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The role of ferroptosis and iron metabolism dysregulation in the pathophysiology of cardiovascular diseases is increasingly recognized. Conditions such as hypertension, cardiomyopathy, atherosclerosis, myocardial ischemia/reperfusion injury, heart failure, and cardiovascular complications associated with COVID-19 have been linked to these processes. Inflammation is central to these conditions, prompting exploration into the inflammatory and immunoregulatory molecular pathways that mediate ferroptosis and its contribution to cardiovascular disease progression. Notably, emerging evidence highlights interleukin-37 as a protective cytokine with the ability to activate the nuclear factor erythroid 2-related factor 2 pathway, inhibit macrophage ferroptosis, and attenuate atherosclerosis progression in murine models. However, a comprehensive review focusing on interleukin-37 and its protective role against ferroptosis in CVD is currently lacking. This review aims to fill this gap by summarizing existing knowledge on interleukin-37, including its regulatory functions and impact on ferroptosis in conditions such as atherosclerosis and myocardial infarction. We also explore experimental strategies and propose that targeting interleukin-37 to modulate ferroptosis presents a promising therapeutic approach for the prevention and treatment of cardiovascular diseases.
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Enfermedades Cardiovasculares , Ferroptosis , Interleucina-1 , Humanos , Interleucina-1/metabolismo , Enfermedades Cardiovasculares/metabolismo , Animales , COVID-19/metabolismo , COVID-19/inmunología , Aterosclerosis/metabolismo , Aterosclerosis/patología , SARS-CoV-2/metabolismoRESUMEN
TOB/BTG is a family of antiproliferative proteins that play an important role in the regulation of immune responses, acting as lymphocyte activators and macrophage-mediated cytotoxicity. No previous studies have explored their role in patients with psoriasis. The aim of this study was to characterize the expression of TOB/BTG family and their co-localization in skin from patients with psoriasis. This is an exploratory, observational, and cross-sectional study that included 24 plaque psoriasis patients and 15 controls. Gene expression of TOB/BTG family was determinate by RT-PCR. Protein products of TOB/BTG were evaluated by immunohistochemistry and compared with control skin tissues. Holm-Sidak's multiple comparisons test was performed. TOB/BTG family mRNA levels and protein expression were significantly decreased in psoriatic skin tissue compared to non-inflammatory control skin tissue. Double-positive cell TOB1/2, BTG1,2 and BTG4/CD16 expressions were found in normal control skin tissues through epidermis and dermis (p < 0.001) and lesser percentage in patients with mild, almost absent in moderate-severe plaque psoriasis. This is the first report of the TOB/BTG family gene and protein expression in skin tissues by a CD16 + subpopulation in plaque psoriasis. TOB/BTG family protein might represent a new therapeutic target among immune-mediated inflammatory diseases.
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IL-39 (Interleukin-39) is a heterodimeric cytokine composed of IL-23p19 and EBI3 (Epstein-Barr virus-induced gene 3) subunits. Despite the evidence that correlates the role of IL-39 in regulating inflammation, its expression in the intestinal microenvironment of IBD (inflammatory bowel disease) patients is still unknown. Thus, this work was focused on characterizing relative mRNA (messenger RNA) IL-39 expression and intestinal synthesis in IBD patients. This study includes 37 patients diagnosed with ulcerative colitis (UC), 15 with Chron's disease (CD), and 22 controls. Gene expression of IL-39 subunits (IL-23p19/EBI3) was measured by RT-PCR (real time polymerase chain reaction). Intestinal synthesis was evaluated by immunohistochemistry and serum levels by ELISA. Statistical analysis was done using Prism GraphPad V6. Relative mRNA IL-39 expression was increased in patients with active UC and active CD compared to the remission UC, remission CD, and control group. High levels of relative mRNA expression of IL-39 (IL-23p19 subunit) were associated with histological activity. IHQ analysis showed increased IL-39 production in mucosa, submucosa, muscular, and serosa layer of patients with active disease. IL-39 serum production was increased in patients with UC. IL-39 gene's upregulation was found in patients with active IBD and was associated with severe histological activity in UC. This is the first report regarding the role of IL-39 in patients with IBD. The findings suggest that IL-39 might play a role as an inflammatory mediator in active IBD and could be considered a new alternative in treating this condition.
