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1.
Scand J Immunol ; 82(4): 352-60, 2015 Oct.
Artículo en Inglés | MEDLINE | ID: mdl-26072972

RESUMEN

Interaction between TL1A and death receptor 3 (DR3) co-stimulates T cells, induces production of several pro-inflammatory cytokines and has been linked to pathogenesis of inflammatory bowel disease (IBD). This study aimed to establish a link between expression of TL1A and selected TL1A-induced pro-inflammatory cytokines involved in IBD pathogenesis (IL-4, IL-13, IL-17A and IFN-γ) and to investigate a connection between serum concentration of TL1A in patients with IBD and activation of peripheral blood T cells. Elevated levels of IL-4 (2.91-fold) and IL-13 (4.05-fold) mRNA were detected in the inflamed colon mucosa of patients with ulcerative colitis (UC), IFN-γ mRNA was upregulated (3.23-fold) in the inflamed colon mucosa of patients with Crohn's disease (CD), whereas upregulation of IL-17A and TL1A mRNA was present in the inflamed colon mucosa of patients with both CD and UC (IL-17A: 4.48-fold and 2.74-fold, TL1A: 3.19-fold and 3.22-fold, respectively) vs. control subjects. We did not detect any changes in DR3 mRNA expression in the investigated groups of patients. TL1A mRNA level in colon mucosa of patients with IBD correlated only with the level of IL-17A mRNA but no other investigated cytokines. In colon mucosa, expression of TL1A and DR3 was localized to enterocytes and lamina propria mononuclear cells. We did not find any correlation between serum concentrations of TL1A and IL-17A or changes of CD4(+) or CD8(+) lymphocytes phenotype in patients with IBD. Therefore, our data indicate that TL1A may contribute to pathogenesis of IBD via local but not systemic induction of IL-17A but not IL-4, IL-13 or IFN-γ.


Asunto(s)
Colitis Ulcerosa/metabolismo , Colon/metabolismo , Enfermedad de Crohn/metabolismo , Interleucina-17/metabolismo , Mucosa Intestinal/metabolismo , Miembro 15 de la Superfamilia de Ligandos de Factores de Necrosis Tumoral/metabolismo , Adulto , Linfocitos T CD4-Positivos/inmunología , Linfocitos T CD8-positivos/inmunología , Enterocitos/metabolismo , Femenino , Humanos , Interferón gamma/metabolismo , Interleucina-13/metabolismo , Interleucina-17/biosíntesis , Interleucina-17/sangre , Interleucina-4/metabolismo , Masculino , Persona de Mediana Edad , ARN Mensajero/biosíntesis , ARN Mensajero/genética , Miembro 25 de Receptores de Factores de Necrosis Tumoral/genética , Miembro 25 de Receptores de Factores de Necrosis Tumoral/metabolismo , Miembro 15 de la Superfamilia de Ligandos de Factores de Necrosis Tumoral/sangre , Miembro 15 de la Superfamilia de Ligandos de Factores de Necrosis Tumoral/genética , Regulación hacia Arriba
2.
J Crohns Colitis ; 8(8): 802-10, 2014 Aug.
Artículo en Inglés | MEDLINE | ID: mdl-24439762

RESUMEN

BACKGROUND: Ulcerative colitis (UC) is a chronic disease with periods of remission and recurrences. Dysfunction of the local immune response leads to chronic inflammation within the large intestine which triggers morphological changes in the intestinal wall as well as induces the synthesis of numerous factors that have an adverse impact on the bone metabolism. The aim of the study was to determine the expression of RANKL, OPG and IL-33 in mucosal biopsies of UC patients with long disease duration as well as serum level of these cytokines in the context of bone density and bone metabolism. MATERIALS AND METHODS: The UC group consisted of 56 patients with average disease duration of 16y. The control group comprised 37 healthy individuals. Local expression of cytokines was assessed in the biopsies of colonic mucosa by the real-time PCR and immunohistochemistry (IHC), and their serum concentration was measured by ELISA. RESULTS: The increased bone resorption observed in patients with UC was reflected by low bone density and high serum level of C-terminal telopeptide (CTX). Mucosal RANKL expression and serum concentration were similar in UC group and healthy subjects, however, UC patients had higher local expression of OPG and serum OPG concentration. Increased IL-33 gene expression was observed only in UC at the mRNA level. We propose that bone resorption in UC patients despite OPG up-regulation could be caused by IL-33-induced mucosal synthesis of a potent proinflammatory cytokine, such as TNF-α, known as a possible inducer of osteoclastogenesis in the way independent of RANKL.


