosis and cell cycle distribution. Expressions of the differentiation markers, such as keratin 10 and involucrin, were evaluated by quantitative real-time polymerase chain reaction (RT-qPCR). Expressions of the inflammatory cytokines, IL-1ß and IL-6 were tested by ELISA. Results CCK8 assay showed the survival rate had no significant difference between the control and treated group (P > 0.05). Flow cytometry analysis showed cell cycle arrest at S phase in the IL-36ß-treated groups compared with the control group (P < 0.05). RT-qPCR verified the decreased mRNA expressions of keratin 10 and involucrin in the IL-36ß-treated groups compared with the negative control (P < 0.01). ELISA showed 100 ng/ml IL-36ß enhanced levels of IL-1ß and IL-6 in culture supernatants of HaCaT cells compared with the negative control (P < 0.05). Conclusion Taken together, these findings suggest that IL-36ß could induce cell cycle arrest at S phase, inhibit keratin 10 and involucrin expressions and promote inflammatory activity in HaCaT cell lines.


Assuntos
Apoptose/imunologia , Diferenciação Celular/imunologia , Interleucina-1/imunologia , Queratinócitos/imunologia , Pontos de Checagem da Fase S do Ciclo Celular/imunologia , Humanos , Inflamação/imunologia , Inflamação/patologia , Interleucina-1beta/imunologia , Interleucina-6/imunologia , Queratina-10/imunologia , Queratinócitos/patologia , Precursores de Proteínas/imunologia
7.
BMC Neurol ; 19(1): 185, 2019 Aug 05.
Artigo em Inglês | MEDLINE | ID: mdl-31382910

RESUMO

BACKGROUND: Interleukin 36 (IL-36) cytokines belong to the IL-1 family and play an important role in some autoimmune diseases. However, the relationship between IL-36 and neuromyelitis optica spectrum disorders (NMOSD) remains unclear. METHODS: We determined serum IL-36α, IL-36ß and IL-36γ levels and assessed correlations with clinical characteristics in 50 NMOSD patients and 30 healthy controls (HC). RESULTS: The concentrations of serum IL-36ß and IL-36γ were significantly higher in patients with NMOSD than in HCs and decreased during remission. Serum IL-36ß levels were positively correlated with the annual relapse rate (ARR), spinal cord lesion length and Expanded Disability Status Scale (EDSS) scores. CONCLUSIONS: Serum IL-36ß and IL-36γ levels were related to disease activity in NMOSD patients and may be important biomarkers of NMOSD.


Assuntos
Biomarcadores/sangue , Interleucina-1/sangue , Interleucina-1/imunologia , Neuromielite Óptica/sangue , Neuromielite Óptica/imunologia , Adulto , Feminino , Humanos , Masculino , Pessoa de Meia-Idade
8.
Zhongguo Shi Yan Xue Ye Xue Za Zhi ; 27(4): 1201-1207, 2019 Aug.
Artigo em Chinês | MEDLINE | ID: mdl-31418380

RESUMO

OBJECTIVE: To study the correlation of IL-37 with T lymphocytes subsets and NK cells in ITP patients, and to explore its possible mechanisms involved in the pathogenesis of ITP. METHODS: Forty-five patients with newly diagnosed ITP(newly diagnosed group), 32 patients of complete remission (remission group) and 22 healthy persons(control group) were selected. The serum level of IL-37 in 3 groups was determined by enzyme linked immunosorbent assay (ELISA). The mRNA expression of IL-37, IL-17 and IL-18 in peripheral blood mononuclear cells(PBMNC) in 3 groups was measured by real-time fluorescence quantitative polymerase chain reaction (PCR). The number of IL-18Rα+CD4+ T cells and Tim-3+NK cells in the peripheral blood in 3 groups was detected by flow cytometry (FCM). RESULTS: The serum level of IL-37 in the peripheral blood of ITP patients in the newly diagnosed group was significantly higher than that in the control group and the remission group(P<0.01) . The expression level of IL-37 in PBMNC of the ITP patients in newly diagnosed group was higher than that in the control group and the remission group(P<0. 05). The expression level of IL-17 and IL-18 in PBMNC of the ITP patients in newly diagnosed group was higher than that in the control group and the remission group(P<0. 01); the expression of IL-18Rα in CD4+ T cells in newly diagnosed group was significantly higher than that in both the control and the remission group(P<0.01).The expression of Tim-3 in NK cells in ITP patients was significantly lower than that in the control group (P<0. 01). In ITP patients, the serum IL-37 level and IL-18Rα+CD4+T cells ratio both negatively correlated with Plt count (r=-0.58, r=-0.48) moreo-ver the serum IL-37 level also negatively correlated with amount of CD4+ T cells and NK cells (r=-0.29, r=-0.28), but positively correlated with amount of CD8+ T cells (r=0.329). CONCLUSION: The IL-37 and its receptors may play an immunoregulatory role in CD4+ T cells and NK cells, the IL-37 may be a therapeutic target for ITP patients.