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Prompt diagnosis of ST-segment elevation myocardial infarction (STEMI) is essential for initiating timely treatment. MicroRNAs have recently emerged as biomarkers in cardiovascular diseases. This study aimed to evaluate the discriminatory capacity of serum microRNAs in identifying an ischemic origin in patients presenting with chest discomfort to the Emergency Department. The study included 98 participants (78 with STEMI and 20 with nonischemic chest discomfort). Significant differences in the expression levels of miR-133b, miR-126, and miR-155 (but not miR-1, miR-208, and miR-208b) were observed between groups. miR-133b and miR-155 exhibited 97% and 93% sensitivity in identifying STEMI patients, respectively. miR-126 demonstrated a specificity of 90% in identifying STEMI patients. No significant associations were found between microRNAs and occurrence of major adverse cardiovascular events (MACE). However, patients with MACE had higher levels of interleukin (IL)-15, IL-21, IFN-γ-induced protein-10, and N-terminal pro B-type natriuretic peptide compared to non-MACE patients. Overall, there were significant associations among the expression levels of microRNAs. However, microRNAs did not demonstrate associations with either inflammatory markers or cardiovascular risk scores. This study highlights the potential of microRNAs, particularly miR-133b and miR-126, as diagnostic biomarkers for distinguishing patients with STEMI from those presenting with nonischemic chest discomfort to the Emergency Department.
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The gene of A-kinase anchor protein 12 (AKAP12) regulates cell cycle progression, cell motility, and morphology through its multiple scaffolding domains. However, the role of AKAP12 expression in ulcerative colitis (UC) patients has not been yet described. The aim of the study was to describe the gene and protein of AKAP12 expression in patients with UC and its association regarding the disease severity. We included a total of 40 patients with confirmed diagnosis of UC and 25 controls without endoscopic evidence of colitis or neoplasia. The relative quantification of the gene expression was performed by real-time PCR for AKAP12. Kruskal-Wallis was used to test differences among groups, and Spearman correlation to assess the relationship between AKAP12 gene and clinical outcomes. The extent of disease was evaluated using total colonoscopy, and biopsies were taken from rectum segments. The AKAP12 gene expression was increased in colonic mucosa from patients with active UC when compared with UC remission and control group. The overexpression of AKAP12 in patients with UC was associated with the presence of extensive colitis (p = 0.04, RM = 12, IC = 1.29-186.37). AKAP12/CD16 double positive cells were higher in submucosa (p = 0.04), muscular (p < 0.001), and cells from serosa (p < 0.001) in patients affected by UC in comparison to controls. The overexpression of AKAP12 was associated with the extent of disease. This is the first report about the role of AKAP12 in patients with UC suggesting that this gene and its protein could be involved in the modulation of the disease.
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Proteínas de Anclaje a la Quinasa A/genética , Proteínas de Ciclo Celular/genética , Colitis Ulcerosa/genética , Expresión Génica , Biomarcadores , Biopsia , Estudios de Casos y Controles , Colitis Ulcerosa/diagnóstico , Colitis Ulcerosa/metabolismo , Colonoscopía , Manejo de la Enfermedad , Susceptibilidad a Enfermedades , Femenino , Perfilación de la Expresión Génica , Humanos , Inmunohistoquímica , Mucosa Intestinal/metabolismo , Mucosa Intestinal/patología , Masculino , Unión ProteicaRESUMEN
BACKGROUND: The clinical endoscopic phenotypes of gastroesophageal reflux disease (GERD) are classified as Barrett's esophagus (BE), erosive esophagitis (EE) and non-erosive gastroesophageal reflux disease (NERD). NERD is subclassified as abnormal acid exposure (AAE) and normal acid exposure (NAE) based on pH monitoring study results. The aim of this study was to characterize genes involved in the pathophysiology and immune response of GERD. METHODS: This is an observational and cross-sectional study. All patients with BE, EE, AAE, and NAE and a control group were subjected to superior endoscopy (with biopsies of esophageal mucosa). Relative mRNA quantification of cytokine and target genes was conducted by quantitative Polymerase Chain Reaction (RT-qPCR). Changes in the expression of genes associated with inflammation were assessed for each disease phenotype. Statistical analysis of differential gene expression was performed using the Mann-Whitney U non-parametric test. A p value < 0.05 was considered significant. RESULTS: A total of 82 patients were included and were divided into the following groups: Group BE, 16 (19.51%); Group EE, 23 (28.04%); Group AAE, 13 (15.86%); NAE 13 (15.86%); and Control Group, 17 (20.73%). Compared with the control group, patients with BE exhibited increased IL-8 expression (p < 0.05) and increased levels of IL-10, MMP-3, and MMP-9. Patients with EE exhibited increased levels of IL-1B, IL-6 and IL-10 (p < 0.05), and patients with AAE exhibited increased expression of IL-1B, IL-6, IFN-γ and TNF-α (p < 0.05). AAE exhibited increased IL-1B and TNF-α expression compared with NAE (p < 0.05). CONCLUSION: This study demonstrates the differential expression of mediators of inflammation in the esophageal mucosa of patients with different GERD endoscopic phenotypes. IL-1B and TNF-α could be useful to differentially diagnose AAE and NAE in the non-erosive phenotype using endoscopic biopsies.
