1.Genes Involved in Interleukin-1 Receptor Type II Activities Are Associated With Asthmatic Phenotypes.
Anne Marie MADORE ; Vanessa T VAILLANCOURT ; Emmanuelle BOUZIGON ; Chloé SARNOWSKI ; Florent MONIER ; Marie Hélène DIZIER ; Florence DEMENAIS ; Catherine LAPRISE
Allergy, Asthma & Immunology Research 2016;8(5):466-470
PURPOSE: Interleukin-1 (IL-1) plays a key role in inflammation and immunity and its decoy receptor, IL-1R2, has been implicated in transcriptomic and genetic studies of asthma. METHODS: Two large asthma family collections, the French-Canadian Saguenay-Lac-St-Jean (SLSJ) study and the French Epidemiological Study on the Genetics and Environment of Asthma (EGEA), were used to investigate the association of SNPs in 10 genes that modulate IL-1R2 activities with asthma, allergic asthma, and atopy. Gene-gene interactions were also tested. RESULTS: One SNP in BACE2 was associated with allergic asthma in the SLSJ study and replicated in the EGEA study before statistical correction for multiple testing. Additionally, two SNPs in the MMP2 gene were replicated in both studies prior to statistical correction and reached significance in the combined analysis. Moreover, three gene-gene interactions also survived statistical correction in the combined analyses (BACE1-IL1RAP in asthma and allergic asthma and IL1R1-IL1RAP in atopy). CONCLUSIONS: Our results highlight the relevance of genes involved in the IL-1R2 activity in the context of asthma and asthma-related traits.
Asthma
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Epidemiologic Studies
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Genetics
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Humans
;
Inflammation
;
Interleukin-1*
;
Phenotype*
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Polymorphism, Single Nucleotide
;
Receptors, Interleukin-1 Type II*
2.Lessons for the pathogenesis of rheumatoid arthritis acquired from experimental animal models.
Hanyang Medical Reviews 2005;25(2):53-66
Rheumatoid arthritis, a common human disease with a prevalence of about 1%, is characterized by inflammatory autoimmune responses. However, the etiopathogenesis of rheumatoid arthritis is still incompletely understood. A variety of experimental animal models has been established to investigate the pathogenesis of rheumatoid arthritis. A collageninduced arthritis model which is one of the most widely used experimental murine models is triggered by T cell responses specific to exogenous type II collagen. These T cells play a pivotal role in shaping inflammatory events in which autoantibodies, proinflammatory mediators, and innate effector cells are involved. Recently, a spontaneous arthritis model named K/BxN has been established. These mice are genetically programmed to exhibit predominance of a T cell population bearing autoantigenspecific T cell receptor molecules. Autoantigenspecific antibodies whose generation is solely dependent on the activity of autoantigen-specific T cells serve as a functional scaffold for the inflammatory events during the distal effector phase. These two models exhibit clinical and immunologic manifestations quite similar to those of rheumatoid arthritis and share a common aspect regarding that development of autoimmunity precede the inflammatory effector phase. However, these two models employ somewhat different effector pathways at the distal end-stage of arthritis. In addition to these two models, other experimental models of rheumatoid arthritis have been developed. These include spanteneous models such as TNF-alpa transgenic mice, IL-1 receptor antagonistdeficient mice and Zap-70 mutation mice, and induced models such as bacterial cell wall- and adjuvant-induced arthritis. The experimental animal models, all together, largely contribute to the improvement of Rheumatology, in terms of both the pathogenesis investigation and therapeutic approach.
Animals
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Antibodies
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Arthritis
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Arthritis, Experimental
;
Arthritis, Rheumatoid*
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Autoantibodies
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Autoimmunity
;
Collagen Type II
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Humans
;
Interleukin-1
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Mice
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Mice, Transgenic
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Models, Animal*
;
Models, Theoretical
;
Prevalence
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Receptors, Antigen, T-Cell
;
Rheumatology
;
Synovitis
;
T-Lymphocytes
3.Change of MyD88-independent signal transduction of Toll-like receptor 4 in immunological pathogenesis of Kawasaki disease.
Guo-bing WANG ; Cheng-rong LI ; Ying ZU
Chinese Journal of Pediatrics 2007;45(11):818-823
OBJECTIVEKawasaki disease (KD) is an acute febrile, multi-system endangeitis, which is mainly found in early childhood. Its etiology is still unknown. A great deal of clinical evidence and epidemiologic data suggest that KD is correlated with an acute immune dysfunction caused by infection. Many evidences in the past suggested that over-expression of proinflammatory cytokines, co-stimulatory molecules and chemokines, which were observed in KD, may contribute to the pathologic lesion of vascular endothelial cells. But the causative factors are still unknown. Toll-like receptor is a type I trans-membrane protein which could recognize ligands of pathogenic microbes, induce interferon beta (IFN-beta) and promote gene transcription of proinflammatory cytokines, co-stimulatory molecules and chemokines. This study was designed to investigate the role of MyD88-independent signal transduction of Toll-like receptor 4 in immunological pathogenesis of KD.
