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1.
Mol Cell Endocrinol ; 544: 111541, 2022 03 15.
Artigo em Inglês | MEDLINE | ID: mdl-34973370

RESUMO

Glucocorticoid (GC)-induced osteonecrosis of the femoral head (ONFH) accounts for a big portion of non-traumatic ONFH; nevertheless, the pathogenesis has not yet been fully understood. GC-induced endothelial dysfunction might be a major contributor to ONFH progression. The Gene Expression Omnibus (GEO) dataset was analyzed to identify deregulated miRNAs in ONFH; among deregulated miRNAs, the physiological functions of miR-122-5p on ONFH and endothelial dysfunction remain unclear. In the present study, miR-122-5p showed to be under-expressed within GC-induced ONFH femoral head tissues and GC-stimulated bone microvascular endothelial cells (BMECs). In human umbilical vein endothelial cells (HUVECs) and BMECs, GC stimulation significantly repressed cell viability, promoted cell apoptosis and increased the mRNA expression of proinflammatory cytokines, such as TNF-α, IL-1ß, and IFN-γ. After overexpressing miR-122-5p, GC-induced endothelial injuries were attenuated, as manifested by rescued cell viability, cell migration, and tube formation capacity. Regarding the BMP signaling, GC decreased the protein levels of BMP-2/6/7 and SMAD-1/5/8, whereas miR-122-5p overexpression significantly attenuated the inhibitory effects of GC on these proteins. Online tool and experimental analyses revealed the direct binding between miR-122-5p and GREM2, a specific antagonist of BMP-2. In contrast to miR-122-5p overexpression, GREM2 overexpression aggravated GC-induced endothelial injury; GREM2 silencing partially eliminated the effects of miR-122-5p inhibition on GC-stimulated HUVECs and BMECs. Finally, GREM2 silencing reversed the suppressive effects of GC on BMP-2/6/7 and SMAD-1/5/8, and attenuated the effects of miR-122-5p inhibition on these proteins upon GC stimulation. Conclusively, the present study demonstrates a miR-122-5p/GREM2 axis modulating the GC-induced endothelial damage via the BMP/SMAD signaling. Considering the critical role of endothelial function in ONFH pathogenesis, the in vivo role and clinical application of the miR-122-5p/GREM2 axis is worthy of further investigation.


Assuntos
Glucocorticoides , MicroRNAs , Apoptose , Citocinas/metabolismo , Cabeça do Fêmur/metabolismo , Cabeça do Fêmur/patologia , Glucocorticoides/metabolismo , Glucocorticoides/farmacologia , Células Endoteliais da Veia Umbilical Humana/metabolismo , Humanos , MicroRNAs/genética , MicroRNAs/metabolismo , Transdução de Sinais
2.
Immun Inflamm Dis ; 10(3): e577, 2022 03.
Artigo em Inglês | MEDLINE | ID: mdl-34939360

RESUMO

BACKGROUND: Traumatic brain injury (TBI) impairs cognitive function. Systemic inflammation plays important role in cognitive deficits. It remains unclear if systemic inflammation in TBI is associated with poor cognitive function. METHODS: From January 2018 to December 2020, two groups of subjects were recruited: patients with TBI (n = 120), and healthy control (n = 120), followed up to 3 months. Blood was collected from TBI patients and healthy control, and serum inflammatory cytokines including interferon-α (IFN-α), interleukin-1ß (IL-1ß), IL-6, IL-8, IL-10, and tumor necrosis factor-α (TNF-α) were measured at baseline and end of 3 months. Multivariate regression was used for analysis for the relationship between cognitive function and inflammatory cytokines. RESULTS: Inflammatory cytokines were higher in patients with brain injury and remained high at end of 3 months. Some cytokines such as IFN-α, IL-1ß, IL-6, and TNF-α were associated with worsening memory and predicted poor performance. CONCLUSION: Systemic inflammation in patients with TBI predicts poor cognitive function.


