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81.
Critical negative regulation of type 1 T cell immunity and immunopathology by signaling adaptor DAP12 during intracellular infection 总被引:1,自引:0,他引:1
Divangahi M Yang T Kugathasan K McCormick S Takenaka S Gaschler G Ashkar A Stampfli M Gauldie J Bramson J Takai T Brown E Yokoyama WM Aoki N Xing Z 《Journal of immunology (Baltimore, Md. : 1950)》2007,179(6):4015-4026
Transmembrane signaling adaptor DAP12 has increasingly been recognized for its important role in innate responses. However, its role in the regulation of antimicrobial T cell responses has remained unknown. In our current study, we have examined host defense, T cell responses, and tissue immunopathology in models of intracellular infection established in wild-type and DAP12-deficient mice. During mycobacterial infection, lack of DAP12 leads to pronounced proinflammatory and Th1 cytokine responses, overactivation of Ag-specific CD4 and CD8 T cells of type 1 phenotype, and heightened immunopathology both in the lung and lymphoid organs. DAP12-deficient airway APC display enhanced NF-kappaB activation and cytokine responses upon TLR stimulation or mycobacterial infection in vitro. Of importance, adoptive transfer of Ag-loaded DAP12-deficient APC alone could lead to overactivation of transferred transgenic or endogenous wild-type T cells in vivo. We have further found that the immune regulatory role by DAP12 is not restricted only to intracellular bacterial infection, since lack of this molecule also leads to uncontrolled type 1 T cell activation and severe immunopathology and tissue injury during intracellular viral infection. Our study thus identifies DAP12 as an important novel immune regulatory molecule that acts, via APC, to control the level of antimicrobial type 1 T cell activation and immunopathology. 相似文献
82.
Noda M Kariura Y Pannasch U Nishikawa K Wang L Seike T Ifuku M Kosai Y Wang B Nolte C Aoki S Kettenmann H Wada K 《Journal of neurochemistry》2007,101(2):397-410
Bradykinin (BK) has been reported to be a mediator of brain damage in acute insults. Receptors for BK have been identified on microglia, the pathologic sensors of the brain. Here, we report that BK attenuated lipopolysaccharide (LPS)-induced release of tumor necrosis factor-alpha (TNF-alpha) and interleukin-1beta from microglial cells, thus acting as an anti-inflammatory mediator in the brain. This effect was mimicked by raising intracellular cAMP or stimulating the prostanoid receptors EP2 and EP4, while it was abolished by a cAMP antagonist, a prostanoid receptor antagonist, or by an inhibitor of the inducible cyclooxygenase (cyclooxygenase-2). BK also enhanced formation of prostaglandin E(2) and expression of microsomal prostaglandin E synthase. Expression of BK receptors and EP2/EP4 receptors were also enhanced. Using physiological techniques, we identified functional BK receptors not only in culture, but also in microglia from acute brain slices. BK reduced LPS-induced neuronal death in neuron-microglia co-cultures. This was probably mediated via microglia as it did not affect TNF-alpha-induced neuronal death in pure neuronal cultures. Our data imply that BK has anti-inflammatory and neuroprotective effects in the central nervous system by modulating microglial function. 相似文献
83.
Kimura MY Iwamura C Suzuki A Miki T Hasegawa A Sugaya K Yamashita M Ishii S Nakayama T 《Journal of immunology (Baltimore, Md. : 1950)》2007,178(8):4926-4936
Schnurri-2 (Shn-2) is a large zinc-finger containing protein, and it plays a critical role in cell growth, signal transduction and lymphocyte development. In Shn-2-deficient CD4 T cells, the activation of NF-kappaB was up-regulated and their ability to differentiate into Th2 cells was enhanced. We herein demonstrate that Th1 and Th2 memory cells are not properly generated from Shn-2-deficient effector Th1/Th2 cells. Even a week after the transfer of effector Th1/Th2 cells into syngeneic mice, a dramatic decrease in the number of Shn-2-deficient donor T cells was detected particularly in the lymphoid organs. The transferred Shn-2-deficient Th1/Th2 cells express higher levels of the activation marker CD69. No significant defect in the BrdU incorporation in the Shn-2-deficient transferred CD4 T cells was observed. The numbers of apoptotic cells were selectively higher in Shn-2-deficient donor Th1/Th2 cell population. Moreover, Shn-2-deficient effector Th1 and Th2 cells showed an increased susceptibility to cell death in in vitro cultures with increased expression of FasL. Transfer of Th2 effector cells over-expressing the p65 subunit of NF-kappaB resulted in a decreased number of p65-expressing cells in the lymphoid organs. As expected, T cell-dependent Ab responses after in vivo immunization of Shn-2-deficient mice were significantly reduced. Thus, Shn-2 appears to control the generation of memory Th1/Th2 cells through a change in their susceptibility to cell death. 相似文献
84.
