RESUMEN
Many conditions, such as inflammation and physical exercise, can induce endoplasmic reticulum (ER) stress. Toll-like Receptor 4 (TLR4) can trigger inflammation and ER stress events. However, there are still no data in the literature regarding the role of TLR4 in ER stress during exercise in skeletal muscle. Therefore, the current investigation aimed to verify the responses of ER stress markers in wild-type (WT) and Tlr4 global knockout (KO) mice after acute and chronic physical exercise protocols. Eight-week-old male WT and KO mice were submitted to acute (moderate or high intensity) and chronic (4-week protocol) treadmill exercises. Under basal conditions, KO mice showed lower performance in the rotarod test. Acute high-intensity exercise increased eIF2α protein in the WT group. After the acute high-intensity exercise, there was an increase in Casp3 and Ddit3 mRNA for the KO mice. Acute moderate exercise increased the cleaved Caspase-3/Caspase-3 in the KO group. In response to chronic exercise, the KO group showed no improvement in any performance evaluation. The 4-week chronic protocol did not generate changes in ATF6, CHOP, p-IRE1α, p-eIF2α/eIF2α, and cleaved Caspase-3/Caspase-3 ratio but reduced BiP protein compared with the KO-Sedentary group. These results demonstrate the global deletion of Tlr4 seems to have the same effects on UPR markers of WT animals after acute and chronic exercise protocols but decreased performance. The cleaved Caspase-3/Caspase-3 ratio may be activated by another pathway other than ER stress in Tlr4 KO animals.
Asunto(s)
Apoptosis , Músculo Esquelético , Receptor Toll-Like 4 , Animales , Masculino , Ratones , Caspasa 3/metabolismo , Estrés del Retículo Endoplásmico , Endorribonucleasas/metabolismo , Inflamación/metabolismo , Ratones Endogámicos C57BL , Ratones Noqueados , Músculo Esquelético/metabolismo , Músculo Esquelético/patología , Receptor Toll-Like 4/genética , Receptor Toll-Like 4/metabolismo , Condicionamiento Físico AnimalRESUMEN
Toll-like Receptors (TLRs), such as the TLR4, are genes encoding transmembrane receptors of the same name, which induce a pro- or anti-inflammatory response according to their expression as the host's first line of defense against pathogens, such as infectious ones. Single nucleotide polymorphisms (SNPs) are the most common type of mutation in the human genome and can generate functional modification in genes. The aim of this article is to review in which infectious diseases there is an association of susceptibility or protection by the TLR4 SNP rs4986790. A systematic review and meta-analysis of the literature was conducted in the Science Direct, PUBMED, MEDLINE, and SciELO databases between 2011 and 2021 based on the dominant genotypic model of this SNP for general and subgroup analysis of infectious agent type in random effect. Summary odds ratios (ORs) and corresponding 95% confidence intervals (CIs) were calculated for genotypic comparison. I2 statistics were calculated to assess the presence of heterogeneity between studies and funnel plots were inspected for indication of publication bias. A total of 27 articles were included, all in English. Among the results achieved, the categories of diseases that were most associated with the SNP studied were in decreasing order of number of articles: infections by bacteria (29.63%); caused by viruses (22.23%); urinary tract infection-UTI (7.4%), while 11 studies (40.74%) demonstrated a nonsignificant association. In this meta-analysis, a total of 5599 cases and 5871 controls were finalized. The present meta-analysis suggests that there is no significant association between TLR4-rs4986790 SNP and infections (OR = 1,11; 95% CI: 0,75-1,66; p = 0,59), but in the virus subgroup it was associated with a higher risk (OR = 2,16; 95% CI: 1,09-4,30; p = 0,03). The subgroups of bacteria and parasites did not show statistical significance (OR = 0,86; 95% CI: 0,56-1,30; p = 0,47, and no estimate of effects, respectively). Therefore, it has been shown that a diversity of infectious diseases is related to this polymorphism, either by susceptibility or even severity to them, and the receptor generated is also crucial for the generation of cell signaling pathways and immune response against pathogens.