Assuntos
Lesões Encefálicas Traumáticas , Lesões Encefálicas , Lesões Encefálicas/complicações , Lesões Encefálicas Traumáticas/complicações , Cognição , Citocinas , Humanos , Inflamação
3.
Transl Psychiatry ; 12(1): 76, 2022 02 23.
Artigo em Inglês | MEDLINE | ID: mdl-35197458

RESUMO

Attention-deficit/hyperactivity disorder (ADHD) is a common childhood mental disorder with undetermined pathophysiological mechanisms. The gut microbiota and immunological dysfunction may influence brain functions and social behaviours. In the current study, we aimed to explore the correlation of gut microbiome imbalance and inflammation in the pathophysiology of ADHD. Forty-one children with ADHD and thirty-nine healthy-control (HC) individuals were recruited. Faecal samples from all participants were collected and submitted for 16 S rRNA V3-V4 amplicon microbiome sequencing analysis. The plasma levels of 10 cytokines, including TNF-α, IL-6, IL-1ß, IL-2, IL-10, IL-13, IL-17A, IFN-α2, IFN-γ, and MCP-1, were determined using a custom-made sandwich enzyme-linked immunosorbent assay (ELISA) developed by Luminex Flowmetrix. There was no significant difference between the ADHD and HC groups in species diversity in the faeces, as determined with α-diversity and ß-diversity analysis. In the ADHD group, three differentially abundant taxonomic clades at the genus level were observed, namely Agathobacter, Anaerostipes, and Lachnospiraceae. Top differentially abundant bacteria and representative biological pathways were identified in children with ADHD using linear discriminant analysis (LDA) effect size (LEfSe), and the phylogenetic investigation of communities by reconstruction of unobserved states (PICRUSt) analysis, respectively. The plasma levels of TNF-α were significantly lower in children with ADHD than in HCs. Within the ADHD group, the levels of TNF-α were negatively correlated with ADHD symptoms and diversity of the gut microbiome. Our study provides new insights into the association between gut microbiome dysbiosis and immune dysregulation, which may contribute to the pathophysiology of ADHD.


Assuntos
Transtorno do Deficit de Atenção com Hiperatividade , Microbioma Gastrointestinal , Criança , Citocinas/genética , Disbiose , Microbioma Gastrointestinal/genética , Humanos , Filogenia
4.
Nihon Yakurigaku Zasshi ; 157(5): 293-298, 2022.
Artigo em Japonês | MEDLINE | ID: mdl-36047138

RESUMO

Asthma therapy in general has improved a lot in recent years, but it is still a major problem that severe asthma, which accounts for 10 to 20%, still suffers from strong symptoms on a daily basis despite all therapeutic agents used in combination. American SARP and European ENFUMOSA started in 2000 to advance pathophysiological insights of severe asthma. Clinical usage of antibodies and inhibitors against IgE, TNF, IL-5, IL-4, IL-13, and TSLP are also accumulating. Some of these molecular-targeted drugs improve respiratory function and reduce acute exacerbations in patients with severe asthma. Until now, cytokines have been assumed to be involved in chronic inflammation, but it is also interesting to elucidate the pathways of how cytokines are involved in respiratory function and acute exacerbations. We registered approximately 100 steroid-dependent asthma patients in Japan. Although long-lasting poor control of the disease was considered the cause of severe asthma in the past, steroid dependence in one third of the cases occurred within 2-3 years after the onset. Steroid resistance seems a key process from the early stage of the disease. Steroid resistance of T cell level was induced by extracellular co-stimulation and cytokine signals. The inhibition may improve steroid sensitivity and treat steroid-resistant asthma. Therefore, we established a steroid-resistant asthma model for the first time by transferring steroid resistant T cell clones, and analyzed the steroid sensitivity recovery effect of CTLA4-Ig. In addition, a multicenter, double-blind, placebo-controlled exploratory trial was performed as a POC study investigating the efficacy of abatacept in treatment-resistant severe asthma. Elucidation of the pathophysiology and mechanism by which steroids do not work is expected to be a breakthrough for the prevention and treatment of severe asthma.


Assuntos
Asma , Citocinas , Método Duplo-Cego , Humanos , Japão , Esteroides/uso terapêutico
5.
Nat Commun ; 13(1): 4703, 2022 09 01.
Artigo em Inglês | MEDLINE | ID: mdl-36050303

RESUMO

Atopic diseases, including atopic dermatitis (AD) and asthma, affect a large proportion of the population, with increasing prevalence worldwide. AD often precedes the development of asthma, known as the atopic march. Allergen sensitization developed through the barrier-defective skin of AD has been recognized to be a critical step leading to asthma, in which thymic stromal lymphopoietin (TSLP) was previously shown to be critical. In this study, using a laser-assistant microporation system to disrupt targeted skin layers for generating micropores at a precise anatomic depth of mouse skin, we model allergen exposure superficially or deeply in the skin, leading to epicutaneous sensitization or dermacutaneous sensitization that is associated with a different cytokine microenvironment. Our work shows a differential requirement for TSLP in these two contexts, and identifies an important function for IL-1ß, which is independent of TSLP, in promoting allergen sensitization and subsequent allergic asthma.