Asunto(s)
Huesos/metabolismo , Colitis Ulcerosa/metabolismo , Interleucinas/metabolismo , Osteoprotegerina/metabolismo , Ligando RANK/metabolismo , Adulto , Densidad Ósea , Estudios de Casos y Controles , Colitis Ulcerosa/sangre , Femenino , Humanos , Interleucina-33 , Interleucinas/sangre , Mucosa Intestinal/metabolismo , Masculino , Persona de Mediana Edad , Osteoprotegerina/sangre , Ligando RANK/sangre
3.
J Physiol Pharmacol ; 60 Suppl 4: 57-62, 2009 Oct.
Artículo en Inglés | MEDLINE | ID: mdl-20083852

RESUMEN

OBJECTIVE: FHIT gene encodes human diadenosine triphosphate hydrolase involved in the regulation of cell cycle and nucleotide metabolism and is a candidate tumor suppressor gene. AIM: To investigate expression of FHIT gene at the mRNA and protein levels in sporadic inflammatory bowel disease (IBD). MATERIALS AND METHODS: FHIT mRNA was quantified by the validated real-time PCR (QPCR) and FHIT protein was detected by immunohistochemistry (IHC) in mucosal biopsies of 139 ulcerative colitis (UC), 19 Crohn's disease (CD) and 37 control patients. RESULTS: Significant FHIT gene overexpression was found in 78% of active UC but not in CD. IHC showed comparable results to QPCR. CONCLUSION: The local up-regulation of FHIT gene and protein expression in active UC may represent an adequate response against inflammatory challenge of epithelial cell homeostasis and protect against DNA damage and cell cycle disturbances.


Asunto(s)
Ácido Anhídrido Hidrolasas/biosíntesis , Enfermedades Inflamatorias del Intestino/metabolismo , Proteínas de Neoplasias/biosíntesis , Ácido Anhídrido Hidrolasas/genética , Adolescente , Adulto , Anciano , Colitis Ulcerosa/genética , Colitis Ulcerosa/metabolismo , Colitis Ulcerosa/patología , Enfermedad de Crohn/genética , Enfermedad de Crohn/metabolismo , Enfermedad de Crohn/patología , Cartilla de ADN , Femenino , Humanos , Inmunohistoquímica , Enfermedades Inflamatorias del Intestino/genética , Mucosa Intestinal/metabolismo , Mucosa Intestinal/patología , Masculino , Persona de Mediana Edad , Proteínas de Neoplasias/genética , Polonia , ARN Mensajero/biosíntesis , ARN Mensajero/genética , Reacción en Cadena de la Polimerasa de Transcriptasa Inversa , Adulto Joven
4.
J Physiol Pharmacol ; 60 Suppl 4: 63-70, 2009 Oct.
Artículo en Inglés | MEDLINE | ID: mdl-20083853

