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61.
Peripheral tolerance and the qualitative characteristics of autoreactive T cell clones in primary biliary cirrhosis 总被引:1,自引:0,他引:1
Kawano A Shimoda S Kamihira T Ishikawa F Niiro H Soejima Y Taketomi A Maehara Y Nakamura M Komori A Migita K Ishibashi H Azuma M Gershwin ME Harada M 《Journal of immunology (Baltimore, Md. : 1950)》2007,179(5):3315-3324
Primary biliary cirrhosis is characterized by autoreactive T cells specific for the mitochondrial Ag PDC-E2(163-176). We studied the ability of eight T cell clones (TCC) specific for PDC-E2(163-176) to proliferate or become anergic in the presence of costimulation signals. TCC were stimulated with either human PDC-E2(163-176), an Escherichia coli 2-oxoglutarate dehydrogenase mimic (OGDC-E2(34-47)), or analogs with amino acid substitutions using HLA-matched allogeneic PBMC or mouse L-DR53 fibroblasts as APC. Based on their differential responses to these peptides (human PDC-E2(163-176), E. coli OGDC-E2(34-47)) in the different APC systems, TCC were classified as costimulation dependent or independent. Only costimulation-dependent TCC could become anergic. TCC with costimulation-dependent responses to OGDC-E2 become anergic to PDC-E2 when preincubated with mimic, even if costimulation is independent for PDC-E2(163-176). Anergic TCC produced IL-10. One selected TCC could not become anergic after preincubation with PDC-E2(163-176)-pulsed L-DR53 but became anergic using L-DR53 pulsed with PDC-E2 peptide analogs with a substitution at a critical TCR binding site. TCC that only respond to peptide-pulsed PBMC, but not L-DR53, proliferate with peptide-pulsed CD80/CD86-transfected L-DR53; however, anergy was not induced with peptide-pulsed L-DR53 transfected with only CD80 or CD86. These data highlight that costimulation plays a dominant role in maintaining peripheral tolerance to PBC-specific Ags. They further suggest that, under specific circumstances, molecular mimicry of an autoantigen may restore rather than break peripheral tolerance. 相似文献
62.
Tsubaki M Kato C Manno M Ogaki M Satou T Itoh T Kusunoki T Tanimori Y Fujiwara K Matsuoka H Nishida S 《Molecular and cellular biochemistry》2007,304(1-2):53-60
Osteolytic lesions are rapidly progressive during the terminal stages of myeloma, and the bone pain or bone fracture that
occurs at these lesions decreases the patients’ quality of life to a notable degree. In relation to the etiology of this bone
destruction, it has been reported recently that MIP-1α, produced in large amounts in myeloma patients, acts indirectly on
osteoclastic precursor cells, and activates osteoclasts by way of bone-marrow stromal cells or osteoblasts, although the details
of this process remain obscure. In the present study, our group investigated the mechanism by which RANKL expression is induced
by MIP-1α and the effects of MIP-1α on the activation of osteoclasts. RANKL mRNA and RANKL protein expressions increased in
both ST2 cells and MC3T3–E1 cells in a MIP-1α concentration-dependent manner. RANKL mRNA expression began to increase at 1 h
after the addition of MIP-1α; the increase became remarkable at 2 h, and continuous expression was observed subsequently.
Both ST2 and MC3T3-E1 cells showed similar levels of increased RANKL protein expression at 1, 2, and 3 days after the addition
of MIP-1α. After the addition of MIP-1α, the amount of phosphorylated ERK1/2 and Akt protein expressions showed an increase,
as compared to the corresponding amount in the control group. On the other hand, the amount of phosphorylated p38MAPK protein
expression showed a decrease from the amount in the control group after the addition of MIP-1α. U0126 (a MEK1/2 inhibitor)
or LY294002 (a PI3K inhibitor) was added to ST2 and MC3T3-E1 cells, and was found to inhibit RANKL mRNA and RANKL protein
expression in these cells. When SB203580, a p38MAPK inhibitor, was added, RANKL mRNA and RANKL protein expression were increased
in these cells. MIP-1α was found to promote osteoclastic differentiation of C7 cells, an osteoclastic precursor cell line,
in a MIP-1α concentration-dependent manner. MIP-1α promoted differentiation into osteoclasts more extensively in C7 cells
incubated together with ST2 and MC3T3-E1 cells than in C7 cells incubated alone. These results suggested that MIP-1α directly
acts on the osteoclastic precursor cells and induces osteoclastic differentiation. This substance also indirectly induces
osteoclastic differentiation through the promotion of RANKL expression in bone-marrow stromal cells and osteoblasts. The findings
of this investigation suggested that activation of the MEK/ERK and the PI3K/Akt pathways and inhibition of p38MAPK pathway
were involved in RANKL expression induced by MIP-1α in bone-marrow stromal cells and osteoblasts. This finding may be useful
in the development of an osteoclastic inhibitor that targets intracellular signaling factors. 相似文献
63.
