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Dependent Functions (dependent + function)

Distribution by Scientific Domains

Medical Sciences	50%

Selected Abstracts

Synthesis and receptor binding of IgG1 peptides derived from the IgG Fc region

JOURNAL OF MOLECULAR RECOGNITION, Issue 2 2004
Katalin Uray
Abstract The IgG binding Fc, receptors (Fc,Rs) play a key role in defence against pathogens by linking humoral and cell-mediated immune responses. Impaired expression and/or function of Fc,R may result in the development of pathological autoimmunity. Considering the functions of Fc,Rs, they are potential target molecules for drug design to aim at developing novel anti-inflammatory and immunomodulatory therapies. Previous data mostly obtained by X-ray analysis of ligand,receptor complexes indicate the profound role of the CH2 domain in binding to various Fc,Rs. Our aim was to localize linear segments, which are able to bind and also to modulate the function of the low affinity Fc,Rs, like Fc,RIIb and Fc,RIIIa. To this end a set of overlapping octapeptides was prepared corresponding to the 231,298 sequence of IgG1 CH2 domain and tested for binding to human recombinant soluble Fc,RIIb. Based on these results, a second group of peptides was synthesized and their binding properties to recombinant soluble Fc,RIIb, as well as to Fc,Rs expressed on the cell surface, was investigated. Here we report that peptide representing the Arg255,Ser267 sequence of IgG1 is implicated in the binding to Fc,RIIb. In addition we found that peptides corresponding to the Arg255,Ser267, Lys288,Ser298 or Pro230,Val240 when presented in a multimeric form conjugated to branched chain polypeptide in uniformly oriented copies induced the release of TNF,, a pro-inflammatory cytokine from MonoMac monocyte cell line. These findings indicate that these conjugated peptides are able to cluster the activating Fc,Rs, and mediate Fc,R dependent function. Peptide Arg255,Ser267 can also be considered as a lead for further functional studies. Copyright © 2004 John Wiley & Sons, Ltd. [source]

NTPDase1 governs P2X7 -dependent functions in murine macrophages

EUROPEAN JOURNAL OF IMMUNOLOGY, Issue 5 2010
Sébastien A. Lévesque
Abstract P2X7 receptor is an adenosine triphosphate (ATP)-gated ion channel within the multiprotein inflammasome complex. Until now, little is known about regulation of P2X7 effector functions in macrophages. In this study, we show that nucleoside triphosphate diphosphohydrolase 1 (NTPDase1)/CD39 is the dominant ectonucleotidase expressed by murine peritoneal macrophages and that it regulates P2X7 -dependent responses in these cells. Macrophages isolated from NTPDase1-null mice (Entpd1,/,) were devoid of all ADPase and most ATPase activities when compared with WT macrophages (Entpd1+/+). Entpd1,/, macrophages exposed to millimolar concentrations of ATP were more susceptible to cell death, released more IL-1, and IL-18 after TLR2 or TLR4 priming, and incorporated the fluorescent dye Yo-Pro-1 more efficiently (suggestive of increased pore formation) than Entpd1+/+ cells. Consistent with these observations, NTPDase1 regulated P2X7 -associated IL-1, release after synthesis, and this process occurred independently of, and prior to, cytokine maturation by caspase-1. NTPDase1 also inhibited IL-1, release in vivo in the air pouch inflammatory model. Exudates of LPS-injected Entpd1,/, mice had significantly higher IL-1, levels when compared with Entpd1+/+ mice. Altogether, our studies suggest that NTPDase1/CD39 plays a key role in the control of P2X7 -dependent macrophage responses. [source]

Osteoblast Deletion of Exon 3 of the Androgen Receptor Gene Results in Trabecular Bone Loss in Adult Male Mice,

JOURNAL OF BONE AND MINERAL RESEARCH, Issue 3 2007
Amanda J Notini
Abstract The mechanism of androgen action on bone was studied in male mice with the AR deleted in mature osteoblasts. These mice had decreased trabecular bone volume associated with a decrease in trabecular number, suggesting that androgens may act directly on osteoblasts to maintain trabecular bone. Introduction: Androgens modulate bone cell activity and are important for the maintenance of bone mass. However, the mechanisms by which they exert these actions on bone remain poorly defined. The aim of this study was to investigate the role of androgens acting through the classical androgen receptor (AR) signaling pathways (i.e., DNA-binding dependent pathways) in osteoblasts using male mice in which exon 3 of the AR gene was deleted specifically in mature osteoblasts. Materials and Methods: Mice with a floxed exon 3 of the AR gene were bred with Col 2.3-cre transgenic mice, in which Cre recombinase is expressed in mineralizing osteoblasts. The skeletal phenotype of mutant mice was assessed by histomorphometry and quantitative ,CT at 6, 12, and 32 weeks of age (n = 8 per group). Wildtype, hemizygous exon 3 floxed and hemizygous Col 2.3-cre male littermates were used as controls. Data were analyzed by one-way ANOVA and Tukey's posthoc test. Results: ,CT analysis of the fifth lumbar vertebral body showed that these mice had reduced trabecular bone volume (p < 0.05) at 32 weeks of age compared with controls. This was associated with a decrease in trabecular number (p < 0.01) at 12 and 32 weeks of age, suggesting increased bone resorption. These effects were accompanied by a reduction in connectivity density (p < 0.01) and an increase in trabecular separation (p < 0.01). A similar pattern of trabecular bone loss was observed in the distal femoral metaphysis at 32 weeks of age. Conclusions: These findings show that inactivation of the DNA binding,dependent functions of the AR, specifically in mature osteoblasts in male mice, results in increased bone resorption and decreased structural integrity of the bone, leading to a reduction in trabecular bone volume at 32 weeks of age. These data provide evidence of a role for androgens in the maintenance of trabecular bone volume directly through DNA binding,dependent actions of the AR in mature osteoblasts. [source]

Characterization of HasB, a Serratia marcescens TonB-like protein specifically involved in the haemophore-dependent haem acquisition system

MOLECULAR MICROBIOLOGY, Issue 4 2001
Annick Paquelin
In Gram-negative bacteria, the TonB,ExbB,ExbD inner membrane multiprotein complex is required for active transport of diverse molecules through the outer membrane. We present evidence that Serratia marcescens, like several other Gram-negative bacteria, has two TonB proteins: the previously characterized TonBSM, and also HasB, a newly identified component of the has operon that encodes a haemophore-dependent haem acquisition system. This system involves a soluble extracellular protein (the HasA haemophore) that acquires free or haemoprotein-bound haem and presents it to a specific outer membrane haemophore receptor (HasR). TonBSM and HasB are significantly similar and can replace each other for haem acquisition. However, TonBSM, but not HasB, mediates iron acquisition from iron sources other than haem and haemoproteins, showing that HasB and TonBSM only display partial redundancy. The reconstitution in Escherichia coli of the S. marcescens Has system demonstrated that haem uptake is dependent on the E. coli ExbB, ExbD and TonB proteins and that HasB is non-functional in E. coli. Nevertheless, a mutation in the HasB transmembrane anchor domain allows it to replace TonBEC for haem acquisition. As the change affects a domain involved in specific TonBEC,ExbBEC interactions, HasB may be unable to interact with ExbBEC, and the HasB mutation may allow this interaction. In E. coli, the HasB mutant protein was functional for haem uptake but could not complement the other TonBEC -dependent functions, such as iron siderophore acquisition, and phage DNA and colicin uptake. Our findings support the emerging hypothesis that TonB homologues are widespread in bacteria, where they may have specific functions in receptor,ligand uptake systems. [source]