METHODSThirty-two children with KD and 16 age-matched healthy children were studied. Reverse-transcription PCR (RT-PCR) and real-time PCR were used to evaluate the mRNA levels of Toll-like receptor 4 and the molecules such as Toll-IL-1-receptor domain containing adaptor inducing IFN-beta (TRIF), TRIF-related adaptor molecule (TRAM), TANK-binding kinase 1 (TBK-1), IFN-beta, interferon-gamma-inducible protein 10 (IP-10), regulated on activation normal T cells expressed and secreted (RANTES), inducible nitric oxide synthase (iNOS) and suppressor of cytokine signaling 1 (SOCS-1) in monocytes/macrophages (MC), which participate in MyD88-independent signal transduction of toll-like receptors. Expression of costimulatory molecules such as CD40 in MC was analyzed by flow cytometry. Methylation-specific PCR was performed to analyze the methylation status of cytosine-phosphate-guanine (CpG) motif in SOCS-1 gene.
RESULTS(1) Compared with healthy controls, transcription levels of the molecules such as TLR4, TRIF, TRAM, TBK-1 and IFN-beta, were significantly up-regulated during acute phase of KD (P < 0.05), and down-regulated after treatment with intravenous immunoglobulin therapy. (2) Expression of iNOS and chemokines such as IP10 and RANTES in MC during acute phase of KD was remarkably elevated (P < 0.05), and down-regulated to some extents after treatment with intravenous immunoglobulin therapy. (3) Expression of costimulatory molecule CD40 in MC increased significantly during acute phase of KD [(6.19 +/- 2.25)% vs. (2.00 +/- 1.37)%, P < 0.05], while the protein levels of CD40 in KD-coronary artery lesion (CAL)(+) group was found to be significantly higher than that of KD-CAL-group [KD-CAL, (9.63 +/- 2.96)% vs. (4.12 +/- 1.91)%, P < 0.05]. (4) Expression levels of SOCS-1 mRNA were significantly up-regulated during acute phase of KD [(4.31 +/- 0.83) x 10(-3) vs. (1.09 +/- 0.23) x 10(-3), P < 0.05], and the levels of SOCS-1 gene in KD-CAL(+) group was found to be significantly lower than that of KD-CAL(-) group [(5.73 +/- 1.04) x 10(-3) vs (1.94 +/- 0.46) x 10(-3), P < 0.05]. (5) The CpG island of SOCS-1 DNA in KD patients was remarkably demethylated [(26.9 +/- 8.6)% vs (5.9 +/- 1.4)%, P < 0.05], and demethylation levels of SOCS-1 in KD-CAL(-) group were higher than that in KD-CAL+ group [(35.1 +/- 10.3)% vs. (13.2 +/- 3.7)%, P < 0.05].
CONCLUSIONAberrant activation of MyD88-independent pathways of Toll-like receptor 4 may be one of the factors causing disturbed immunological function in KD.
Child ; Humans ; Interleukin-1 ; metabolism ; Macrophages ; drug effects ; pathology ; Nitric Oxide Synthase Type II ; metabolism ; Pyrimidinones ; pharmacology ; Signal Transduction ; drug effects ; physiology ; Thiazoles ; pharmacology ; Toll-Like Receptor 4 ; metabolism ; Toll-Like Receptors ; deficiency ; drug effects ; metabolism
4.Predictive Value of Conjointly Examined IL-1ra, TNF-R I, TNF-R II, and RANTES in Patients with Primary Glomerulonephritis.
Journal of Korean Medical Science 2013;28(2):261-267
Interleukin-1 receptor antagonist (IL-1ra), tumor necrosis factor soluble receptors (sTNF-R) type I and II, and regulated upon activation, normal T-cell expressed and secreted (RANTES) play an important role in the modulation of primary glomerulonephritis (GN) course. The aim of the study was to assess whether pre-treatment measurements of IL-1ra, sTNF-R, and RANTES assessed conjointly may be useful as predicting factors in patients with GN. In 84 patients (45 males and 39 female) serum concentration (pg/mL) and urinary excretion (pg/mgCr) of cytokines were measured. After 12 months of therapy with steroids and cyclophosphamide the patients were divided into two subgroups: Responders (R) and Non-Responders (NR) according to the treatment results. The urinary IL-1ra, TNF-RI and RII were significantly higher in R than NR (1,732 vs 646 with P < 0.001, 13.1 vs 6.3 with P = 0.005, and 33.6 vs 14.4 with P = 0.012). The urinary RANTES excretion was increased in NR (79.6 vs 28.5; P < 0.001). The multivariable analysis showed that if conjointly assessed, only urinary IL-1ra, TNF-R I and R II, RANTES with 85% probability pointed the feature remission (R). In conclusion, the urinary excretion of IL-1ra, TNF-R I and R II, and RANTES examined conjointly are effective in predicting favorable response to immunosuppressive treatment in patients with GN.