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Citocinas , Reflujo Gastroesofágico , Biopsia , Estudios Transversales , Citocinas/genética , Reflujo Gastroesofágico/genética , Perfilación de la Expresión Génica , Humanos , FenotipoRESUMEN
BACKGROUND: Ulcerative colitis (UC) is an inflammatory disease of the intestine. The genetics factors play an important role in the pathogenesis of UC. SPARC exacerbates colonic inflammatory symptoms in dextran sodium sulphate-induced murine colitis. The aim of the study was to measure the gene expression and intestinal production of SPARC in patients with UC and controls as well as, to determine its correlation with histological activity. METHODS: We included 40 patients with confirmed diagnosis of UC, and 20 controls without endoscopic evidence of any type of colitis or neoplasia. The relative quantification of the gene expression was performed by real time PCR. GAPDH was used as housekeeping gene for normalization purposes and quality controls. Protein expression was determined by immunohistochemistry. RESULTS: The gene expression of SPARC was increased in patients with active UC vs in remission UC and vs. controls (P = 0.005). There was no significant difference between patients with remission UC and controls. The overexpression of SPARC in patients with active UC correlated significantly with mild histological activity (P = 0.06, OR = 7.77, IC = 0.77-77.9) moderate (P = 0.06, OR = 8.1, IC 95%=0.79-82.73), and severe (P = 0.03, OR = 6.5, IC 95%=1.09-38.6). Double positive SPARC+/CD16+ cells were localized mainly in submucosa, muscular layer, and adventitia, and in perivascular inflammatory infiltrates in patients with active UC. CONCLUSION: The gene and protein expression of SPARC is increased in active UC. SPARC could be a marker of intestinal inflammation and its expression correlates with histological activity.
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Colitis Ulcerosa/etiología , Colitis Ulcerosa/metabolismo , Mucosa Intestinal/metabolismo , Osteonectina/biosíntesis , Adulto , Anciano , Biomarcadores , Colitis Ulcerosa/diagnóstico , Estudios Transversales , Susceptibilidad a Enfermedades , Femenino , Expresión Génica , Humanos , Inmunohistoquímica , Mucosa Intestinal/inmunología , Mucosa Intestinal/patología , Masculino , Persona de Mediana Edad , Osteonectina/genética , Adulto JovenRESUMEN
BACKGROUND: Cow's milk protein allergy (CMPA) is the most prevalent food allergy in children, and its pathogenesis remains poorly understood. It has been shown that the combination of genetic predisposition, perinatal factors, and intestinal imbalance of the immune response mediated by cytokines may play an essential role in CMPA pathogenesis. AIM: To characterize the gene expression of Th1, Th2, and Th17 cytokines in the duodenum and rectum in patients with CMPA. METHODS: This is an observational, descriptive, cross-sectional, prospective study. We used specific IgE (ImmunoCAP®) in serum and biopsies from the rectum and duodenum for the detection of cytokine messenger RNA levels by real-time PCR in patients with a positive oral food challenge for CMPA. We analyzed the relative quantification of the gene expression of cytokines by real-time PCR, and we used the housekeeping gene GAPDH for normalization purposes. RESULTS: Thirty children (13 male and 17 female) were evaluated. All patients had an open challenge for CMPA. IgE specific to casein, alfa-lactalbumin, and beta-lactoglobulin was negative in all patients. In terms of cytokine levels, the levels of TNFα, IL-6, IL-12 (Th1), IL-4, IL-10, IL-13 (Th2), and IL-17 were found to be higher in the rectum than in the duodenum (p < 0.05). IL-15 was found to be higher in the duodenum than in the rectum (p < 0.05). CONCLUSIONS: In the present study we observed that the immune response in CMPA seems to be mediated by a Th1, Th2, and Th17 cytokine profile, with the rectum being the main affected site.