Assuntos
Asma , Dermatite Atópica , Alérgenos , Animais , Asma/complicações , Citocinas , Camundongos , Pele
6.
Mediators Inflamm ; 2022: 9242383, 2022.
Artigo em Inglês | MEDLINE | ID: mdl-36046760

RESUMO

Thymic stromal lymphopoietin (TSLP), long known to be involved in Th2 response, is also implicated in multiple inflammatory dermatoses and cancers. The purpose of this study was to improve our understanding of the expression of TSLP in the skin of those dermatoses. Lesional specimens of representative immune-related dermatoses, including lichen planus (LP), discoid lupus erythematosus (DLE), eczema, bullous pemphigoid (BP), psoriasis vulgaris (PsV), sarcoidosis, and mycosis fungoides (MF), were retrospectively collected and analyzed by immunohistochemistry. Morphologically, TSLP was extensively expressed in the epidermis of each dermatosis, but the expression was weak in specimens of DLE. In a semiquantitative analysis, TSLP was significantly expressed in the epidermis in LP, BP, eczema, PsV, sarcoidosis, and MF. TSLP expression was higher in the stratum spinosum in LP, eczema, BP, PsV, and MF and higher in the stratum basale in sarcoidosis and PsV. Moreover, we found positive TSLP staining in the dermal infiltrating inflammatory cells of BP, PsV, and sarcoidosis. Our observation of TSLP in different inflammatory dermatoses might provide a novel understanding of TSLP in the mechanism of diseases with distinctly different immune response patterns and suggest a potential novel therapeutic target of those diseases.


Assuntos
Eczema , Psoríase , Sarcoidose , Citocinas/metabolismo , Humanos , Estudos Retrospectivos
7.
Biol Pharm Bull ; 45(9): 1364-1372, 2022.
Artigo em Inglês | MEDLINE | ID: mdl-36047206

RESUMO

Rheumatoid arthritis (RA) is systemic autoimmune arthritis that causes joint inflammation and destruction. Accumulating evidence has shown that inhibitors of class I histone deacetylases (HDACs) (i.e., HDAC1, 2, 3, and 8) are potential therapeutic candidates as targeted synthetic disease-modifying antirheumatic drugs (tsDMARDs). Nevertheless, the inhibition of class I HDACs has severe adverse effects because of their broad spectrum. We evaluated the therapeutic effect of a novel selective HDAC1 inhibitor TTA03-107 for collagen-induced arthritis (CIA) and collagen antibody-induced arthritis (CAIA) models in mice. We also examined the effect of TTA03-107 in bone marrow-derived macrophages (BMDMs) and T helper 17 (Th17) cells in vitro. Here, we delineate that TTA03-107 reduced the severity of autoimmune arthritis without obvious adverse effects in CIA and CAIA models. Moreover, TTA03-107 suppressed the production of inflammatory cytokines, such as interleukin (IL)-1ß, tumor necrosis factor (TNF)-α, and IL-17A, in serum and joint tissue. In vitro treatment of BMDMs with TTA03-107 dampened the M1 differentiation and inflammatory cytokine production. TTA03-107 also suppressed the differentiation of Th17 cells. These results demonstrate that TTA03-107 can attenuate the development of arthritis in experimental RA models by inhibiting the differentiation and activation of macrophages and Th17 cells. Therefore, TTA03-107 is a potential tsDMARD candidate.


Assuntos
Antirreumáticos , Artrite Experimental , Artrite Reumatoide , Inibidores de Histona Desacetilases , Animais , Antirreumáticos/uso terapêutico , Artrite Experimental/patologia , Artrite Reumatoide/tratamento farmacológico , Artrite Reumatoide/patologia , Citocinas/metabolismo , Inibidores de Histona Desacetilases/uso terapêutico , Camundongos , Células Th17 , Fator de Necrose Tumoral alfa/metabolismo
8.
J Neuroinflammation ; 19(1): 212, 2022 Sep 01.
Artigo em Inglês | MEDLINE | ID: mdl-36050707