Assuntos
Interleucina-1/imunologia , Púrpura Trombocitopênica Idiopática , Linfócitos T CD8-Positivos , Citometria de Fluxo , Humanos , Células Matadoras Naturais , Leucócitos Mononucleares , Subpopulações de Linfócitos T
9.
Nat Immunol ; 20(9): 1138-1149, 2019 09.
Artigo em Inglês | MEDLINE | ID: mdl-31427775

RESUMO

Interleukin (IL)-1R3 is the co-receptor in three signaling pathways that involve six cytokines of the IL-1 family (IL-1α, IL-1ß, IL-33, IL-36α, IL-36ß and IL-36γ). In many diseases, multiple cytokines contribute to disease pathogenesis. For example, in asthma, both IL-33 and IL-1 are of major importance, as are IL-36 and IL-1 in psoriasis. We developed a blocking monoclonal antibody (mAb) to human IL-1R3 (MAB-hR3) and demonstrate here that this antibody specifically inhibits signaling via IL-1, IL-33 and IL-36 in vitro. Also, in three distinct in vivo models of disease (crystal-induced peritonitis, allergic airway inflammation and psoriasis), we found that targeting IL-1R3 with a single mAb to mouse IL-1R3 (MAB-mR3) significantly attenuated heterogeneous cytokine-driven inflammation and disease severity. We conclude that in diseases driven by multiple cytokines, a single antagonistic agent such as a mAb to IL-1R3 is a therapeutic option with considerable translational benefit.


Assuntos
Anticorpos Bloqueadores/farmacologia , Anticorpos Monoclonais/farmacologia , Proteína Acessória do Receptor de Interleucina-1/antagonistas & inibidores , Peritonite/imunologia , Pneumonia/imunologia , Psoríase/imunologia , Células A549 , Animais , Linhagem Celular Tumoral , Modelos Animais de Doenças , Células HEK293 , Humanos , Imiquimode/toxicidade , Inflamação/patologia , Interleucina-1/imunologia , Proteína Acessória do Receptor de Interleucina-1/imunologia , Interleucina-1beta/imunologia , Interleucina-33/imunologia , Masculino , Camundongos , Camundongos Endogâmicos C57BL , Ovalbumina/toxicidade , Peritonite/tratamento farmacológico , Peritonite/patologia , Pneumonia/tratamento farmacológico , Pneumonia/patologia , Psoríase/tratamento farmacológico , Psoríase/patologia , Transdução de Sinais/imunologia , Ácido Úrico/toxicidade
10.
Korean J Parasitol ; 57(3): 217-223, 2019 Jun.
Artigo em Inglês | MEDLINE | ID: mdl-31284343

RESUMO

Acanthamoeba castellanii has ubiquitous distribution and causes primary acanthamoebic keratitis (AK). AK is a common disease in contact lens wearers and results in permanent visual impairment or blindness. In this study, we observed the cytopathic effect, in vitro cytotoxicity, and secretion pattern of cytokines in human corneal epithelial cells (HCECs) induced by A. castellanii trophozoites and/or cysts. Morphological observation revealed that panked dendritic HCECs co-cultured with amoeba cysts had changed into round shape and gradually died. Such changes were more severe in co-culture with cyst than those of co-cultivation with trophozoites. In vitro cytotoxicity assay revealed the highest cytotoxicity to HCECs in the co-culture system with amoeba cysts. A. castellanii induced the expression of IL-1α, IL-6, IL-8, and CXCL1 in HCECs. Secreted levels of IL-1α, IL-6, and IL-8 in HCECs co-cultured with both trophozoites and cysts were increased at an early incubation time (3 and 6 hr). These results suggested that cytopathic changes and pro-inflammatory cytokines release of HCECs in response to A. castellanii, especially amoebic cysts, are an important mechanism for AK development.