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Citocinas/metabolismo , Duodeno/metabolismo , Regulación de la Expresión Génica/inmunología , Hipersensibilidad a la Leche/inmunología , Proteínas de la Leche/inmunología , Recto/metabolismo , Animales , Bovinos , Estudios Transversales , Citocinas/genética , Humanos , Lactante , MasculinoRESUMEN
It has been reported that EMMPRIN is involved in the regulation of immune response and the induction of MMPs production by fibroblasts. The aim of this study was to describe the intestinal gene expression and protein production of EMMPRIN, MMP23 and MMP10 in patients with ulcerative colitis (UC) and Crohn's disease (CD) and compared them with a control group. Gene expression of EMMPRIN, MMP10 and MMP23B was measured by RT-PCR. In order to determine EMMPRIN and MMP protein expression, colonic tissues were immunostained. The results of the study showed EMMPRIN gene expression was upregulated in rectal mucosa from active (a)UC versus aCD patients (P = .045), remission (r)CD group (P = .0009) and controls (P < .0001). We detected differences between rUC and aCD (P = .004), rCD (P < .0001) or control group (P < .0001). EMMPRIN showed a higher expression in mucosa (intraepithelial lymphocytes), submucosa and adventitia (endothelial cells) from aCD patients. MMP23 levels were increased in aUC and aCD compared to rUC and rCD and the control group (P = .0001). EMMPRIN+/MMP23+âexpressing cells were localized mainly in mucosa, muscular and adventitia from active UC patients. MMP10 gene expression was increased in aUC versus CD patients and the control group (P = .0001). MMP10 gene expression is associated with inflammation in UC patients (P = .0001, r2 = .585). EMMPRIN+/MMP10+âproducing cells were found mainly in all intestinal layers and perivascular inflammatory infiltrates from aUC patients. In conclusion, EMMPRIN, MMP23 and MMP10 were upregulated in patients with active UC versus remission UC , CD and control groups suggesting that, they are involved in the inflammatory process.
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Basigina/genética , Expresión Génica , Enfermedades Inflamatorias del Intestino/genética , Metaloproteinasa 10 de la Matriz/genética , Metaloendopeptidasas/genética , Adulto , Anciano , Basigina/metabolismo , Biomarcadores , Biopsia , Estudios de Casos y Controles , Estudios Transversales , Susceptibilidad a Enfermedades , Femenino , Perfilación de la Expresión Génica , Humanos , Inmunohistoquímica , Enfermedades Inflamatorias del Intestino/metabolismo , Enfermedades Inflamatorias del Intestino/patología , Enfermedades Inflamatorias del Intestino/terapia , Masculino , Metaloproteinasa 10 de la Matriz/metabolismo , Metaloendopeptidasas/metabolismo , Persona de Mediana Edad , Unión ProteicaRESUMEN
In recent years, the role of anti-proliferative TOB proteins in the regulation of immune response by inhibiting T cell activation has been demonstrated. Nevertheless, no previous studies have explored their expression in patients with IBD. The aim of the study was to characterize the gene and protein expression of the TOB/BTG family in intestinal tissue of patients with IBD. This is an observational and cross-sectional study that included 63 IBD patients. Gene expression of TOB/BTG family was measured by RT-PCR. Protein expression of TOB/CD16 and BTG/Ki-67 was evaluated by immunohistochemistry. TOB/BTG family mRNAs were detected and quantitated by RT-qPCR in rectal and ileum biopsies from UC patients and CD patients, respectively, and non-inflammatory control tissues. Results showed that TOB1 and BTG1 gene expression was decreased in the colonic mucosa from patients with UC compared with the control group. The TOB2 and BTG2 genes were over-expressed in the colonic mucosa of patients with UC in remission compared with the active UC and control group. The high TOB2 gene expression was associated with histological remission (P = .01). TOB1/CD16, TOB2/CD16, BTG1/Ki-67, BTG2/Ki-67 and BTG4/Ki-67 single and double positive cells were mostly NK, macrophages, epithelial cells, connective tissue cells and perivascular inflammatory infiltrates in tissues from patients with UC and CD. This is the first depiction of the TOB/BTG family gene and protein expression in rectal and ileum tissues by a CD16+ subpopulation in IBD.
