RESUMEN
BACKGROUND: Pseudo-allergic reactions are potentially fatal hypersensitivity responses caused by mast cell activation. α-linolenic acid (ALA) is known for its anti-allergic properties. However, its potential anti-pseudo-allergic effects were not much investigated. PURPOSE: To investigate the inhibitory effects of ALA on IgE-independent allergy in vitro, and in vivo, as well as the mechanism underlying its effects. METHODS/STUDY DESIGNS: The anti-anaphylactoid activity of ALA was evaluated in passive cutaneous anaphylaxis reaction (PCA) and systemic anaphylaxis models. Calcium imaging was used to assess intracellular Ca2+ mobilization. The release of cytokines and chemokines was measured using enzyme immunoassay kits. Western blot analysis was conducted to investigate the molecules of Lyn-PLCγ-IP3R-Ca2+ and Lyn-p38/NF-κB signaling pathway. RESULTS: ALA (0, 1.0, 2.0, and 4.0 mg/kg) dose-dependently reduced serum histamine, chemokine release, vasodilation, eosinophil infiltration, and the percentage of degranulated mast cells in C57BL/6 mice. In addition, ALA (0, 50, 100, and 200 µM) reduced Compound 48/80 (C48/80) (30 µg/ml)-or Substance P (SP) (4 µg/ml)-induced calcium influx, mast cell degranulation and cytokines and chemokine release in Laboratory of Allergic Disease 2 (LAD2) cells via Lyn-PLCγ-IP3R-Ca2+ and Lyn-p38/NF-κB signaling pathway. Moreover, ALA (0, 50, 100, and 200 µM) inhibited C48/80 (30 µg/ml)- and SP (4 µg/ml)-induced calcium influx in Mas-related G-protein coupled receptor member X2 (MrgX2)-HEK293 cells and in vitro kinase assays confirmed that ALA inhibited the activity of Lyn kinase. In response to 200 µM of ALA, the activity of Lyn kinase by (7.296 ± 0.03751) × 10-5 units/µl and decreased compared with C48/80 (30 µg/ml) by (8.572 ± 0.1365) ×10-5 units/µl. CONCLUSION: Our results demonstrate that ALA might be a potential Lyn kinase inhibitor, which could be used to treat pseudo-allergic reaction-related diseases such as urticaria.
Asunto(s)
Anafilaxia/tratamiento farmacológico , Antialérgicos/farmacología , Anafilaxis Cutánea Pasiva/efectos de los fármacos , Ácido alfa-Linolénico/farmacología , Familia-src Quinasas/antagonistas & inhibidores , Animales , Degranulación de la Célula/efectos de los fármacos , Quimiocinas/metabolismo , Relación Dosis-Respuesta a Droga , Humanos , Inmunoglobulina E/inmunología , Masculino , Mastocitos/efectos de los fármacos , Mastocitos/inmunología , Ratones Endogámicos C57BL , Proteínas del Tejido Nervioso/metabolismo , Inhibidores de Proteínas Quinasas/farmacología , Receptores Acoplados a Proteínas G/metabolismo , Receptores de Neuropéptido/metabolismo , p-Metoxi-N-metilfenetilamina/toxicidad , Familia-src Quinasas/química , Familia-src Quinasas/inmunología , Familia-src Quinasas/metabolismoRESUMEN
Resveratrol, a phytochemical, acts several cellular signaling pathways and has anti-inflammatory potentials. The purpose of this study is to research the therapeutic effect of resveratrol in collagen-induced arthritis (CIA) model in rats and whether resveratrol affects the activities of signaling pathways those are potent pathogenic actors of rheumatoid arthritis. Arthritis was induced by intradermal injection of chicken type II collagen combined with incomplete Freund's adjuvant in Wistar albino rats. One day after the onset of arthritis (day 14), resveratrol (20 mg/kg/day) was given via oral gavage, until day 29. The paws of the rats were obtained for further analysis. Tissue Wnt5a, mitogen-activated protein kinase (MAPK), Src tyrosine kinase and signal transducer, and activator of transcription-3 (STAT3) mRNA expressions were determined by real-time polymerase chain reaction. Resveratrol ameliorated the clinical and histopathological (perisynovial inflammation and cartilage-bone destruction) findings of inflammatory arthritis. The tissue mRNA expressions of Wnt5a, MAPK3, Src kinase, and STAT3 were increased in the sham group compared to the control group. Resveratrol supplement decreased their expressions. The present study shows that Src kinase, STAT3, and Wnt signaling pathway are active in the CIA model. Resveratrol inhibits these signaling pathways and ameliorates inflammatory arthritis. © 2018 BioFactors, 45(1):69-74, 2019.