RESUMEN
This study aimed to investigate the association of serum high-mobility group box-1 (HMGB1) and toll-like receptor 4 (TLR4) expressions with the risk of epilepsy as well as their correlations with disease severity and resistance to anti-epilepsy drugs. One hundred and five epilepsy patients and 100 healthy controls (HCs) were enrolled in this case-control study, and serum samples were collected from all participants to assess the HMGB1 and TLR4 expressions by enzyme-linked immunosorbent assay (ELISA). Both serum HMGB1 (P<0.001) and TLR4 (P<0.001) expressions were higher in epilepsy patients than in HCs, and they displayed good predictive values for risk of epilepsy. Moreover, HMGB1 was positively correlated with TLR4 level (r=0.735, P<0.001). HMGB1 and TLR4 levels were both elevated in patients with an average seizure duration >5 min compared to patients with a seizure duration ≤5 min (P=0.001 and P=0.014, respectively). Also, HMGB1 and TLR4 were increased in patients with seizure frequency >3 times per month compared to patients with seizure frequency ≤3 times per month (both P=0.001). In addition, HMGB1 and TLR4 expressions were higher in intractable cases compared to drug-responsive cases (P<0.001). In conclusion, both HMGB1 and TLR4 expressions were correlated with increased risk and severity of epilepsy and their level was higher in patients resistant to anti-epilepsy drugs.
Asunto(s)
Humanos , Masculino , Femenino , Adulto , Proteína HMGB1/sangre , Epilepsia/sangre , Receptor Toll-Like 4/sangre , Anticonvulsivantes/uso terapéutico , Índice de Severidad de la Enfermedad , Ensayo de Inmunoadsorción Enzimática , Estudios de Casos y Controles , Valor Predictivo de las Pruebas , Factores de Riesgo , Epilepsia/tratamiento farmacológicoRESUMEN
Pancreatic cancer (PC) is an aggressive malady with proclivity for early metastasis. Overexpression of toll-like receptor 4 (TLR4) in pancreatic ductal adenocarcinoma, the most common type of pancreatic malignancy, correlates to tumor size, lymph node involvement, venous invasion and pathological stage. Lipopolysaccharides (LPS) are natural TLR4 ligands that have been shown to increase the invasive ability of PC cells. However, rapid inactivation of circulating LPS and low systemic absorption of inhaled LPS from the bronchoalveolar compartment make other agonists such as saturated fatty acids more suitable to be considered for TLR4-related cell invasiveness. Interestingly, PC risk was strongly associated to intake of saturated fat from animal food sources, in particular to consumption of saturated palmitic acid (PA). In the present study, we investigated the influence of PA on the invasive capacity of human PC cells AsPC-1. Using specific inhibitors, we found that PA stimulation of these tumor cells induced a TLR4-mediated cell invasion. Our results also indicate that the signaling events downstream of TLR4 involved generation of reactive oxygen species, activation of nuclear factor-kappa beta, and secretion and activation of matrix metalloproteinase 9 (MMP-9). Furthermore, PA stimulation decreased the levels of the micro RNA 29c (miR-29c). Of note, while inhibition of miR-29c increased MMP-9 mRNA levels, MMP-9 secretion and activation, and invasiveness, miR-29c mimic abrogated all these PA-stimulated effects. These results strongly suggest that miR-29c could be an attractive potential pharmacological agent for antitumoral therapy in PC.