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Proteínas Inmediatas-Precoces/metabolismo , Enfermedades Inflamatorias del Intestino/metabolismo , Proteínas Supresoras de Tumor/metabolismo , Adulto , Proliferación Celular/fisiología , Colitis/metabolismo , Colon/metabolismo , Estudios Transversales , Células Epiteliales/metabolismo , Femenino , Expresión Génica/fisiología , Humanos , Mucosa Intestinal/metabolismo , Antígeno Ki-67/metabolismo , Macrófagos/metabolismo , Masculino , Persona de Mediana Edad , ARN Mensajero/metabolismo , Receptores de IgG/metabolismoRESUMEN
METHODS: Detection of H. pylori infection was performed by a 13C-urea breath test in 31 patients with UC. In each patient, a serum sample was drawn to measure IL-10 by the ELISA technique. Based on the primary breath test result, two groups were formed and serum IL-10 was measured. RESULTS: Serological IL-10 levels in patients with UC and negative 13C-urea breath test was 10.28 pg/ml whereas in patients with UC and positive 13C-urea breath test was 5.5 pg/ml (P = 0.035). IL-10 levels were higher in the inflammatory endoscopic and histological active groups which tested positive in the 13C-urea breath tests for H. pylori (P < 0.05). CONCLUSIONS: The role of IL-10 secretion in patients with UC in determining the clinicopathological outcome of infection merits further study. This study suggests an association between serum IL-10 and disease severity in patients with UC and HP infection.
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INTRODUCTION: TRPVs are a group of receptors with a channel activity predominantly permeable to Ca2+. This subfamily is involved in the development of gastrointestinal diseases such as ulcerative colitis (UC). The aim of the study was to characterize the gene and protein expression of the TRPV subfamily in UC patients and controls. METHODS: We determined by quantitative PCR the gene expression of TRPV2, TRPV3, TRPV4, TRPV5, and TRPV6 in 45 UC patients (29 active UC and 16 remission UC) and 26 noninflamed controls. Protein expression was evaluated in 5 µm thick sections of formalin-fixed, paraffin-embedded tissue from 5 customized severe active UC patients and 5 control surgical specimens. RESULTS: TRPV2 gene expression was increased in the control group compared with active UC and remission patients (P = 0.002 and P = 0.05, respectively). TRPV3 gene expression was significantly higher in controls than in active UC patients (P = 0.002). The gene expression of TRPV4 was significantly higher in colonic tissue from patients with remission UC compared with active UC patients (P = 0.05) and controls (P = 0.005). TRPV5 had significantly higher mRNA levels in a control group compared with active UC patients (P = 0.02). The gene expression of TRPV6 was significantly higher in the colonic tissue from patients with active UC compared with the control group (P = 0.05). The protein expression of TRPV2 was upregulated in the mucosa and submucosa from the controls compared with the UC patients (P ≤ 0.003). The protein expression of TRPV3 and TRPV4 was upregulated in all intestinal layers from the controls compared with the UC patients (P < 0.001). TRPV5 was upregulated in the submucosa and serosa from the controls vs. UC patients (P < 0.001). TRPV6 was upregulated in all intestinal layers from the UC patients vs. controls (P ≤ 0.001). CONCLUSION: The TRPV subfamily clearly showed a differential expression in the UC patients compared with the controls, suggesting their role in the pathophysiology of UC.
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Canales de Calcio/metabolismo , Colitis Ulcerosa/metabolismo , Colon/metabolismo , Mucosa Intestinal/metabolismo , Canales Catiónicos TRPV/metabolismo , Adulto , Anciano , Canales de Calcio/genética , Colitis Ulcerosa/genética , Femenino , Regulación de la Expresión Génica , Humanos , Persona de Mediana Edad , Canales Catiónicos TRPV/genética , Adulto JovenRESUMEN
The Wnt signaling pathway is a crucial regulator of the intestinal epithelium homeostasis and is altered in most colon cancers. While the role of aberrant canonical, ß-catenin-dependent Wnt signaling has been well established in colon cancer promotion, much less is known about the role played by noncanonical, ß-catenin-independent Wnt signaling in this type of cancer. This work aimed to characterize the noncanonical signal transduction pathway in colon cancer cells. To this end, we used the prototype noncanonical ligand, Wnt5a, in comparison with Wnt3a, the prototype of a canonical ß-catenin activating ligand. The analysis of the expression profile of Wnt receptors in colon cancer cell lines showed a clear increase in both level expression and variety of Frizzled receptor types expressed in colon cancer cells compared with non-malignant cells. We found that Wnt5a activates a typical Wnt/Ca++ - noncanonical signaling pathway in colon malignant cells, inducing the hyperphosphorylation of Dvl1, Dvl2 and Dvl3, promoting Ca++ mobilization as a result of phospholipase C (PLC) activation via pertussis toxin-sensitive G-protein, and inducing PLC-dependent cell migration. We also found that while the co-receptor Ror2 tyrosine kinase activity is not required for Ca++ mobilization-induced by Wnt5a, it is required for the inhibitory effects of Wnt5a on the ß-catenin-dependent transcriptional activity. Unexpectedly, we found that although the prototype canonical Wnt3a ligand was unique in stimulating the ß-catenin-dependent transcriptional activity, it also simultaneously activated PLC, promoted Ca++ mobilization, and induced Rho kinase and PLC-dependent cell migration. Our data indicate, therefore, that a Wnt ligand can activate at the same time the so-called Wnt canonical and noncanonical pathways inducing the formation of complex signaling networks to integrate both pathways in colon cancer cells.
