scholarly journals Deficiency of decay-accelerating factor and complement receptor 1–related gene/protein y on murine platelets leads to complement-dependent clearance by the macrophage phagocytic receptor CRIg

Blood ◽  
2008 ◽  
Vol 112 (4) ◽  
pp. 1109-1119 ◽  
Author(s):  
David D. Kim ◽  
Takashi Miwa ◽  
Yuko Kimura ◽  
Reto A. Schwendener ◽  
Menno van Lookeren Campagne ◽  
...  
Keyword(s):  
Human Platelets ◽  
Transfer Model ◽  
Complement Receptor ◽  
Dependent Manner ◽  
Complement Receptors ◽  
Related Gene ◽  
Decay Accelerating Factor ◽  
Gene Ablation ◽  
Complement Receptor 1

Abstract Complement activation on human platelets is known to cause platelet degranulation and activation. To evaluate how normal platelets escape complement attack in vivo, we studied the fate of murine platelets deficient in 2 membrane complement regulatory proteins using an adoptive transfer model. We show here that deficiency of either decay-accelerating factor (DAF) or complement receptor 1–related gene/protein y (Crry) on murine platelets was inconsequential, whereas DAF and Crry double deficiency led to rapid clearance of platelets from circu-lation in a complement- and macrophage-dependent manner. This finding contrasted with the observation on erythrocytes, where Crry deficiency alone resulted in complement susceptibility. Quantitative flow cytometry revealed that DAF and Crry were expressed at similar levels on platelets, whereas Crry expression was 3 times higher than DAF on erythrocytes. Antibody blocking or gene ablation of the newly identified complement receptor CRIg, but not complement receptor 3 (CR3), rescued DAF/Crry-deficient platelets from complement-dependent elimination. Surprisingly, deficiency of CRIg, CR3, and other known complement receptors failed to prevent Crry-deficient erythrocytes from complement-mediated clearance. These results show a critical but redundant role of DAF and Crry in platelet survival and suggest that complement-opsonized platelets and erythrocytes engage different complement receptors on tissue macrophages in vivo.

Fibrinogen binding to the integrin αIIbβ3 modulates store-mediated calcium entry in human platelets

Blood ◽  
2001 ◽  
Vol 97 (9) ◽  
pp. 2648-2656 ◽  
Author(s):  
Juan A. Rosado ◽  
Else M. Y. Meijer ◽  
Karly Hamulyak ◽  
Irena Novakova ◽  
Johan W. M. Heemskerk ◽  
...  
Keyword(s):  
Actin Cytoskeleton ◽  
Actin Polymerization ◽  
Adenosine Diphosphate ◽  
Inhibitory Effect ◽  
Human Platelets ◽  
Dependent Manner ◽  
Concentration Dependent Manner ◽  
Integrin Αiibβ3 ◽  
Fibrinogen Binding

Abstract Effects of the occupation of integrin αIIbβ3 by fibrinogen on Ca++signaling in fura-2–loaded human platelets were investigated. Adding fibrinogen to washed platelet suspensions inhibited increases in cytosolic [Ca++] concentrations ([Ca++]i) evoked by adenosine diphosphate (ADP) and thrombin in a concentration-dependent manner in the presence of external Ca++ but not in the absence of external Ca++ or in the presence of the nonselective cation channel blocker SKF96365, indicating selective inhibition of Ca++entry. Fibrinogen also inhibited store-mediated Ca++ entry (SMCE) activated after Ca++ store depletion using thapsigargin. The inhibitory effect of fibrinogen was reversed if fibrinogen binding to αIIbβ3 was blocked using RDGS or abciximab and was absent in platelets from patients homozygous for Glanzmann thrombasthenia. Fibrinogen was without effect on SMCE once activated. Activation of SMCE in platelets occurs through conformational coupling between the intracellular stores and the plasma membrane and requires remodeling of the actin cytoskeleton. Fibrinogen inhibited actin polymerization evoked by ADP or thapsigargin in control cells and in cells loaded with the Ca++ chelator dimethyl BAPTA. It also inhibited the translocation of the tyrosine kinase p60src to the cytoskeleton. These results indicate that the binding of fibrinogen to integrin αIIbβ3 inhibits the activation of SMCE in platelets by a mechanism that may involve modulation of the reorganization of the actin cytoskeleton and the cytoskeletal association of p60src. This action may be important in intrinsic negative feedback to prevent the further activation of platelets subjected to low-level stimuli in vivo.

scholarly journals Decay-accelerating Factor (DAF), Complement Receptor 1 (CR1), and Factor H Dissociate the Complement AP C3 Convertase (C3bBb) via Sites on the Type A Domain of Bb

2001 ◽  
Vol 277 (2) ◽  
pp. 1107-1112 ◽  
Author(s):  
Dennis E. Hourcade ◽  
Lynne Mitchell ◽  
Lisa A. Kuttner-Kondo ◽  
John P. Atkinson ◽  
M. Edward Medof
Keyword(s):  
Type A ◽  
Factor H ◽  
Complement Receptor ◽  
Decay Accelerating Factor ◽  
Complement Receptor 1