RESUMO

BACKGROUND: Interleukin-27 (IL-27) can trigger both pro- and anti-inflammatory responses. This cytokine is elevated in the central nervous system (CNS) of multiple sclerosis (MS) patients, but how it influences neuroinflammatory processes remains unclear. As astrocytes express the receptor for IL-27, we sought to determine how these glial cells respond to this cytokine and whether such exposure alters their interactions with infiltrating activated T lymphocytes. To determine whether inflammation shapes the impact of IL-27, we compared the effects of this cytokine in non-inflamed and inflamed conditions induced by an IL-1ß exposure. MAIN BODY: Transcriptomic analysis of IL-27-exposed human astrocytes showed an upregulation of multiple immune genes. Human astrocytes increased the secretion of chemokines (CXCL9, CXCL10, and CXCL11) and the surface expression of proteins (PD-L1, HLA-E, and ICAM-1) following IL-27 exposure. To assess whether exposure of astrocytes to IL-27 influences the profile of activated T lymphocytes infiltrating the CNS, we used an astrocyte/T lymphocyte co-culture model. Activated human CD4+ or CD8+ T lymphocytes were co-cultured with astrocytes that have been either untreated or pre-exposed to IL­27 or IL-1ß. After 24 h, we analyzed T lymphocytes by flow cytometry for transcription factors and immune molecules. The contact with IL-27-exposed astrocytes increased the percentages of T-bet, Eomes, CD95, IL-18Rα, ICAM-1, and PD-L1 expressing CD4+ and CD8+ T lymphocytes and reduced the proportion of CXCR3-positive CD8+ T lymphocytes. Human CD8+ T lymphocytes co-cultured with human IL-27-treated astrocytes exhibited higher motility than when in contact with untreated astrocytes. These results suggested a preponderance of kinapse-like over synapse-like interactions between CD8+ T lymphocytes and IL-27-treated astrocytes. Finally, CD8+ T lymphocytes from MS patients showed higher motility in contact with IL-27-exposed astrocytes compared to healthy donors' cells. CONCLUSION: Our results establish that IL-27 alters the immune functions of human astrocytes and shapes the profile and motility of encountered T lymphocytes, especially CD8+ T lymphocytes from MS patients.


Assuntos
Interleucina-27 , Esclerose Múltipla , Astrócitos/metabolismo , Antígeno B7-H1/metabolismo , Linfócitos T CD8-Positivos , Citocinas/metabolismo , Humanos , Molécula 1 de Adesão Intercelular/metabolismo , Interleucina-27/metabolismo , Interleucinas
9.
World J Gastroenterol ; 28(26): 3063-3070, 2022 Jul 14.
Artigo em Inglês | MEDLINE | ID: mdl-36051337

RESUMO

Crohn's disease (CD) is driven by the loss of tolerance to intestinal microbiota and excessive production of pro-inflammatory cytokines. These pro-inflammatory cytokines are produced by macrophages and dendritic cells (DCs) upon sensing the intestinal microbiota by the pattern recognition receptors (PRRs). Impaired activation of PRR-mediated signaling pathways is associated with chronic gastrointestinal inflammation, as shown by the fact that loss-of-function mutations in the nucleotide-binding oligomerization domain 2 gene increase the risk of CD development. Autophagy is an intracellular degradation process, during which cytoplasmic nutrients and intracellular pathogens are digested. Given that impaired reaction to intestinal microbiota alters signaling pathways mediated by PRRs, it is likely that dysfunction of the autophagic machinery is involved in the development of CD. Indeed, the loss-of-function mutation T300A in the autophagy related 16 like 1 (ATG16L1) protein, a critical regulator of autophagy, increases susceptibility to CD. Recent studies have provided evidence that ATG16L1 is involved not only in autophagy, but also in PRR-mediated signaling pathways. ATG16L1 negatively regulates pro-inflammatory cytokine responses of macrophages and DCs after these cells sense the intestinal microbiota by PRRs. Here, we discuss the molecular mechanisms underlying the development of CD in the T300A ATG16L1 mutation by focusing on PRR-mediated signaling pathways.


Assuntos
Proteínas Relacionadas à Autofagia , Doença de Crohn , Autofagia/genética , Proteínas Relacionadas à Autofagia/genética , Proteínas Relacionadas à Autofagia/metabolismo , Proteínas de Transporte/genética , Proteínas de Transporte/metabolismo , Doença de Crohn/genética , Doença de Crohn/imunologia , Citocinas/metabolismo , Humanos , Imunidade Inata , Inflamação , Mutação , Receptores de Reconhecimento de Padrão/genética , Receptores de Reconhecimento de Padrão/metabolismo
10.
Mol Med ; 28(1): 104, 2022 09 04.
Artigo em Inglês | MEDLINE | ID: mdl-36058917