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Neoplasias del Colon/metabolismo , Proteínas Wnt/metabolismo , Vía de Señalización Wnt , Animales , Calcio/metabolismo , Línea Celular Tumoral , Movimiento Celular/efectos de los fármacos , Neoplasias del Colon/patología , Proteínas de Unión al GTP/metabolismo , Humanos , Ligandos , Ratones , Modelos Biológicos , Toxina del Pertussis/farmacología , Fosforilación/efectos de los fármacos , Isoformas de Proteínas/metabolismo , Estabilidad Proteica/efectos de los fármacos , Receptores Huérfanos Similares al Receptor Tirosina Quinasa/metabolismo , Receptores Wnt/metabolismo , Factores de Tiempo , Transcripción Genética/efectos de los fármacos , Vía de Señalización Wnt/efectos de los fármacos , beta Catenina/metabolismoRESUMEN
The transient receptor potential vanilloid 1 (TRPV1) may play a role in the pathogenesis of ulcerative colitis (UC). The aim of the study was to determine the gene and protein expression of TRPV1 in UC patients and noninflamed controls. Gene expression was performed by RT-PCR, and protein expression was performed by immunohistochemistry. The gene expression of TRPV1 was significantly increased in the remission UC group compared to active UC patients (P = 0.002), and an upregulation of the TRPV1 gene was associated with clinical outcomes such as age at diagnosis (<40 years) (P = 0.02) and clinical disease course characterized by relapsing and continuous activity (P = 0.07). TRPV1 immunoreactive cells were conspicuously higher in all intestinal layers from active UC patients compared with noninflamed control tissue. These findings suggest that TRPV1 might be involved in UC pathogenesis.
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Colitis Ulcerosa/inmunología , Colitis Ulcerosa/metabolismo , Inflamación/inmunología , Inflamación/metabolismo , Canales Catiónicos TRPV/metabolismo , Adulto , Colon/inmunología , Colon/metabolismo , Femenino , Humanos , Inmunohistoquímica , Interleucina-6/metabolismo , Masculino , Persona de Mediana EdadRESUMEN
BACKGROUND: The CARD family plays an important role in innate immune response by the activation of NF-κB. The aim of this study was to determine the gene expression and to enumerate the protein-expressing cells of some members of the CARD family (CARD9, CARD10, CARD11, CARD14 and CARD15) in patients with IBD and normal controls without colonic inflammation. METHODS: We included 48 UC patients, 10 Crohn's disease (CD) patients and 18 non-inflamed controls. Gene expression was performed by RT-PCR and protein expression by immunohistochemistry. CARD-expressing cells were assessed by estimating the positively staining cells and reported as the percentage. RESULTS: The CARD9 and CARD10 gene expression was significantly higher in UC groups compared with CD (P < 0.001). CARD11 had lower gene expression in UC than in CD patients (P < 0.001). CARD14 gene expression was higher in the group with active UC compared to non-inflamed controls (P < 0.001). The low expression of CARD14 gene was associated with a benign clinical course of UC, characterized by initial activity followed by long-term remission longer than 5 years (P = 0.01, OR = 0.07, 95%CI:0.007-0.70). CARD15 gene expression was lower in UC patients versus CD (P = 0.004). CARD9 protein expression was detected in inflammatory infiltrates; CARD14 in parenchymal cells, while CARD15 in inflammatory and parenchymal cells. CARD9-, CARD14- and CARD15 - expressing cells were significantly higher in patients with active UC versus non-inflamed controls (P < 0.05). CONCLUSION: The CARD family is involved in the inflammatory process and might be involved in the IBD pathophysiology.