Assuntos
Ceratite por Acanthamoeba/imunologia , Acanthamoeba castellanii/fisiologia , Córnea/citologia , Células Epiteliais/imunologia , Trofozoítos/fisiologia , Ceratite por Acanthamoeba/parasitologia , Acanthamoeba castellanii/crescimento & desenvolvimento , Células Cultivadas , Córnea/imunologia , Córnea/parasitologia , Células Epiteliais/parasitologia , Humanos , Interleucina-1/genética , Interleucina-1/imunologia , Interleucina-6/genética , Interleucina-6/imunologia , Interleucina-8/genética , Interleucina-8/imunologia , Trofozoítos/crescimento & desenvolvimento
11.
Arthritis Rheumatol ; 71(11): 1849-1857, 2019 11.
Artigo em Inglês | MEDLINE | ID: mdl-31216122

RESUMO

OBJECTIVE: To define inflammation-related host-microbe interactions in experimental spondyloarthritis (SpA) using novel inter-omic approaches. METHODS: The relative frequency of gut microbes was determined by 16S ribosomal RNA (rRNA) gene sequencing, and gene expression using RNA-Seq of host tissue. HLA-B27/human ß2 -microglobulin-transgenic (HLA-B27-transgenic) and wild-type rats from dark agouti, Lewis, and Fischer backgrounds were used. Inter-omic analyses using Cytoscape were employed to identify relevant relationships. PICRUSt was used to predict microbial functions based on known metagenomic profiles. RESULTS: Inter-omic analysis revealed several gut microbes that were strongly associated with dysregulated cytokines driving inflammatory response pathways, such as interleukin-17 (IL-17), IL-23, IL-17, IL-1, interferon-γ (IFNγ), and tumor necrosis factor (TNF). Many microbes were uniquely associated with inflammation in Lewis or Fischer rats, and one was relevant on both backgrounds. Several microbes that were strongly correlated with immune dysregulation were not differentially abundant in HLA-B27-transgenic compared to wild-type controls. A multi-omic network analysis revealed non-overlapping clusters of microbes in Lewis and Fischer rats that were strongly linked to overlapping dysregulated immune/inflammatory genes. Prevotella, Clostridiales, and Blautia were important in Lewis rats, while Akkermansia muciniphila and members of the Lachnospiraceae family dominated in Fischer rats. Inflammation-associated metabolic pathway perturbation (e.g., butanoate, propanoate, lipopolysaccharide, and steroid biosynthesis) was also predicted from both backgrounds. CONCLUSION: Inter-omic and network analysis of gut microbes and the host immune response in experimental SpA provides an unprecedented view of organisms strongly linked to dysregulated IL-23, IL-17, IL-1, IFNγ, and TNF. Functional similarities between these organisms may explain why animals of different genetic backgrounds exhibit common patterns of immune dysregulation, possibly through perturbation of similar metabolic pathways. These results highlight the power of linking analyses of gut microbiota with the host immune response to gain insights into the role of dysbiotic microbes in SpA beyond taxonomic profiling.


Assuntos
Artrite Experimental/imunologia , Artrite Experimental/microbiologia , Citocinas/imunologia , Microbioma Gastrointestinal/genética , Antígeno HLA-B27/imunologia , Espondiloartropatias/imunologia , Espondiloartropatias/microbiologia , Animais , Clostridiales , Disbiose/imunologia , Disbiose/microbiologia , Feminino , Perfilação da Expressão Gênica , Antígeno HLA-B27/genética , Humanos , Interferon gama/imunologia , Interleucina-1/imunologia , Interleucina-17/imunologia , Interleucina-23/imunologia , Masculino , Prevotella , RNA Ribossômico 16S/genética , Ratos , Ratos Endogâmicos F344 , Ratos Endogâmicos Lew , Ratos Transgênicos , Fator de Necrose Tumoral alfa/imunologia , Verrucomicrobia
12.
Mol Immunol ; 112: 322-329, 2019 08.
Artigo em Inglês | MEDLINE | ID: mdl-31238287