RESUMEN

OBJECTIVE: FHIT gene, mapped at FRA3B site, encodes human diadenosine triphosphate hydrolase involved in the regulation of cell cycle and nucleotide metabolism. Decreased FHIT gene expression was previously observed in various types of human cancer, however, quantification of FHIT mRNA was seldom performed. AIM: To investigate loss of heterozygosity (LOH) at FRA3B, expression of FHIT gene at the mRNA and protein levels in sporadic colorectal carcinoma (CRC) and benign colon adenoma. MATERIALS AND METHODS: FHIT mRNA was quantified by the validated realtime PCR (QPCR) in tumor samples of 84 CRC patients and mucosal biopsies of 15 adenomas, in comparison to 37 control patients, whereas subgroup of 57 CRC, 10 adenoma and 10 control cases were selected for immunohistochemical (IHC) detection of the native FHIT protein and LOH determination at FRA3B. RESULTS: Higher level of FHIT mRNA was found in 86% of CRC (P<0.001) and 60% of adenomas (P=0.016). IHC showed comparable results to QPCR (P=0.003), revealing the strongest presence of FHIT protein in Dukes' C/D stages (P<0.001) and N1/N2 lymph nodes metastasis in CRC (P=0.04). FHIT gene expression and Dukes' and G staging were positively correlated in CRC as analyzed by QPCR and IHC. Deletion analysis of the fragile FRA3B site revealed the highest LOH frequency at D3S1234 in 32.5% of CRC informative cases, however, LOH did not correspond to QPCR, IHC or clinical-pathological variables. CONCLUSION: Our data suggest that reduction or absence of the FHIT gene expression is not a prerequisite for colorectal cancer development and progression.


Asunto(s)
Ácido Anhídrido Hidrolasas/biosíntesis , Adenoma/metabolismo , Neoplasias Colorrectales/metabolismo , Proteínas de Neoplasias/biosíntesis , Ácido Anhídrido Hidrolasas/genética , Adenoma/genética , Adenoma/patología , Adulto , Anciano , Neoplasias Colorrectales/genética , Neoplasias Colorrectales/patología , Cartilla de ADN , Femenino , Humanos , Inmunohistoquímica , Mucosa Intestinal/metabolismo , Mucosa Intestinal/patología , Pérdida de Heterocigocidad , Masculino , Persona de Mediana Edad , Proteínas de Neoplasias/genética , Polonia , Estudios Prospectivos , ARN/biosíntesis , ARN/genética , ARN Mensajero/biosíntesis , ARN Mensajero/genética , Reacción en Cadena de la Polimerasa de Transcriptasa Inversa
5.
J Physiol Pharmacol ; 60 Suppl 4: 71-5, 2009 Oct.
Artículo en Inglés | MEDLINE | ID: mdl-20083854

RESUMEN

OBJECTIVE: Although there is a convincing evidence supporting an important role for microorganisms in the pathogenesis of Inflammatory Bowel Disease (IBD) which comprises ulcerative colitis (UC) and Crohn's disease (CD), the specific mechanisms involved remain unclear. Toll-like receptors (TLR) recognize various molecules of microbiota including flagellin, the principal protein of motile comensal and pathogenic bacteria implicated in the pathogenesis of IBD. AIM: To investigate the expression of the TLR-5 receptors at the mRNA and protein levels in the mucosa of UC patients. MATERIALS AND METHODS: TLR-5 mRNA was quantified by the validated real-time PCR (QPCR) in mucosal biopsies of 99 UC patients and 34 control patients and TLR-5 protein was detected by immunohistochemistry (IHC) in 57 UC and 10 control patients. RESULTS: Significantly decreased TLR-5 gene expression at mRNA and protein level was found in the mucosa of patients with moderate and severe disease activity as compared to patients with low UC activity and control. TLR-5 immunoreactivity was found in the mucosa of UC patients and normal controls in the cytoplasm of enterocytes and at their basolateral domain. However, the intensity of the IHC reaction in specimens from UC patients was substantially lower than in control samples. CONCLUSION: The decreased expression of TLR-5 gene and protein in the mucosa of UC patients suggests that down-regulation of TLR-5 is probably caused by the increased number of ligand molecules in the proximity of epithelial cells in the inflamed tissue.


Asunto(s)
Colitis Ulcerosa/metabolismo , Mucosa Intestinal/metabolismo , Receptor Toll-Like 5/biosíntesis , Adulto , Anciano , Anciano de 80 o más Años , Femenino , Humanos , Inmunohistoquímica , Masculino , Persona de Mediana Edad , Polonia , Estudios Prospectivos , ARN/biosíntesis , ARN/genética , ARN/aislamiento & purificación , Reacción en Cadena de la Polimerasa de Transcriptasa Inversa , Adulto Joven
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