Adult
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Cyclophosphamide/therapeutic use
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Female
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Glomerulonephritis/drug therapy/*metabolism/pathology
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Humans
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Immunosuppressive Agents/therapeutic use
;
Interleukin 1 Receptor Antagonist Protein/*analysis/blood/urine
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Lymphocyte Activation
;
Male
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Middle Aged
;
Multivariate Analysis
;
Predictive Value of Tests
;
Receptors, Tumor Necrosis Factor, Type I/*analysis/blood/urine
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Receptors, Tumor Necrosis Factor, Type II/*analysis/blood/urine
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Steroids/therapeutic use
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T-Lymphocytes/immunology/metabolism
5.Cell-type specific regulation of thrombospondin-1 expression and its promoter activity by regulatory agents.
Soo A KIM ; Jong Hoon KANG ; In Ho CHO ; Sung Won BAE ; Kyong Ja HONG
Experimental & Molecular Medicine 2001;33(3):117-123
Thrombospondin-1 (TSP-1), a multifunctional protein that is able to function as a negative regulator of solid tumor progression and angiogenesis, is normally present at a very low level but rapidly elevated in pathological tissues. To understand the cellular regulation of TSP-1 expression, the mode of it's expression in Hep3B, SK-HEP-1, and porcine aortic endothelial (PAE) cells was examined in the presence of all-trans retinoic acid (ATRA), interleukin-6 (IL-6), interferon-gamma (IFN-gamma), or phorbol 12-myristate 13-acetate (PMA). ATRA or IL-6 induced a dose-dependent increase of TSP-1 protein and mRNA levels in PAE cells, while they negatively regulated TSP-1 expression in the Hep3B and SK-HEP-1 cells. In contrast, PMA showed just the opposite effects on the TSP-1 expression in the same cells. IFN-gamma had little effect on TSP-1 level in Hep3B and PAE cells. The TSP-1 expression in SK-HEP-1 cells by these agents showed a close resemblance to that of liver cells rather than that of the endothelial cell line. Possible TSP-1 promoter-mediated responses by ATRA, IL-6, IFN-gamma, or PMA in Hep3B and PAE cells examined with luciferase activity of TSP-LUC reporter plasmid showed that levels of TSP-1 promoter activity were lower than that of the expressed TSP-1 protein and mRNA levels. Transfection of c-Jun and/or RARalpha expression vectors into Hep3B and PAE cells resulted in the enhanced TSP-1 promoter activity as well as the increments of of its protein and mRNA level. These results suggest that regulatory agents-induced TSP-1 expression may be attributed to mRNA stability and/or translational activation in concert with transcriptional activation and TSP-1 expression may be independently controlled via each signal pathway stimulated by PMA or ATRA.
Animal
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Cell Line
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Endothelium, Vascular/cytology/drug effects/metabolism
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*Gene Expression Regulation/drug effects
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Genes, Reporter
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Genes, jun
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Human
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Immunoblotting
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Interferon Type II/pharmacology
;
Interleukin-6/pharmacology
;
*Promoter Regions (Genetics)
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Proto-Oncogene Proteins c-jun/genetics/metabolism
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Receptors, Retinoic Acid/genetics/metabolism
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Recombinant Fusion Proteins/metabolism
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Tetradecanoylphorbol Acetate/pharmacology
;
Thrombospondin 1/*genetics/metabolism
;
Transcription, Genetic
;
Tretinoin/pharmacology
6.In vivo ligation of glucocorticoid-induced TNF receptor enhances the T-cell immunity to herpes simplex virus type 1.
Soojin LA ; Eunhwa KIM ; Byungsuk KWON
Experimental & Molecular Medicine 2005;37(3):193-198
GITR (glucocorticoid-induced TNF receptor) is a recently identified member of the TNF receptor superfamily. The receptor is preferentially expressed on CD4+CD25+ regulatory T cells and GITR signals break the suppressive activity of the subset. In this study, we wanted to reveal the in vivo function of GITR in herpes simplex virus type 1 (HSV-1) infection. A single injection of anti-GITR mAb (DTA-1) immediately after viral infection significantly increased the number of CD4+ and CD8+ T cells expressing CD25, an activation surface marker, and secreting IFN-gamma. We confirmed these in vivo observations by showing ex vivo that re-stimulation of CD4+ or CD8+ T cells with a CD4+ or CD8+ T-cell-specific HSV-1 peptide, respectively, induced a significant elevation in cell proliferation and in IFN-gamma secretion. Our results indicate that GITR signals play a critical role in the T-cell immunity to HSV-1.
Animals
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Antibodies, Monoclonal/pharmacology
;
CD4-Positive T-Lymphocytes/immunology
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CD8-Positive T-Lymphocytes/immunology
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Cell Proliferation
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Female
;
Glucocorticoids/*pharmacology
;
Herpes Simplex/*immunology
;
Herpesvirus 1, Human/pathogenicity
;
*Immunity, Cellular
;
Interferon Type II/secretion
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*Lymphocyte Activation
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Mice
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Mice, Inbred BALB C
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Peptide Fragments/metabolism
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Receptors, Interleukin-2/metabolism
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Receptors, Nerve Growth Factor/genetics/immunology/*metabolism
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Receptors, Tumor Necrosis Factor/genetics/immunology/*metabolism
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Research Support, Non-U.S. Gov't
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T-Lymphocytes/*immunology/metabolism/virology