RESUMO

OBJECTIVE: The morbidity and prevalence of type 2 diabetes mellitus (DM) are increasing in the elderly population. Interleukin 37 (IL-37) play important roles in anti-inflammatory and anti-bacteria immune responses, but its role in the development of type 2 DM in the elderly is unclear. Therefore, we investigated whether IL-37 is associated with type 2 DM in the elderly and the underlying mechanism. METHODS: Hospitalized patients (aged 65-95 years) with recently diagnosed type 2 diabetes mellitus were studied retrospectively and compared with healthy subjects without glucose metabolism abnormalities. A diabetic mouse model was established by feeding ob/ob mice (C57BL/6) a high-fat, carbohydrate-free diet. Plasma glucose and insulin levels were determined by glucose oxidase assay and radioimmunoassay, respectively. The IL-37 expression level was determined by real-time PCR, western blot and ELISA (Enzyme-linked immunoassay). RESULTS: Statistic analysis showed that the IL-37 level was significantly associated with type 2 DM and insulin resistance in the elderly. The patients were then divided into insulin therapy sensitive and resistant group according to their response to insulin therapy. Data showed that the IL-37 was highly expressed in the insulin therapy sensitive group. And this was related to the less severe gut microbiota dysbiosis. In the mice model, overexpressing the IL-37 could suppress the gut microbiota dysbiosis and also the diabetes development. CONCLUSION: Thus our results showed that higher IL-37 was associated with increased insulin sensitive in elderly type 2 DM patients through suppressing the gut microbiota dysbiosis.


Assuntos
Diabetes Mellitus Tipo 2/imunologia , Disbiose/imunologia , Microbioma Gastrointestinal/imunologia , Interleucina-1/imunologia , Idoso , Idoso de 80 Anos ou mais , Animais , Linhagem Celular , Diabetes Mellitus Experimental/imunologia , Diabetes Mellitus Experimental/microbiologia , Diabetes Mellitus Tipo 2/microbiologia , Dieta Hiperlipídica/efeitos adversos , Disbiose/microbiologia , Feminino , Células HEK293 , Humanos , Resistência à Insulina/imunologia , Masculino , Camundongos , Camundongos Endogâmicos C57BL
13.
Dermatol Ther ; 32(4): e12943, 2019 07.
Artigo em Inglês | MEDLINE | ID: mdl-31012218

RESUMO

Psoriasis (PS) is an autoimmune disorder characterized by chronic inflammatory skin immune-mediated disease which occurs in 2-4% of the worldwide population. PS is associated with an increased risk of cardiovascular disease and depression, and 30% of PS patients are affected with psoriatic arthritis. PS presents excessive keratinocyte proliferation, abnormal differentiation, and elevated mast cell (MC) number. In PS, there are enhanced type I interferon (IFN), angiogenesis, and over-expression of several proinflammatory cytokines, such as tumor necrosis factor and interleukin (IL)-1 family members generated by several immune cells including MCs. MCs are hematopoietic cells that reside in vascularized tissues, which, upon appropriate activation, release proinflammatory cytokines, an effect worsened by acute stress and PS. In recent years, IL-37 emerged as an anti-inflammatory cytokine which binds to alpha chain of the IL-18 receptor alpha (IL-18Rα) and downregulates MyD88. This effect leads to the inhibition of nuclear factor-κB (NF-κB) and mitogen activation protein kinase, with the suppression of inflammatory response. These observations candidate IL-37 as a potential new therapeutic cytokine for inflammatory disorders including PS.


Assuntos
Interleucina-1/administração & dosagem , Mastócitos/imunologia , Psoríase/tratamento farmacológico , Animais , Anti-Inflamatórios/administração & dosagem , Anti-Inflamatórios/imunologia , Humanos , Inflamação/tratamento farmacológico , Inflamação/imunologia , Interleucina-1/imunologia , Psoríase/imunologia
14.
J Immunol ; 202(10): 3020-3032, 2019 05 15.
Artigo em Inglês | MEDLINE | ID: mdl-30988118