Complement receptor 1 inhibitors for prevention of immune-mediated red cell destruction: potential use in transfusion therapy

Blood ◽  
2003 ◽  
Vol 101 (12) ◽  
pp. 5046-5052 ◽  
Author(s):  
Karina Yazdanbakhsh ◽  
Stanley Kang ◽  
Daniel Tamasauskas ◽  
Dorothy Sung ◽  
Andromachi Scaradavou
Keyword(s):  
Tissue Injury ◽  
Soluble Form ◽  
Complement Receptor ◽  
Classical Pathway ◽  
Human Group ◽  
Transfusion Therapy ◽  
Complement Receptor 1 ◽  
Potential Use

AbstractActivation of complement cascade via the antibody-mediated classical pathway can initiate red blood cell (RBC) destruction, causing transfusion reactions and hemolytic anemia. In the present study, we have assessed the ability of a human recombinant soluble form of complement receptor 1 (sCR1) to inhibit complement-mediated RBC destruction in vitro and in vivo. Using an in vitro alloimmune incompatibility model, sCR1 inhibited complement activation and prevented hemolysis. Following transfusion of human group O RBCs into mice lacking detectable pre-existing antibodies against the transfused RBCs, systemic coadministration of 10 mg/kg sCR1, a dose well tolerated in human subjects for prevention of tissue injury, completely inhibited the in vivo clearance of the transfused RBCs and surface C3 deposition in the first hour after transfusion, correlating with the half-life of sCR1 in the circulation. Treatment with sCR1 increased the survival of transfused human group A RBCs in the circulation of mice with pre-existing anti-A for 2 hours after transfusion by 50%, reduced intravascular hemolysis, and lowered the levels of complement deposition (C3 and C4), but not immunoglobulin G (IgG) or IgM, on the transfused cells by 100-fold. We further identified potential functional domains in CR1 that can act to limit complement-mediated RBC destruction in vitro and in vivo. Collectively, our data highlight a potential use of CR1-based inhibitors for prevention of complement-dependent immune hemolysis.

scholarly journals Prevention of Collagen-Induced Arthritis in Mice Transgenic for the Complement Inhibitor Complement Receptor 1-Related Gene/Protein y

2003 ◽  
Vol 171 (4) ◽  
pp. 2109-2115 ◽  
Author(s):  
Nirmal K. Banda ◽  
Damian M. Kraus ◽  
Michele Muggli ◽  
Alison Bendele ◽  
V. Michael Holers ◽  
...  
Keyword(s):  
Complement Receptor ◽  
Complement Inhibitor ◽  
Related Gene ◽  
Collagen Induced Arthritis ◽  
Complement Receptor 1

scholarly journals Modulation of Androgen Receptor Transactivation by the SWI3-Related Gene Product (SRG3) in Multiple Ways

2005 ◽  
Vol 25 (12) ◽  
pp. 4841-4852 ◽  
Author(s):  
Cheol Yi Hong ◽  
Ji Ho Suh ◽  
Kabsun Kim ◽  
Eun-Yeung Gong ◽  
Sung Ho Jeon ◽  
...  
Keyword(s):  
Androgen Receptor ◽  
Gene Product ◽  
Dependent Manner ◽  
Related Gene ◽  
Developmentally Regulated ◽  
Prostate Development ◽  
Mouse Prostate ◽  
Alternative Function ◽  
Regulatory Loop

ABSTRACT The SWI3-related gene product (SRG3), a component of the mouse SWI/SNF complex, has been suggested to have an alternative function. Here, we demonstrate that in the prostate transactivation of the androgen receptor (AR) is modulated by SRG3 in multiple ways. The expression of SRG3, which is developmentally regulated in the prostate, is induced by androgen through AR. SRG3 in turn enhances the transactivation of AR, providing a positive feedback regulatory loop. The SRG3 coactivation of AR transactivation is achieved through the recruitment of coactivator SRC-1, the protein level of which is upregulated by SRG3, providing another pathway of positive regulation. Interestingly, SRG3 coactivation of AR transactivation is fully functional in BRG1/BRM-deficient C33A cells and the AR/SRG3/SRC-1 complex formed in vivo contains neither BRG1 nor BRM protein, suggesting the possibility of an SRG3 function independent of the SWI/SNF complex. Importantly, the AR/SRG3/SRC-1 complex occupies androgen response elements on the endogenous SRG3 and PSA promoter in an androgen-dependent manner in mouse prostate and LNCaP cells, respectively, inducing gene expression. These results suggest that the multiple positive regulatory mechanisms of AR transactivation by SRG3 may be important for the rapid proliferation of prostate cells during prostate development and regeneration.

scholarly journals In vivo inhibition of the antibody response by a complement receptor-specific monoclonal antibody.