Asunto(s)
Metaloproteinasa 9 de la Matriz/metabolismo , FN-kappa B/metabolismo , Invasividad Neoplásica , Ácido Palmítico/farmacología , Neoplasias Pancreáticas/patología , Especies Reactivas de Oxígeno/metabolismo , Transducción de Señal , Receptor Toll-Like 4/metabolismo , Línea Celular Tumoral , Humanos , MicroARNs/genética , MicroARNs/metabolismo , Neoplasias Pancreáticas/enzimología , Neoplasias Pancreáticas/metabolismoRESUMEN
Formaldehyde (FA) is an environmental and occupational pollutant that induces programming mechanisms on the acquired immune host defense in offspring when exposed during the prenatal period. Hence, here we investigated whether the exposure of FA on pregnant rats could affect the development of an innate acute lung injury in offspring induced by lipopolissacaride (LPS) injection. Pregnant Wistar rats were exposed to FA (0.92 mg/m(3)) or vehicle (distillated water), both 1 h/day, 5 days/week, from 1 to 21 days of pregnancy. Non-manipulated rats were used as control. After 30 days of birth, the offspring was submitted to injection of LPS (Salmonella abortus equi, 5 mg/kg, i.p.). Systemic and lung inflammatory parameters were evaluated 24 h later. Exposure to FA during gestation abolished the development of acute lung injury in offspring, as observed by reduced number of leukocytes in the bronchoalveolar fluid (BAL), in the blood and in the bone marrow, and decreased myeloperoxidase activity in the lung. Moreover, phagocytes from BAL presented normal phagocytosis, but reduced oxidative burst. Alterations on the profile of inflammatory cytokines were evidenced by reduced mRNA levels of IL-6 and elevated levels of IL-10 and IFN gamma in the lung tissue. Indeed, mRNA levels of toll-likereceptor-4 and nuclear factor-kappa B translocation into the nucleus were also reduced. Additionally, hyperresponsiveness to methacholine was blunted in the trachea of offspring of FA exposed mothers. Together, our data clearly show that FA exposure in the prenatal period modifies the programming mechanisms of the innate defense in the offspring leading to impaired defense against infections.
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Lesión Pulmonar Aguda/prevención & control , Contaminantes Atmosféricos/toxicidad , Formaldehído/toxicidad , Inmunidad Innata/efectos de los fármacos , Exposición por Inhalación/efectos adversos , Pulmón/efectos de los fármacos , Exposición Materna/efectos adversos , Neumonía/prevención & control , Efectos Tardíos de la Exposición Prenatal , Transporte Activo de Núcleo Celular , Lesión Pulmonar Aguda/inducido químicamente , Lesión Pulmonar Aguda/genética , Lesión Pulmonar Aguda/inmunología , Lesión Pulmonar Aguda/metabolismo , Lesión Pulmonar Aguda/fisiopatología , Animales , Citocinas/genética , Citocinas/metabolismo , Modelos Animales de Enfermedad , Femenino , Regulación de la Expresión Génica , Edad Gestacional , Mediadores de Inflamación/metabolismo , Lipopolisacáridos , Pulmón/inmunología , Pulmón/metabolismo , FN-kappa B/genética , FN-kappa B/metabolismo , Fagocitos/efectos de los fármacos , Fagocitos/inmunología , Fagocitos/metabolismo , Neumonía/inducido químicamente , Neumonía/genética , Neumonía/inmunología , Neumonía/metabolismo , Neumonía/fisiopatología , Embarazo , ARN Mensajero/metabolismo , Ratas Wistar , Receptor Toll-Like 4/genética , Receptor Toll-Like 4/metabolismo , Tráquea/efectos de los fármacos , Tráquea/fisiopatologíaRESUMEN
Components of high molecular-weight (PI) obtained from Ascaris suum extract down-regulate the Th1/Th2-related immune responses induced by ovalbumin (OVA)-immunization in mice. Furthermore, the PI down-modulates the ability of dendritic cells (DCs) to activate T lymphocytes by an IL-10-mediated mechanism. Here, we evaluated the role of toll like receptors 2 and 4 (TLR2 and 4) in the modulatory effect of PI on OVA-specific immune response and the PI interference on DC full activation. An inhibition of OVA-specific cellular and humoral responses were observed in wild type (WT) or in deficient in TLR2 (TLR2(-/-)) or 4 (TLR4(-/-)) mice immunized with OVA plus PI when compared with OVA-immunized mice. Low expression of class II MHC, CD40, CD80 and CD86 molecules was observed in lymph node (LN) cells from WT, TLR2(-/-) or TLR4(-/-) mice immunized with OVA plus PI compared with OVA-primed cells. We also verified that PI was able to modulate the activation of DCs derived from bone marrow of WT, TLR2(-/-) or TLR4(-/-) mice induced in vitro by agonists of TLRs, as observed by a decreased expression of class II MHC and costimulatory molecules and by low secretion of pro-inflammatory cytokines. Its effect was accompanied by IL-10 synthesis. In this sense, the modulatory effect of PI on specific-immune response and DC activation is independent of TLR2 or TLR4.