Nakanishi J Wada Y Matsumoto K Azuma M Kikuchi K Ueda S 《Cancer immunology, immunotherapy : CII》2007,56(8):1173-1182
PURPOSE: The programmed death-1 (PD-1)/B7-H1 (also called PD-L1) pathway negatively regulates T cell activation and has been suggested to play an important role in regulating antitumor host immunity. To investigate the clinical significance of B7-H1 expression to the tumor grade and postoperative prognosis of patients with urothelial cancer, we analyzed the relationship between B7-H1 expression and various clinicopathological features and postoperative prognosis. EXPERIMENTAL DESIGN: Sixty-five urothelial cancer cases were examined. B7-H1 expression in tumors and the numbers and phenotypes of tumor-infiltrating lymphocytes were evaluated by immunohistochemistry and flow cytometry. RESULTS: A substantial expression of B7-H1 was observed in all urothelial cancers investigated. Tumor specimens from patients with higher WHO grade or primary tumor classifications showed significantly higher percentages of tumor-associated B7-H1. Tumor-associated B7-H1 expression was significantly associated with a high frequency of postoperative recurrence and poor survival rate. Furthermore, multivariate analysis indicated that tumor-associated B7-H1 was more significant prognostic factor than WHO grade. CONCLUSIONS: Our results demonstrate that the aberrant expression of B7-H1 in urothelial cancer is associated with aggressive tumors, suggesting a regulatory role of tumor-associated B7-H1 in antitumor immunity. Therefore, the manipulation of tumor-associated B7-H1 may become a beneficial target for immunotherapy in human urothelial cancer. 相似文献
64.
Teno N Miyake T Ehara T Irie O Sakaki J Ohmori O Gunji H Matsuura N Masuya K Hitomi Y Nonomura K Horiuchi M Gohda K Iwasaki A Umemura I Tada S Kometani M Iwasaki G Cowan-Jacob SW Missbach M Lattmann R Betschart C 《Bioorganic & medicinal chemistry letters》2007,17(22):6096-6100
Pyrrolopyrimidine, a novel scaffold, allows to adjust interactions within the S3 subsite of cathepsin K. The core intermediate 10 facilitated the P3 optimization and identified highly potent and selective cathepsin K inhibitors 11-20. 相似文献
65.
A histone lysine methyltransferase activated by non-canonical Wnt signalling suppresses PPAR-gamma transactivation 总被引:4,自引:0,他引:4
66.
Takahashi Miyuki Takasugi Toshiyuki Kawakami Arisa Wei Ran Ando Kanae Ohshima Toshio Hisanaga Shin-ichi 《Neurochemical research》2022,47(9):2773-2779
Neurochemical Research - Valproic acid (VPA) is a drug used for the treatment of epilepsy, seizures, migraines, and bipolar disorders. Cyclin-dependent kinase 5 (Cdk5) is a Ser/Thr kinase activated... 相似文献
67.
Miyamoto Y Banno Y Yamashita T Fujimoto T Oi S Moritoh Y Asakawa T Kataoka O Takeuchi K Suzuki N Ikedo K Kosaka T Tsubotani S Tani A Funami M Amano M Yamamoto Y Aertgeerts K Yano J Maezaki H 《Bioorganic & medicinal chemistry》2011,19(1):172-185
We have previously discovered nicotinic acid derivative 1 as a structurally novel dipeptidyl peptidase IV (DPP-4) inhibitor. In this study, we obtained the X-ray co-crystal structure between nicotinic acid derivative 1 and DPP-4. From these X-ray co-crystallography results, to achieve more potent inhibitory activity, we targeted Arg125 as a potential amino acid residue because it was located near the pyridine core, and some known DPP-4 inhibitors were reported to interact with this residue. We hypothesized that the guanidino group of Arg125 could interact with two hydrogen-bond acceptors in a bidentate manner. Therefore, we designed a series of 3-pyridylacetamide derivatives possessing an additional hydrogen-bond acceptor that could have the desired bidentate interaction with Arg125. We discovered the dihydrochloride of 1-{[5-(aminomethyl)-2-methyl-4-(4-methylphenyl)-6-(2-methylpropyl)pyridin-3-yl]acetyl}-l-prolinamide (13j) to be a potent and selective DPP-4 inhibitor that could interact with the guanidino group of Arg125 in a unique bidentate manner. 相似文献
68.