RESUMO

The inflammatory response to infection or injury dramatically increases the hematopoietic demand on the bone marrow to replace effector leukocytes consumed in the inflammatory response. In the setting of infection, pathogen-associated molecular patterns induce emergency hematopoiesis, activating hematopoietic stem and progenitor cells to proliferate and produce progeny for accelerated myelopoiesis. Sterile tissue injury due to trauma also increases leukocyte demand; however, the effect of sterile tissue injury on hematopoiesis is not well described. We find that tissue injury alone induces emergency hematopoiesis in mice subjected to polytrauma. This process is driven by IL-1/MyD88-dependent production of G-CSF. G-CSF induces the expansion of hematopoietic progenitors, including hematopoietic stem cells and multipotent progenitors, and increases the frequency of myeloid-skewed progenitors. To our knowledge, these data provide the first comprehensive description of injury-induced emergency hematopoiesis and identify an IL-1/MyD88/G-CSF-dependent pathway as the key regulator of emergency hematopoiesis after injury.


Assuntos
Fator Estimulador de Colônias de Granulócitos/imunologia , Hematopoese/imunologia , Interleucina-1/imunologia , Fator 88 de Diferenciação Mieloide/imunologia , Ferimentos e Lesões/imunologia , Animais , Fator Estimulador de Colônias de Granulócitos/genética , Hematopoese/genética , Interleucina-1/genética , Camundongos , Camundongos Knockout , Fator 88 de Diferenciação Mieloide/genética , Ferimentos e Lesões/genética , Ferimentos e Lesões/patologia
15.
Immunity ; 50(4): 778-795, 2019 04 16.
Artigo em Inglês | MEDLINE | ID: mdl-30995499

RESUMO

Forty years after its naming, interleukin-1 (IL-1) is experiencing a renaissance brought on by the growing understanding of its context-dependent roles and advances in the clinic. Recent studies have identified important roles for members of the IL-1 family-IL-18, IL-33, IL-36, IL-37, and IL-38-in inflammation and immunity. Here, we review the complex functions of IL-1 family members in the orchestration of innate and adaptive immune responses and their diversity and plasticity. We discuss the varied roles of IL-1 family members in immune homeostasis and their contribution to pathologies, including autoimmunity and auto-inflammation, dysmetabolism, cardiovascular disorders, and cancer. The trans-disease therapeutic activity of anti-IL-1 strategies argues for immunity and inflammation as a metanarrative of modern medicine.


Assuntos
Imunidade Adaptativa/imunologia , Citocinas/fisiologia , Imunidade Inata/imunologia , Inflamação/imunologia , Interleucina-1/fisiologia , Animais , Doenças Cardiovasculares/imunologia , Citocinas/genética , Citocinas/imunologia , Gastroenteropatias/imunologia , Hematopoese/imunologia , Humanos , Interleucina-1/imunologia , Linfócitos/imunologia , Camundongos , Camundongos Knockout , Família Multigênica , Neoplasias/imunologia , Doenças Neurodegenerativas/imunologia , Receptores de Citocinas/genética , Receptores de Citocinas/imunologia
16.
Nat Commun ; 10(1): 1376, 2019 03 26.
Artigo em Inglês | MEDLINE | ID: mdl-30914642

RESUMO

IL-9-producing CD4+ (Th9) cells are a subset of CD4+ T-helper cells that are endowed with powerful antitumor capacity. Both IL-4 and TGF-ß have been reported to be indispensable for Th9 cell-priming and differentiation. Here we show, by contrast, that Th9 cell development can occur in the absence of TGF-ß signaling. When TGF-ß was replaced by IL-1ß, the combination of IL-1ß and IL-4 efficiently promoted IL-9-producing T cells (Th9IL-4+IL-1ß). Th9IL-4+ IL-1ß cells are phenotypically distinct T cells compared to classic Th9 cells (Th9IL-4+TGF-ß) and other Th cells, and are enriched for IL-1 and NF-κB gene signatures. Inhibition of NF-κB but not TGF-ß-signaling negates IL-9 production by Th9IL-4+IL-1ß cells. Furthermore, when compared with classic Th9IL-4+TGF-ß cells, Th9IL-4+IL-1ß cells are less exhausted, exhibit cytotoxic T effector gene signature and tumor killing function, and exert a superior antitumor response in a mouse melanoma model. Our study thus describes an alternative pathway for Th9 cell differentiation and provides a potential avenue for antitumor therapies.