Nadai M Kato M Yoshizumi H Kimura M Kurono S Abe F Saito H Hasegawa T 《Life sciences》2007,81(15):1175-1182
Whether organic anion and cation transporters are involved in the renal excretion of xanthine derivatives, 3-methylxanthie and enprofylline, remains unclear. In this study, we have investigated the effects of typically predominant substrates for organic anion and cation transporters on the tubular secretion of 3-methylxanthine and enprofylline in rats. In the renal clearance experiments using typical substrates for organic anion transporters, probenecid and p-aminohippurate, probenecid (20 mg/kg), but not p-aminohippurate (100 mg/kg), significantly decreased the renal clearance and clearance ratio of 3-methylxanthine and enprofylline. The typical substrates for organic cation transport systems, tetraethylammonium (30.6 mg/kg) and cimetidine (50 or 100 mg/kg), significantly decreased the renal clearance and clearance ratio of 3-methylxanthine and enprofylline. These results suggest that the renal secretory transport of 3-methylxanthine and enprofylline are mediated by probenecid-, cimetidine- and tetraethylammonium-sensitive transport systems. Uric acid, an organic anion, significantly inhibited the renal secretion of 3-methylxanthine, but not enprofylline, suggesting that the renal tubular transport of 3-methylxanthine is also mediated via uric acid-sensitive transport system. These findings suggest the possibility that both organic anion and cation transporters are, at least, involved in the renal tubular transport of 3-methylxanthine and enprofylline in rats. 相似文献
85.
Setsuie R Wang YL Mochizuki H Osaka H Hayakawa H Ichihara N Li H Furuta A Sano Y Sun YJ Kwon J Kabuta T Yoshimi K Aoki S Mizuno Y Noda M Wada K 《Neurochemistry international》2007,50(1):119-129
The I93M mutation in ubiquitin carboxyl-terminal hydrolase L1 (UCH-L1) was reported in one German family with autosomal dominant Parkinson's disease (PD). The causative role of the mutation has, however, been questioned. We generated transgenic (Tg) mice carrying human UCHL1 under control of the PDGF-B promoter; two independent lines were generated with the I93M mutation (a high- and low-expressing line) and one line with wild-type human UCH-L1. We found a significant reduction in the dopaminergic neurons in the substantia nigra and the dopamine content in the striatum in the high-expressing I93M Tg mice as compared with non-Tg mice at 20 weeks of age. Although these changes were absent in the low-expressing I93M Tg mice, 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP) treatment profoundly reduced dopaminergic neurons in this line as compared with wild-type Tg or non-Tg mice. Abnormal neuropathologies were also observed, such as silver staining-positive argyrophilic grains in the perikarya of degenerating dopaminergic neurons, in I93M Tg mice. The midbrains of I93M Tg mice contained increased amounts of insoluble UCH-L1 as compared with those of non-Tg mice, perhaps resulting in a toxic gain of function. Collectively, our data represent in vivo evidence that expression of UCHL1(I93M) leads to the degeneration of dopaminergic neurons. 相似文献
86.
The genus Jesogammarus contains 16 species in two subgenera, Jesogammarus and Annanogammarus. To examine relationships among species in the genus, a molecular phylogenetic study including eight species of the former subgenus and four of the latter was conducted using partial DNA sequences of the mitochondrial COI and 12S rRNA genes. MP, NJ, and ML trees based on the combined COI and 12S data indicated monophyly of the subgenus Annanogammarus, though the monophyly of Jesogammarus was left unresolved. Consistent with few morphological differences, Jesogammarus (A.) naritai and J. (A.) suwaensis showed low genetic differentiation and did not show reciprocal monophyly, which suggests a close affinity of these taxa. 相似文献
87.