RESUMO

BACKGROUND: Inflammatory bowel disease (IBD) is a common chronic remitting disease with no satisfactory treatment. The aim of this study was to investigate the protective effect of α7 nicotinic acetylcholine receptor (α7nAChR), and to determine the underlying mechanism of its activity. METHODS: The expression and distribution of α7nAChR in the intestinal tissue of patients with ulcerative colitis and Crohn's disease were analyzed. The effects of vagal excitation on murine experimental colitis were investigated. The colitis model was induced in C57BL/6 mice by the administration of 3% dextran sulfate sodium (DSS). The therapeutic group received treatment with the α7nAChR agonist PNU-282987 by intraperitoneal injection. RESULTS: Our results showed that there was significantly increased expression of α7nAChR in colitis and Crohn's disease intestinal tissue, and its expression was mainly located in macrophages and neutrophils, which were extensively infiltrated in the disease status. Treatment with an α7nAChR agonist potently ameliorated the DSS-induced illness state, including weight loss, stool consistency, bleeding, colon shortening, and colon histological injury. α7nAChR agonist exerted anti-inflammatory effects in DSS colitis mice by suppressing the secretion of multiple types of proinflammatory factors, such as IL6, TNFα, and IL1ß, and it also inhibited the colonic infiltration of inflammatory cells by blocking the DSS-induced overactivation of the NF-κB and MAPK signaling pathways. Mechanistically, activation of α7nAChR decreased the number of infiltrated M1 macrophages in the colitis intestine and inhibited the phagocytosis ability of macrophages, which were activated in response to LPS stimulation. CONCLUSION: Thus, an α7nAChR agonist ameliorated colonic pathology and inflammation in DSS-induced colitis mice by blocking the activation of inflammatory M1 macrophages.


Assuntos
Colite , Doença de Crohn , Animais , Colite/induzido quimicamente , Colite/tratamento farmacológico , Colite/patologia , Colo/patologia , Doença de Crohn/metabolismo , Doença de Crohn/patologia , Citocinas/metabolismo , Sulfato de Dextrana/efeitos adversos , Sulfato de Dextrana/metabolismo , Modelos Animais de Doenças , Camundongos , Camundongos Endogâmicos C57BL , NF-kappa B/metabolismo , Receptor Nicotínico de Acetilcolina alfa7/metabolismo
11.
BMC Cancer ; 22(1): 953, 2022 Sep 05.
Artigo em Inglês | MEDLINE | ID: mdl-36064338

RESUMO

PURPOSE: Adenocarcinomas of the esophagus (AEG) and stomach (AS) are among the most common cancers worldwide. Novel markers for risk stratification and guiding treatment are strongly needed. Activin is a multi-functional cytokine with context specific pro- and anti-tumorigenic effects. We aimed to investigate the prognostic role of activin tumor protein expression in AEG/ASs. METHODS: Tissue from a retrospective cohort of 277 patients with AEG/AS treated primarily by surgery at the Charité - Universitätsmedizin Berlin was collected and analyzed by immunohistochemistry using a specific antibody to the activin homodimer inhibin beta A. Additionally, we evaluated T-cell infiltration and PD1 expression as well as expression of PD-L1 by immunohistochemistry as possible confounding factors. Clinico-pathologic data were collected and correlated with activin protein expression. RESULTS: Out of 277 tumor samples, 72 (26.0%) exhibited high activin subunit inhibin beta A protein expression. Higher expression was correlated with lower Union for International Cancer Control (UICC) stage and longer overall survival. Interestingly, activin subunit expression correlated with CD4+ T-cell infiltration, and the correlation with higher overall survival was exclusively seen in tumors with high CD4+ T-cell infiltration, pointing towards a role of activin in the tumor immune response in AEG/ASs. CONCLUSION: In our cohort of AEG/AS, higher activin subunit levels were correlated with longer overall survival, an effect exclusively seen in tumors with high CD4+ cell infiltration. Further mechanistic research is warranted discerning the exact effect of this context specific cytokine.


Assuntos
Ativinas , Adenocarcinoma , Adenocarcinoma/cirurgia , Animais , Citocinas , Equidae/metabolismo , Neoplasias Esofágicas , Humanos , Subunidades beta de Inibinas , Inibinas , Prognóstico , Estudos Retrospectivos , Estômago
12.
Sci Rep ; 12(1): 15084, 2022 Sep 05.
Artigo em Inglês | MEDLINE | ID: mdl-36064574