Assuntos
Interleucina-1beta/farmacologia , Interleucina-4/farmacologia , Linfopoese/efeitos dos fármacos , Linfócitos T Auxiliares-Indutores/efeitos dos fármacos , Fator de Crescimento Transformador beta/farmacologia , Animais , Diferenciação Celular/imunologia , Linhagem Celular Tumoral , Interleucina-1/genética , Interleucina-1/imunologia , Interleucina-9 , Linfopoese/imunologia , Melanoma Experimental/imunologia , Camundongos , NF-kappa B/genética , NF-kappa B/imunologia , Fenótipo , Subpopulações de Linfócitos T/citologia , Subpopulações de Linfócitos T/efeitos dos fármacos , Subpopulações de Linfócitos T/imunologia , Linfócitos T Citotóxicos/citologia , Linfócitos T Citotóxicos/imunologia , Linfócitos T Auxiliares-Indutores/citologia , Linfócitos T Auxiliares-Indutores/imunologia , Transcriptoma
17.
Immunopharmacol Immunotoxicol ; 41(2): 299-311, 2019 Apr.
Artigo em Inglês | MEDLINE | ID: mdl-30907193

RESUMO

Objective: Gene expression level of T helper cell transcription factors and cytokines production in type-2 diabetes mellitus (T2DM) patients treated with mono- or combined sitagliptin and vitamin D3 (VitD3) were evaluated. Methods: Fifty-four nephropathic and 57 non-nephropathic T2DM patients were divided into the subgroups based on their treatment with/without sitagliptin and VitD3. The expression of T-bet, RORγt, BCL6, and FOXP3 was evaluated using real-time PCR. The levels of IFN-γ, IL-6, IL-17, IL-21, TGF-ß, and IL-37 were assessed in PBMC supernatants using ELISA. Results: The production of IFN-γ and IL-17 was increased in untreated (without sitagliptin and VitD3) nephropathic and non-nephropathic T2DM patients compared with healthy controls, whereas FOXP3 expression was decreased. Treatment with sitagliptin alone or in combination with VitD3 reduced the production of IFN-γ in the patients. Production of IL-17 and IL-21 and the expression of RORγt and BCL6 was diminished in patients treated with combined sitagliptin and VitD3, whereas the production of IL-37 and FOXP3 expression were increased in the patients treated with sitagliptin or sitagliptin plus VitD3. Conclusion: These data demonstrate that sitagliptin in combination with VitD3 may accelerate the process of T2DM treatment by exerting synergic anti-inflammatory effects on immune system through upregulation of FOXP3 and IL-37, and downregulation of RORγt and BCL6 as well as IFN-γ, IL-17 and IL-21 production. Combined sitagliptin and VitD3 can be safely utilized to modulate the inflammatory conditions of T2DM.


Assuntos
Colecalciferol/farmacologia , Diabetes Mellitus Tipo 2/imunologia , Fatores de Transcrição Forkhead/imunologia , Interleucina-1/imunologia , Fosfato de Sitagliptina/farmacologia , Linfócitos T Auxiliares-Indutores/imunologia , Regulação para Cima/efeitos dos fármacos , Adulto , Diabetes Mellitus Tipo 2/patologia , Feminino , Humanos , Masculino , Pessoa de Meia-Idade , Linfócitos T Auxiliares-Indutores/patologia
18.
J Immunol ; 202(6): 1687-1692, 2019 03 15.
Artigo em Inglês | MEDLINE | ID: mdl-30718298

RESUMO

Several types of psoriasiform dermatitis are associated with increased IL-36 cytokine activity in the skin. A rare, but severe, psoriasis-like disorder, generalized pustular psoriasis (GPP), is linked to loss-of-function mutations in the gene encoding IL-36RA, an important negative regulator of IL-36 signaling. To understand the effects of IL-36 dysregulation in a mouse model, we studied skin inflammation induced by intradermal injections of preactivated IL-36α. We found the immune cells infiltrating IL-36α-injected mouse skin to be of dramatically different composition than those infiltrating imiquimod-treated skin. The IL-36α-induced leukocyte population comprised nearly equal numbers of CD4+ αß T cells, neutrophils, and inflammatory dendritic cells, whereas the imiquimod-induced population comprised γδ T cells and neutrophils. Ligands for chemokine receptors CCR6 and CXCR2 are increased in both GPP and IL-36α-treated skin, which led us to test an optimized small-molecule antagonist (CCX624) targeting CCR6 and CXCR2 in the IL-36α model. CCX624 significantly reduced the T cell, neutrophil, and inflammatory dendritic cell infiltrates and was more effective than saturating levels of an anti-IL-17RA mAb at reducing inflammatory symptoms. These findings put CCR6 and CXCR2 forward as novel targets for a mechanistically distinct therapeutic approach for inflammatory skin diseases involving dysregulated IL-36 signaling, such as GPP.