Asunto(s)
Antiinflamatorios/farmacología , Artritis Experimental/tratamiento farmacológico , Resveratrol/farmacología , Factor de Transcripción STAT3/genética , Vía de Señalización Wnt/efectos de los fármacos , Familia-src Quinasas/genética , Administración Oral , Animales , Artritis Experimental/genética , Artritis Experimental/inmunología , Artritis Experimental/patología , Huesos/efectos de los fármacos , Huesos/inmunología , Huesos/patología , Cartílago/efectos de los fármacos , Cartílago/inmunología , Cartílago/patología , Esquema de Medicación , Femenino , Regulación de la Expresión Génica , Miembro Posterior , Inflamación , Proteína Quinasa 3 Activada por Mitógenos/genética , Proteína Quinasa 3 Activada por Mitógenos/inmunología , Ratas , Ratas Wistar , Factor de Transcripción STAT3/antagonistas & inhibidores , Factor de Transcripción STAT3/inmunología , Proteína Wnt-5a/genética , Proteína Wnt-5a/inmunología , Familia-src Quinasas/antagonistas & inhibidores , Familia-src Quinasas/inmunologíaRESUMEN
Microglia are the major component of intrinsic brain immune system in neuroinflammation. Although wogonin expresses anti-inflammatory function in microglia, little is known about the molecular mechanisms of the protective effect of wogonin against microglia activation. The aim of this study was to evaluate how wogonin exerts its anti-inflammatory function in BV2 microglial cells after LPS/INFγ administration. Wogonin not only inhibited LPS/ INFγ-induced PGE2 and NO production without affecting cell viability but also exhibited parallel inhibition on LPS/INFγ-induced expression of iNOS and COX-2 in the same concentration range. While LPS/INFγ-induced expression of P-p65 and P-IκB was inhibited by wogonin-only weak inhibition on P-p38 and P-JNK were observed, whereas it significantly attenuated the P-ERK1/2 and its upstream activators P-MEK1/2 and P-Src in a parallel concentration-dependent manner. These results indicated that the blockade of PGE2 and NO production by wogonin in LPS/INFγ-stimulated BV2 cells is attributed mainly to interference in the Src-MEK1/2-ERK1/2-NFκB-signaling pathway.
Asunto(s)
Antiinflamatorios/farmacología , Dinoprostona/inmunología , Flavanonas/farmacología , Lipopolisacáridos/inmunología , Microglía/efectos de los fármacos , Óxido Nítrico/inmunología , Animales , Línea Celular , Supervivencia Celular/efectos de los fármacos , Medicamentos Herbarios Chinos/farmacología , Interferón gamma/administración & dosificación , Interferón gamma/inmunología , Lipopolisacáridos/administración & dosificación , Sistema de Señalización de MAP Quinasas/efectos de los fármacos , Ratones , Microglía/citología , Microglía/inmunología , FN-kappa B/inmunología , Transducción de Señal/efectos de los fármacos , Familia-src Quinasas/inmunologíaRESUMEN
The activity of tyrosine kinases is central to many cellular processes, and accumulating evidence suggests that their role in inflammation is no less profound. Three main tyrosine kinase families, the Src, Tec and Syk kinase families are intimately involved in TLR signalling, the critical first step in cellular recognition of invading pathogens and tissue damage. Their activity results in changes in gene expression in affected cells. Key amongst these genes are the cytokines, which orchestrate both the duration and extent of inflammation. Tyrosine kinases also play important roles in cytokine function, and are implicated in signalling through both pro- and anti-inflammatory cytokines such as TNF, IL-6 and IL-10. Thus, strategies to modulate tyrosine kinase activity have significant therapeutic potential in combating the chronic inflammatory state that is typical of many major health issues that face us today, including Rheumatoid Arthritis, Cardiovascular disease and cancer. Here we review current knowledge of the role of tyrosine kinases in inflammation with particular emphasis on their role in TLR signalling.
Asunto(s)
Inflamación/inmunología , Proteínas Tirosina Quinasas/inmunología , Proteínas Tirosina Quinasas/metabolismo , Transducción de Señal/inmunología , Adyuvantes Inmunológicos/metabolismo , Animales , Complejo Antígeno-Anticuerpo/inmunología , Complejo Antígeno-Anticuerpo/metabolismo , Movimiento Celular/inmunología , Enfermedad Crónica , Citocinas/biosíntesis , Citocinas/inmunología , Citocinas/metabolismo , Quinasa 2 de Adhesión Focal/química , Quinasa 2 de Adhesión Focal/inmunología , Quinasa 2 de Adhesión Focal/metabolismo , Expresión Génica/inmunología , Humanos , Péptidos y Proteínas de Señalización Intracelular/química , Péptidos y Proteínas de Señalización Intracelular/inmunología , Péptidos y Proteínas de Señalización Intracelular/metabolismo , Quinasas Janus/química , Quinasas Janus/inmunología , Quinasas Janus/metabolismo , Ratones , Proteínas Tirosina Quinasas/química , Proteínas Proto-Oncogénicas c-hck/inmunología , Proteínas Proto-Oncogénicas c-hck/metabolismo , Quinasa Syk , Receptores Toll-Like/inmunología , Receptores Toll-Like/metabolismo , Familia-src Quinasas/química , Familia-src Quinasas/inmunología , Familia-src Quinasas/metabolismoRESUMEN
Fc epsilon RI activation of mast cells is thought to involve Lyn and Syk kinases proximal to the receptor and the signaling complex organized by the linker for activation of T cells (LAT). We report here that Fc epsilon RI also uses a Fyn kinase-dependent pathway that does not require Lyn kinase or the adapter LAT for its initiation, but is necessary for mast cell degranulation. Lyn-deficiency enhanced Fyn-dependent signals and degranulation, but inhibited the calcium response. Fyn-deficiency impaired degranulation, whereas Lyn-mediated signaling and calcium was normal. Thus, Fc epsilon RI-dependent mast cell degranulation involves cross-talk between Fyn and Lyn kinases.