Yamazaki D Tabara Y Kita S Hanada H Komazaki S Naitou D Mishima A Nishi M Yamamura H Yamamoto S Kakizawa S Miyachi H Yamamoto S Miyata T Kawano Y Kamide K Ogihara T Hata A Umemura S Soma M Takahashi N Imaizumi Y Miki T Iwamoto T Takeshima H 《Cell metabolism》2011,14(2):231-241
TRIC channel subtypes, namely TRIC-A and TRIC-B, are intracellular monovalent cation channels postulated to mediate counter-ion movements facilitating physiological Ca(2+) release from internal stores. Tric-a-knockout mice developed hypertension during the daytime due to enhanced myogenic tone in resistance arteries. There are two Ca(2+) release mechanisms in vascular smooth muscle cells (VSMCs); incidental opening of ryanodine receptors (RyRs) generates local Ca(2+) sparks to induce hyperpolarization, while agonist-induced activation of inositol trisphosphate receptors (IP(3)Rs) evokes global Ca(2+) transients causing contraction. Tric-a gene ablation inhibited RyR-mediated hyperpolarization signaling to stimulate voltage-dependent Ca(2+) influx, and adversely enhanced IP(3)R-mediated Ca(2+) transients by overloading Ca(2+) stores in VSMCs. Moreover, association analysis identified single-nucleotide polymorphisms (SNPs) around the human TRIC-A gene that increase hypertension risk and restrict the efficiency of antihypertensive drugs. Therefore, TRIC-A channels contribute to maintaining blood pressure, while TRIC-A SNPs could provide biomarkers for constitutional diagnosis and personalized medical treatment of essential hypertension. 相似文献
69.
Miyuki Bohgaki Masaki Matsumoto Tatsuya Atsumi Takeshi Kondo Shinsuke Yasuda Tetsuya Horita Keiichi I. Nakayama Fumihiko Okumura Shigetsugu Hatakeyama Takao Koike 《Journal of cellular and molecular medicine》2011,15(1):141-151
Antiphospholipid syndrome (APS) is characterized by thrombosis and the presence of antiphospholipid antibodies (aPL) that directly recognizes plasma β2‐glycoprotein I (β2GPI). Tissue factor (TF), the major initiator of the extrinsic coagulation system, is induced on monocytes by aPL in vitro, explaining in part the pathophysiology in APS. We previously reported that the mitogen‐activated protein kinase (MAPK) pathway plays an important role in aPL‐induced TF expression on monocytes. In this study, we identified plasma gelsolin as a protein associated with β2GPI by using immunoaffinity chromatography and mass spectrometric analysis. An in vivo binding assay showed that endogenous β2GPI interacts with plasma gelsolin, which binds to integrin a5β1 through fibronectin. The tethering of β2GPI to monoclonal anti‐β2GPI autoantibody on the cell surface was enhanced in the presence of plasma gelsolin. Immunoblot analysis demonstrated that p38 MAPK protein was phosphorylated by monoclonal anti‐β2GPI antibody treatment, and its phosphorylation was attenuated in the presence of anti‐integrin a5β1 antibody. Furthermore, focal adhesion kinase, a downstream molecule of the fibronectin‐integrin signalling pathway, was phosphorylated by anti‐β2GPI antibody treatment. These results indicate that molecules including gelsolin and integrin are involved in the anti‐β2GPI antibody‐induced MAPK pathway on monocytes and that integrin is a possible therapeutic target to modify a prothrombotic state in patients with APS. 相似文献
70.
Kajiro M Tsuchiya M Kawabe Y Furumai R Iwasaki N Hayashi Y Katano M Nakajima Y Goto N Watanabe T Murayama A Oishi H Ema M Takahashi S Kishimoto H Yanagisawa J 《PloS one》2011,6(10):e25871
Protein ubiquitination is a post-translational protein modification that regulates many biological conditions. Trip12 is a HECT-type E3 ubiquitin ligase that ubiquitinates ARF and APP-BP1. However, the significance of Trip12 in vivo is largely unknown. Here we show that the ubiquitin ligase activity of Trip12 is indispensable for mouse embryogenesis. A homozygous mutation in Trip12 (Trip12(mt/mt)) that disrupts the ubiquitin ligase activity resulted in embryonic lethality in the middle stage of development. Trip12(mt/mt) embryos exhibited growth arrest and increased expression of the negative cell cycle regulator p16. In contrast, Trip12(mt/mt) ES cells were viable. They had decreased proliferation, but maintained both the undifferentiated state and the ability to differentiate. Trip12(mt/mt) ES cells had increased levels of the BAF57 protein (a component of the SWI/SNF chromatin remodeling complex) and altered gene expression patterns. These data suggest that Trip12 is involved in global gene expression and plays an important role in mouse development. 相似文献