RESUMO

Dairy cattle experience a profound nutrient deficit postpartum that is associated with immune dysfunction characterized by heightened inflammation and reduced pathogen clearance. The activation of the central nutrient-sensing mTOR pathway is comparatively reduced in leukocytes of early postpartum dairy cows during this time of most pronounced nutrient deficit. We assessed the effect of pharmacological mTOR inhibition (Torin-1, rapamycin) on differentiation of monocyte derived classically (M1) and alternatively (M2) activated macrophages (MPh) and dendritic cells (moDC) from 12 adult dairy cows. Treatment with mTOR inhibitors generated M1 MPh with increased oxidative burst and expression of IL12 subunits but decreased phagocytosis and expression of IL1B, IL6, and IL10. In M2 MPh, treatment inhibited expression of regulatory features (CD163, ARG2, IL10) skewing the cells toward an M1-like phenotype. In moDC, mTOR inhibition increased expression of pro-inflammatory cytokines (IL12A, IL12B, IL1B, IL6) and surface CD80. In co-culture with mixed lymphocytes, mTOR-inhibited moDC exhibited a cytokine profile favoring a Th1 response with increased TNF and IFNG production and decreased IL10 concentrations. We conclude that mTOR inhibition in vitro promoted differentiation of inflammatory macrophages with reduced regulatory features and generation of Th1-favoring dendritic cells. These mechanisms could contribute to immune dysregulation in postpartum dairy cows.


Assuntos
Doenças do Sistema Imunitário , Interleucina-10 , Animais , Bovinos , Citocinas/metabolismo , Células Dendríticas , Feminino , Humanos , Interleucina-10/metabolismo , Interleucina-6/metabolismo , Macrófagos/metabolismo , Período Pós-Parto , Serina-Treonina Quinases TOR/metabolismo
13.
J Neuroinflammation ; 19(1): 216, 2022 Sep 05.
Artigo em Inglês | MEDLINE | ID: mdl-36064575

RESUMO

BACKGROUND: Retinal degenerative diseases are a group of conditions characterized by photoreceptor death and vision loss. Excessive inflammation and microglial activation contribute to the pathology of retinal degenerations and a major focus in the field is identifying more effective anti-inflammatory therapeutic strategies that promote photoreceptor survival. A major challenge to developing anti-inflammatory treatments is to selectively suppress detrimental inflammation while maintaining beneficial inflammatory responses. We recently demonstrated that endogenous levels of the IL-27 cytokine were upregulated in association with an experimental treatment that increased photoreceptor survival. IL-27 is a pleiotropic cytokine that regulates tissue reactions to infection, neuronal disease and tumors by inducing anti-apoptotic and anti-inflammatory genes and suppressing pro-inflammatory genes. IL-27 is neuroprotective in the brain, but its function during retinal degeneration has not been investigated. In this study, we investigated the effect of IL-27 in the rd10 mouse model of inherited photoreceptor degeneration. METHODS: Male and female rd10 mice were randomly divided into experimental (IL-27) and control (saline) groups and intravitreally injected at age post-natal day (P) 18. Retina function was analyzed by electroretinograms (ERGs), visual acuity by optomotor assay, photoreceptor death by TdT-mediated dUTP nick-end labeling (TUNEL) assay, microglia/macrophage were detected by immunodetection of IBA1 and inflammatory mediators by cytoplex and QPCR analysis. The distribution of IL-27 in the retina was determined by immunohistochemistry on retina cross-sections and primary Muller glia cultures. RESULTS: We demonstrate that recombinant IL-27 decreased photoreceptor death, increased retinal function and reduced inflammation in the rd10 mouse model of retinal degeneration. Furthermore, IL-27 injections led to lower levels of the pro-inflammatory proteins Ccl22, IL-18 and IL-12. IL-27 expression was localized to Muller glia and IL-27 receptors to microglia, which are key cell types that regulate photoreceptor survival. CONCLUSION: Our results identify for the first time anti-inflammatory and neuroprotective activities of IL-27 in a genetic model of retinal degeneration. These findings provide new insight into the therapeutic potential of anti-inflammatory cytokines as a treatment for degenerative diseases of the retina.


Assuntos
Interleucina-27 , Degeneração Retiniana , Animais , Anti-Inflamatórios/uso terapêutico , Citocinas , Modelos Animais de Doenças , Feminino , Inflamação/tratamento farmacológico , Masculino , Camundongos , Degeneração Retiniana/patologia
14.
Cell Mol Life Sci ; 79(10): 509, 2022 Sep 06.
Artigo em Inglês | MEDLINE | ID: mdl-36066630