Furuhata S Ando K Oki M Aoki K Ohnishi S Aoyagi K Sasaki H Sakamoto H Yoshida T Ohnami S 《Molecular and cellular biochemistry》2007,298(1-2):125-138
Among the many tissue stem or progenitor cells recently being unveiled, endothelial progenitor cells (EPCs) have attracted
particular attention, not only because of their cardinal role in vascular biology and embryology but also because of their
potential use in the therapeutic development of a variety of postnatal diseases, including cardiovascular and peripheral vascular
disorders and cancer. The aim of this study is to provide some basic and comprehensive information on gene expression of EPCs
to characterize the cells in molecular terms. Here, we focus on EPCs derived from CD34-positive mononuclear cells of human
umbilical cord blood. The EPCs were purified and expanded in culture and analyzed by a high-density oligonucleotide microarray
and real-time RT-PCR analysis. We identified 169 up-regulated and 107 down-regulated genes in the EPCs compared with three
differentiated endothelial cells of human umbilical vein endothelial cells (HUVEC), human lung microvascular endothelial cells
(LMEC) and human aortic endothelial cells (AoEC). It is expected that the obtained list include key genes which are critical
for EPC function and survival and thus potential targets of EPC recognition in vivo and therapeutic modulation of vasculogenesis
in cancer as well as other diseases, in which de novo vasculogenesis plays a crucial role. For instance, the list includes
Syk and galectin-3, which encode protein tyrosine kinase and β-galactoside-binding protein, respectively, and are expressed higher in EPCs than
the three control endothelial cells. In situ hybridization showed that the genes were expressed in isolated cells in the fetal
liver at E11.5 and E14.5 of mouse development. 相似文献
88.
Miyaji T Kouzuma Y Yaguchi J Matsumoto R Kanost MR Kramer KJ Yonekura M 《Insect biochemistry and molecular biology》2007,37(9):960-968
A cysteine protease inhibitor (CPI) with an apparent molecular mass of 11.5kDa was purified from larval hemolymph of the tobacco hornworm (Manduca sexta) by gel filtration on Sephadex G-50 followed by hydrophobic and ion-exchange column chromatographies. The purified cysteine proteinase inhibitor, denoted as MsCPI, strongly inhibited the plant cysteine protease, papain, with a K(i) value of 5.5 x 10(-9)M. Nucleotide sequence analysis of a partial cDNA encoding MsCPI indicated that MsCPI consists of 105 amino acid residues in a sequence that is similar to sarcocystatin A from Sarcophaga peregrina. However, northern blotting and PCR analyses using the specific primers of MsCPI suggested that the mRNA encoding MsCPI had a size of more than 12 kilobases, which included at least six tandemly repeated MsCPI segments. MsCPI was expressed in Escherichia coli and the recombinant protein effectively inhibited cysteine proteases from plants as well as from animals such as cathepsins B (K(i), 6.8 nM), H (3.0 nM), and L (0.87 nM). There was no inhibition exhibited toward trypsin, chymotrypsin, subtilisin, pepsin or themolysin. 相似文献
89.
Matsushita M Sano Y Yokoyama S Takai T Inoue H Mitsui K Todo K Ohmori H Kanazawa H 《American journal of physiology. Cell physiology》2007,293(1):C246-C254
NHE1/SLC9A1 is a ubiquitous isoform of vertebrate Na+/H+ exchangers (NHEs) functioning in maintaining intracellular concentrations of Na+ and H+ ions. Calcineurin homologous protein-1 (CHP1) binds to the hydrophilic region of NHE1 and regulates NHE1 activity but reportedly does not play a role in translocating NHE1 from the endoplasmic reticulum to the plasma membrane. However, an antiport function of NHE1 requiring CHP1 remains to be clarified. Here we established CHP1-deficient chicken B lymphoma DT40 cells by gene targeting to address CHP1 function. CHP1-deficient cells showed extensive decreases in Na+/H+ activities in intact cells. Although NHE1 mRNA levels were not affected, NHE1 protein levels were significantly reduced not only in the plasma membrane but in whole cells. The expression of a CHP1 transgene in CHP1-deficient cells rescued NHE1 protein expression. Expression of mutant forms of CHP1 defective in Ca2+ binding or myristoylation also partially decreased NHE1 protein levels. Knockdown of CHP1 also caused a moderate decrease in NHE1 protein in HeLa cells. These data indicate that CHP1 primarily plays an essential role in stabilization of NHE1 for reaching of NHE1 to the plasma membrane and its exchange activity. membrane protein; transporter; antiporter; quality control; degradation 相似文献
90.
Haploid sporophytes of Osmunda claytoniana (2n = x = 22) were apogamously produced from calli when cultivated on a hormone-free medium. Flow cytometric analysis showed that
ploidy chimeras were spontaneously produced in a haploid sporophyte of O. claytoniana and those of O. japonica that were obtained in the previous study. In the haploid sporophyte of O. claytoniana, a diploid pinnule and a partially diploid terminal segment were produced in a haploid pinna. In O. japonica, a haploid sporophyte yielded a diploid pinna in a haploid frond, and another haploid sporophyte yielded a diploid pinnule
in a haploid pinna. Diploid chimeras were large in size and could be readily distinguished from other haploid parts of the
fronds. It is likely that the chimeras were produced clonally from a single diploid cell that established chromosome doubling. 相似文献