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IL-1 family includes IL-38 (IL-1F10) and the subfamily of IL-36 and is the central mediators of inflammatory diseases, including pustular psoriasis, atopic dermatitis, rheumatoid arthritis, and gut inflammation. The purpose of the study was to evaluate on tissue of the patients with inflammatory bowel disease (IBD), the IL-36α, IL-36ß, IL-36γ, IL-36Ra, and IL-38 gene and cell expression and its correlation with clinical activity. Patients and Methods. A cross-sectional and comparative study was performed. Seventy patients with IBD and 30 noninflamed non-IBD controls were enrolled. Gene expression was measured by RT-PCR. Protein expression was detected by double-staining immunohistochemistry. Results. The mRNA expression of IL-36 family members but not IL-38 was increased in colonic mucosa from patients with active ulcerative colitis versus Crohn's disease group and noninflammatory control group (P<0.05). However, only gene expression of IL-38 was increased in tissue from patients with inactive ulcerative colitis versus active disease and control group (P<0.005). Conversely, gene expression of IL-36Ra was significantly higher in colonic tissue from patients with active versus inactive ulcerative colitis and noninflamed control group (P<0.05). A differential protein overexpression of IL-36α, IL-36ß, IL-36γ, IL-36Ra, and IL-38 by intestinal epithelial cells, macrophages, CD8+ T cells, and/or versus dendritic cells (pDCs) was found in patients with active inflammatory bowel disease compared with noninflamed controls. Conclusion. IL-38 and IL-36 family members' expression was increased by immune and nonimmune cells in patients with active inflammatory bowel disease. These cytokines and IL-36Ra might represent novel therapeutic targets in patients with gut inflammation.
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Células Dendríticas/metabolismo , Células Epiteliales/metabolismo , Regulación de la Expresión Génica , Enfermedades Inflamatorias del Intestino/metabolismo , Interleucina-1/biosíntesis , Interleucinas/biosíntesis , Mucosa Intestinal/metabolismo , Macrófagos/metabolismo , Adulto , Estudios Transversales , Células Dendríticas/patología , Células Epiteliales/patología , Femenino , Humanos , Inmunohistoquímica , Enfermedades Inflamatorias del Intestino/patología , Mucosa Intestinal/patología , Macrófagos/patología , Masculino , Persona de Mediana EdadRESUMEN
TGF-ß type III receptor (TßRIII) is a co-receptor for TGFß family members required for high-affinity binding of these ligands to their receptors, potentiating their cellular functions. TGF-ßs, Bone Morphogenetic Proteins (BMP2/4) and Inhibins/Activins regulate different checkpoints during T cell differentiation. We have previously reported that TßRIII modulates T cell development by protecting developing thymocytes from apoptosis, however the role of this co-receptor in peripheral lymphocytes still remains elusive. Here we describe a detailed characterization of TßRIII expression in murine and human lymphocyte subpopulations demonstrating that this co-receptor is significantly expressed in T but not B lymphocytes and among them, preferentially expressed on naïve and central memory T cells. TßRIII was upregulated after TCR stimulation, in parallel to other early activation markers. In contrast, natural and induced Tregs downregulated TßRIII in association with FoxP3 upregulation. Finally, anti-TßRIII blocking experiments demonstrated that TßRIII promotes TGFß-dependent iTreg conversion in vitro, and suggest that this co-receptor may be involved in modulating peripheral T cell tolerance and could be considered as a potential target to boost T cell immune responses.