RESUMO

Monoclonal antibody (mAb) therapy has successfully been introduced as treatment of several lymphomas and leukemias. However, solid tumors reduce the efficacy of mAb therapy because of an immune-suppressive tumor micro-environment (TME), which hampers activation of effector immune cells. Pro-inflammatory cytokine therapy may counteract immune suppression in the TME and increase mAb efficacy, but untargeted pro-inflammatory cytokine therapy is limited by severe off-target toxicity and a short half-life of cytokines. Antibody-cytokine fusion proteins, also referred to as immunocytokines, provide a solution to either issue, as the antibody both acts as local delivery platform and increases half-life. The antibody can furthermore bridge local cytotoxic immune cells, like macrophages and natural killer cells with tumor cells, which can be eliminated after effector cells are activated via the cytokine. Currently, a variety of different antibody formats as well as a handful of cytokine payloads are used to generate immunocytokines. However, many potential formats and payloads are still left unexplored. In this review, we describe current antibody formats and cytokine moieties that are used for the development of immunocytokines, and highlight several immunocytokines in (pre-)clinical studies. Furthermore, potential future routes of development are proposed.


Assuntos
Imunoterapia , Neoplasias , Anticorpos Monoclonais/uso terapêutico , Citocinas , Humanos , Células Matadoras Naturais , Neoplasias/tratamento farmacológico , Proteínas Recombinantes de Fusão , Microambiente Tumoral
15.
Commun Biol ; 5(1): 917, 2022 Sep 06.
Artigo em Inglês | MEDLINE | ID: mdl-36068291

RESUMO

Pyroptosis, as a proinflammatory form of regulated cell death, plays an important role in multiple cancers. However, the diagnostic and prognostic values of pyroptosis and its interaction with tumor immunity in pan-cancer are still unclear. Here, we show an elevated general expression of 17 pyroptosis-associated genes of tumor patients with high-immune-activity and a reduced pyroptosis in low-immune-activity tumors. Moreover, pyroptosis is positively correlated with immune infiltration and immune-related signatures across 30 types of cancer. Furthermore, our experimental data suggest that pyroptosis directly modulate the expression of immune checkpoint molecules and cytokines. We generate a pyroptosis score model as a potential independent prognostic indicator in melanoma patients. Interestingly, 3 of pyroptosis-associated genes including CASP1, CASP4 and PYCARD, can predict the effectiveness of anti-PD-1 immunotherapy for patients with melanoma. Our study demonstrates that pyroptosis correlates with tumor immunity and prognosis, might be used as a potential target for immune therapy.


Assuntos
Melanoma , Piroptose , Citocinas/metabolismo , Humanos , Melanoma/genética , Prognóstico
16.
Drug Des Devel Ther ; 16: 2901-2917, 2022.
Artigo em Inglês | MEDLINE | ID: mdl-36068788

RESUMO

Purpose: Janus kinase 1 (JAK1) is implicated in multiple inflammatory pathways that are critical for the pathogenesis of asthma, including the interleukin (IL)-4, IL-5, IL-13, and thymic stromal lymphopoietin cytokine signaling pathways, which have previously been targeted to treat allergic asthma. Here, we describe the development of AZD0449 and AZD4604, two novel and highly selective JAK1 inhibitors with promising properties for inhalation. Methods: The effects of AZD0449 and AZD4604 in JAK1 signaling pathways were assessed by measuring phosphorylation of signal transducer and activator of transcription (STAT) proteins and chemokine release using immunoassays of whole blood from healthy human volunteers and rats. Pharmacokinetic studies performed on rats evaluated AZD0449 at a lung deposited dose of 52 µg/kg and AZD4604 at 30 µg/kg. The efficacy of AZD0449 and AZD4604 was assessed by evaluating lung inflammation (cell count and cytokine levels) and the late asthmatic response (average enhanced pause [Penh]). Results: Both compounds inhibited JAK1-dependent cytokine signaling pathways in a dose-dependent manner in human and rat leukocytes. After intratracheal administration in rats, both compounds exhibited low systemic exposures and medium-to-long terminal lung half-lives (AZD0449, 34 hours; AZD4604, 5 hours). Both compounds inhibited STAT3 and STAT5 phosphorylation in lung tissue from ovalbumin (OVA)-challenged rats. AZD0449 and AZD4604 also inhibited eosinophilia in the lung and reduced the late asthmatic response, measured as Penh in the OVA rat model. Conclusion: AZD0449 and AZD4604 show potential as inhibitors of signaling pathways involved in asthmatic immune responses, with target engagement demonstrated locally in the lung. These findings support the clinical development of AZD0449 and AZD4604 for the treatment of patients with asthma.