Assuntos
Anti-Inflamatórios/farmacologia , Interleucina-1/toxicidade , Psoríase/imunologia , Receptores CCR6/antagonistas & inibidores , Receptores de Interleucina-8B/antagonistas & inibidores , Animais , Interleucina-1/imunologia , Camundongos , Camundongos Endogâmicos BALB C , Psoríase/induzido quimicamente , Pele/efeitos dos fármacos , Pele/imunologia
19.
Immunity ; 50(1): 166-180.e7, 2019 01 15.
Artigo em Inglês | MEDLINE | ID: mdl-30650375

RESUMO

Chronic inflammation drives the progression of colorectal cancer (CRC). Increased expression of interleukin (IL)-17A is associated with poor prognosis, and IL-17A blockade curbs tumor progression in preclinical models of CRC. Here we examined the impact of IL-1 signaling, a key regulator of the IL-17 pathway, in different cell types within the CRC microenvironment. Genetic deletion of the IL-1 receptor (IL-1R1) in epithelial cells alleviated tumorigenesis in the APC model of CRC, demonstrating a cell-autonomous role for IL-1 signaling in early tumor seed outgrowth. T cell specific ablation of IL-1R1 decreased tumor-elicited inflammation dependent on IL-17 and IL-22, thereby reducing CRC progression. The pro-tumorigenic roles of IL-1 were counteracted by its effects on myeloid cells, particularly neutrophils, where IL-1R1 ablation resulted in bacterial invasion into tumors, heightened inflammation and aggressive CRC progression. Thus, IL-1 signaling elicits cell-type-specific responses, which, in aggregate, set the inflammatory tone of the tumor microenvironment and determine the propensity for disease progression.


Assuntos
Neoplasias Colorretais/imunologia , Inflamação/metabolismo , Interleucina-17/metabolismo , Interleucina-1/metabolismo , Neutrófilos/imunologia , Salmonelose Animal/imunologia , Salmonella/imunologia , Animais , Carcinogênese , Células Cultivadas , Humanos , Interleucina-1/genética , Interleucina-1/imunologia , Interleucinas/metabolismo , Camundongos , Camundongos Knockout , Neutrófilos/ultraestrutura , Especificidade de Órgãos , Receptores de Interleucina-1/genética , Transdução de Sinais , Microambiente Tumoral
20.
J Biol Regul Homeost Agents ; 33(1): 1-6, 2019.
Artigo em Inglês | MEDLINE | ID: mdl-30656901

RESUMO

Activated mast cells (MCs) secrete a number of compounds including pro-inflammatory and anti-inflammatory cytokines. MCs are a potential source of cytokines and chemokines which participate in allergic reactions and inflammation. MCs can be activated by IgE through its receptor FceRI, but also by Toll-like receptors and/or interleukin (IL)-1. MCs can be a target for both pro-inflammatory and anti-inflammatory cytokines. IL-1 activates MCs to release inflammatory chemical mediators, and cytokines/chemokines, an effect which can be potentially inhibited by IL-37. In addition, IL-36 is also a powerful cytokine with a pro-inflammatory activity. IL-38 binds IL-36R and inhibits the pro-inflammatory activity of IL-36, thus performing a therapeutic action. In this article we review the role of MCs in relation to pro-inflammatory and anti-inflammatory IL-1 family member cytokines and a possible therapeutic effect in inflammatory disorders.


Assuntos
Citocinas/imunologia , Interleucina-1/imunologia , Mastócitos/imunologia , Quimiocinas/imunologia , Humanos , Inflamação/imunologia , Interleucinas/imunologia
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