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Proteoglicanos/metabolismo , Receptores de Antígenos de Linfocitos T/metabolismo , Receptores de Factores de Crecimiento Transformadores beta/metabolismo , Linfocitos T Reguladores/inmunología , Animales , Regulación hacia Abajo , Factores de Transcripción Forkhead/metabolismo , Humanos , Memoria Inmunológica , Técnicas In Vitro , Activación de Linfocitos , Ratones , Ratones Endogámicos C57BL , Ratones Transgénicos , Proteoglicanos/antagonistas & inhibidores , Proteoglicanos/genética , Receptores de Factores de Crecimiento Transformadores beta/antagonistas & inhibidores , Receptores de Factores de Crecimiento Transformadores beta/genética , Transducción de Señal , Linfocitos T Reguladores/clasificación , Linfocitos T Reguladores/metabolismo , Regulación hacia ArribaRESUMEN
The aim of the study was to characterize and quantify tissue gene and protein expression of IL-27 in ulcerative colitis (UC) and Crohn's disease (CD) patients. This is an observational and cross-sectional study. Fifty-four patients with IBD were studied: 27 active UC, 12 inactive UC, 10 active CD, and 5 inactive CD. All patients belonged to the Inflammatory Bowel Disease Clinic at the Instituto Nacional de Ciencias Médicas y Nutrición. We found that IL-27 gene expression was significantly higher in active UC versus inactive UC group (P = 0.015). The IL-27 mRNA expression was increased in patients with active CD compared with inactive CD disease (P = 0.035). The percentage of IL-27 immunoreactive cells was higher in active UC versus active CD patients and non-inflamed tissue controls. The IL-27 was significantly elevated in active UC and CD patients, and it was associated with disease severity.
Asunto(s)
Colitis Ulcerosa/inmunología , Colon/metabolismo , Enfermedad de Crohn/inmunología , Interleucina-27/metabolismo , Mucosa Intestinal/metabolismo , Adulto , Colon/patología , Estudios Transversales , Progresión de la Enfermedad , Femenino , Humanos , Interleucina-27/genética , Mucosa Intestinal/patología , Masculino , Persona de Mediana Edad , ARN Mensajero/análisis , Regulación hacia ArribaRESUMEN
The aim of the study was to characterize and to quantify peripheral and tissue. IL-35- and IL-37-producing cells in Inflammatory Bowel Disease (IBD) patients. We studied a total of 38 active UC, 31 inactive UC, 17 active CD, and 13 inactive CD and 50 non-inflamed tissues as control group. Gene expression was measured by real time polymerase chain reaction (RT-PCR) and protein expression was evaluated in tissue by immunohistochemistry and in peripheral blood mononuclear cells by flow cytometry. Higher levels of IL-35 was produced by intestinal regulatory B cells and circulating regulatory CD4(+) and CD8(+) T cells in active vs. inactive disease or healthy donors (P<0.05). The IL-37 was conspicuously synthesized by circulating B cells, active natural killer cells and monocytes. These results suggest that down-regulation of inflammation in active IBD patients might be based on the increased expression of IL-35 and IL-37.
Asunto(s)
Linfocitos B Reguladores/inmunología , Colitis Ulcerosa/inmunología , Enfermedad de Crohn/inmunología , Interleucina-1/inmunología , Interleucinas/inmunología , Linfocitos T Reguladores/inmunología , Adulto , Anciano , Linfocitos T CD8-positivos/inmunología , Colitis Ulcerosa/patología , Enfermedad de Crohn/patología , Estudios Transversales , Femenino , Expresión Génica , Perfilación de la Expresión Génica , Humanos , Indolamina-Pirrol 2,3,-Dioxigenasa/biosíntesis , Inflamación/inmunología , Interleucina-1/biosíntesis , Interleucina-10/biosíntesis , Subunidad alfa del Receptor de Interleucina-3/biosíntesis , Interleucinas/biosíntesis , Mucosa Intestinal/inmunología , Masculino , Persona de Mediana Edad , Reacción en Cadena en Tiempo Real de la Polimerasa , Adulto JovenRESUMEN
Background. Patients with UC have shown an important defect in the secretion and maintenance of the mucosal barrier as part of inadequate expression of mucin genes. The aim of the present study was to determine the expression of MUC12, MUC16, and MUC20 in colonic tissue from patients with UC in regard to their clinical outcomes. Methods. We included a total of 40 patients with UC and 30 normal controls. Mucin gene expression was performed by RT-PCR and protein expression was detected by immunohistochemistry. Results. Patients with active UC showed no significant expression of MUC12 gene in mucosa compared to the group of patients with UC in remission and the normal control group. MUC16 gene expression was significantly increased in the UC active and remission groups compared to the normal control group (P = 0.03). MUC20 gene expression was found significantly decreased in patients with active UC compared to both remission group (P = 0.001) and normal controls (P = 0.001). Furthermore, an association was found between MUC20 gene expression and the presence of histological remission in patients with UC (P = 0.003, OR = 0.37). Conclusions. An increased gene expression of MUC16 and MUC20 was found in patients with remission UC.