Assuntos
Asma , Inibidores de Janus Quinases , Animais , Asma/metabolismo , Citocinas/metabolismo , Humanos , Janus Quinase 1/metabolismo , Inibidores de Janus Quinases/farmacologia , Pulmão/metabolismo , Ovalbumina , Ratos , Transdução de Sinais
17.
Mediators Inflamm ; 2022: 3878320, 2022.
Artigo em Inglês | MEDLINE | ID: mdl-36060926

RESUMO

Purpose: To determine the clinical efficacy of recombinant human epidermal growth factor (rh-EGF) combined with povidone-iodine (PVI) on patients with pressure ulcers (PUs). Methods: One hundred and five PU patients treated between January 2018 and January 2021 were enrolled and retrospectively analyzed. Of them, 50 patients who received conventional treatment were assigned to the control group (Con group), while 55 patients treated with rh-EGF combined with PVI were assigned to the observation group (Obs group). The two groups were compared in clinical efficacy, PU alleviation (total area reduction rate, total depth reduction rate, and total volume reduction rate), healing time, pain degree (Visual Analog Scale [VAS] score), inflammatory indexes (interleukin-8 [IL-8], tumor necrosis factor-α [TNF-α], and hypersensitive C reactive protein [hs-CRP]), and hydroxyproline content in the wound. Results: The Obs group yielded a higher total effective rate than the Con group (P < 0.05). The Obs group also experienced statistically shorter healing time and milder pain, with better PU alleviation and lower levels of inflammation indexes compared with the Con group (all P < 0.05). In addition, a higher hydroxyproline content in the wound was found in the Obs group. Conclusions: All in all, rh-EGF combined with PVI has a definite curative effect on patients with PUs. It can promote PU alleviation and hydroxyproline secretion in the wound and inhibit pain and inflammatory reactions, which is worthy of clinical promotion.


Assuntos
Fator de Crescimento Epidérmico , Lesão por Pressão , Citocinas , Fator de Crescimento Epidérmico/uso terapêutico , Humanos , Hidroxiprolina , Fatores Imunológicos , Inflamação/tratamento farmacológico , Dor/tratamento farmacológico , Povidona-Iodo/uso terapêutico , Lesão por Pressão/tratamento farmacológico , Estudos Retrospectivos , Supuração/tratamento farmacológico
18.
Zhongguo Ying Yong Sheng Li Xue Za Zhi ; 38(3): 279-283, 2022 Sep.
Artigo em Chinês | MEDLINE | ID: mdl-36062800

RESUMO

Objective: To study the mechanisms of cold exposure mediated ileum mechanical barrier injury in mice. Methods: Twenty mice were randomly divided into the control and cold exposure groups. Both the control and cold exposure groups were placed in the climate room with (24±2)℃ and 40% humidity. The mice in the cold exposure group were moved to the climate room at (4±2)℃ every day for 3 hours for three consecutive weeks. Three weeks later, the ileum tissues of mice were collected. Changes in ileum tissue structure were observed by hematoxylin-eosin staining and Masson staining. The related protein expression levels of the tight junction, inflammatory cytokines, and the NF-κB pathway were detected by Western blot. Results: Compared with the control group, the circular muscle layer of the ileum in cold exposed mice became thin, a large number of inflammatory cells infiltrated, the length of villi became short, the depth of recess was increased, and tissue fibrosis appeared. The expression levels of ideal tight junction-associated proteins in cold exposed mice were decreased significantly (P<0.05), while the protein expression levels of IL-1ß, IL-6 and phosphorescent p65 were increased significantly (P<0.05). Conclusion: Cold exposure can damage the tight junction of the mouse ileum, destroy the integrity of the mechanical barrier and activate the NF-κB signaling pathway to promote the occurrence of the inflammatory response.


Assuntos
Íleo , NF-kappa B , Animais , Citocinas/metabolismo , Íleo/metabolismo , Mucosa Intestinal , Camundongos , NF-kappa B/metabolismo , Junções Íntimas/metabolismo
19.
Methods Cell Biol ; 172: 163-178, 2022.
Artigo em Inglês | MEDLINE | ID: mdl-36064222

RESUMO

Cancer cell-intrinsic type I interferon (IFN-I) activation is required to initiate early innate immune responses and the subsequent radiation-induced anti-tumor immunity. Investigating the secretion of IFN-I cytokines in response to radiation therapy (RT) is therefore a critical readout for selecting the best immunogenic radiation dose-fractionation regimen. In this chapter, we present different ELISA-based quantification techniques that can be utilized to assess the secretion of tumor-derived IFN-I cytokines, namely IFN-α and IFN-ß.


Assuntos
Interferon Tipo I , Neoplasias , Citocinas , Ensaio de Imunoadsorção Enzimática , Imunidade Inata , Interferon Tipo I/farmacologia , Interferon-alfa , Neoplasias/radioterapia
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