1990 ◽  
Vol 172 (2) ◽  
pp. 665-668 ◽  
Author(s):  
B Heyman ◽  
E J Wiersma ◽  
T Kinoshita
Keyword(s):  
Antibody Response ◽  
Serum Antibody ◽  
Keyhole Limpet Hemocyanin ◽  
The Other ◽  
Rosette Formation ◽  
Complement Receptor ◽  
Primary Antibody Response ◽  
Complement Receptor 1 ◽  
Horse Red Blood Cells

BALB/c mice were injected intravenously with three different monoclonal antibodies (mAbs) specific for complement receptor 1 (CR1). Two of the mAbs crossreacted with CR2. 24 h later, the mice were immunized with horse erythrocytes or keyhole limpet hemocyanin (KLH), and the primary antibody response was measured. One of the anti-CR antibodies, 7G6, suppressed greater than 99% of the direct plaque-forming cell response against horse red blood cells (HRBC). The same antibody markedly suppressed the serum antibody responses to both HRBC and KLH. To be optimally suppressive, the mAb had to be injected before suboptimal concentrations of antigen. The other two complement receptor-specific antibodies had very moderate, if any, effects on the antibody response. 7G6 was able to downregulate CR1 and CR2 on the surface of B cells and, in addition, to inhibit rosette formation with C3d-coated sheep erythrocytes (EC3d). One of the antibodies with a weak effect downregulated only CR1. The other downregulated both CR1 and CR2, although not as efficiently as 7G6, and was unable to inhibit EC3d rosette formation. We conclude that the reason 7G6 is outstanding in its suppressive capacity is that it is the only mAb tested that functionally blocks CR2. The data suggest that CR2 is of crucial importance in the initiation of a normal antibody response to physiological concentrations of antigen.

scholarly journals Analyses of the In Vivo Trafficking of Stoichiometric Doses of an Anti-Complement Receptor 1/2 Monoclonal Antibody Infused Intravenously in Mice

2004 ◽  
Vol 173 (4) ◽  
pp. 2297-2306 ◽  
Author(s):  
Emily C. Whipple ◽  
Ryan S. Shanahan ◽  
Andrew H. Ditto ◽  
Ronald P. Taylor ◽  
Margaret A. Lindorfer
Keyword(s):  
Monoclonal Antibody ◽  
Complement Receptor ◽  
Complement Receptor 1

scholarly journals Mouse Complement Receptor-Related Gene y/p65-Neutralized Tumor Vaccine Induces Antitumor Activity In Vivo

2004 ◽  
Vol 173 (1) ◽  
pp. 205-213 ◽  
Author(s):  
Rieko Ohta ◽  
Natalie Kondor ◽  
Natsuki Dohi ◽  
Stephen Tomlinson ◽  
Masaki Imai ◽  
...  
Keyword(s):  
Antitumor Activity ◽  
Tumor Vaccine ◽  
Complement Receptor ◽  
Related Gene

Antithrombotic activity of LB30057, a newly synthesized direct thrombin inhibitor

2003 ◽  
Vol 89 (01) ◽  
pp. 104-111 ◽  
Author(s):  
Kyu-Tae Kang ◽  
Byoung-In Jung ◽  
Ok-Nam Bae ◽  
Moo-Yeol Lee ◽  
Seung-Min Chung ◽  
...  
Keyword(s):  
Water Solubility ◽  
Biological Activities ◽  
High Water ◽  
Human Platelets ◽  
Thrombin Inhibitor ◽  
Dependent Manner ◽  
Concentration Dependent Manner ◽  
Serotonin Secretion ◽  
In Vivo Animal Model

SummaryAn amidrazonophenylalanine derivative, LB30057, inhibits the catalytic activity of thrombin potently by interaction with the active site of thrombin, and has high water solubility. In the present study, we evaluated the effect of LB30057 on the biological activities of thrombin at various tissues, and determined whether thrombin inhibition by LB30057 could reduce the incidence of occlusive thrombosis in an in vivo animal model. Treatment with LB30057 to human plasma prolonged clotting times in a concentration-dependent manner. LB30057 suppressed significantly thrombin-induced phosphatidylserine (PS) exposure in platelets, suggesting that LB30057 could inhibit blood coagulation accelerated by PS exposure. In human platelets, soluble thrombin- and clot-induced platelet aggregation was inhibited by LB30057 potently. Consistent with this finding, LB30057 showed concentration-dependent inhibitory effects on serotonin secretion and P-selectin expression induced by thrombin in platelets. In the blood vessel isolated from the guinea pig, treatment with LB30057 resulted in a concentration-dependent inhibition of thrombin-induced vascular contraction. In vivo study revealed that LB30057 following oral administration significantly increased the time to occlusion and improved carotid arterial patency using rat carotid artery thrombosis model. All these results suggest that LB30057 is a potent inhibitor of biological activities of thrombin at various target tissues and, therefore, might be developed as an anti-thrombotic agent for treatment and prevention of thrombotic diseases.

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