DIVERGENT EFFECTS OF LPS ON EXPRESSION OF IL-1 RECEPTOR FAMILY MEMBERS IN MONONUCLEAR PHAGOCYTES IN VITRO AND IN VIVO

Cytokine ◽  
1998 ◽  
Vol 10 (10) ◽  
pp. 773-780 ◽  
Author(s):  
Simona Saccani ◽  
Nadia Polentarutti ◽  
Giselle Penton-Rol ◽  
John E. Sims ◽  
Alberto Mantovani
Keyword(s):  
Family Members ◽  
Mononuclear Phagocytes ◽  
Receptor Family

scholarly journals NR4A orphan nuclear receptor family members, NR4A2 and NR4A3, regulate neutrophil number and survival

Blood ◽  
2017 ◽  
Vol 130 (8) ◽  
pp. 1014-1025 ◽  
Author(s):  
Lynne R. Prince ◽  
Svenja D. Prosseda ◽  
Kathryn Higgins ◽  
Jennifer Carlring ◽  
Elizabeth C. Prestwich ◽  
...  
Keyword(s):  
Nuclear Receptor ◽  
Family Members ◽  
Orphan Nuclear Receptor ◽  
Neutrophil Number ◽  
Key Points ◽  
Nuclear Receptor Family ◽  
Receptor Family

Key Points We demonstrate an important role for NR4A receptors in regulating neutrophil lifespan and homeostasis in vitro and in vivo. These findings may define targets for therapies for diseases driven by defects in neutrophil number and/or survival.

scholarly journals Monocyte tissue factor induction by lipopolysaccharide (LPS): dependence on LPS-binding protein and CD14, and inhibition by a recombinant fragment of bactericidal/permeability-increasing protein

Blood ◽  
1994 ◽  
Vol 83 (9) ◽  
pp. 2516-2525 ◽  
Author(s):  
K Meszaros ◽  
S Aberle ◽  
R Dedrick ◽  
R Machovich ◽  
A Horwitz ◽  
...  
Keyword(s):  
Tissue Factor ◽  
Mononuclear Cells ◽  
Human Peripheral Blood ◽  
Binding Protein ◽  
Mononuclear Phagocytes ◽  
Factor Vii ◽  
Peripheral Blood Mononuclear ◽  
Recombinant Fragment

Abstract Mononuclear phagocytes, stimulated by bacterial lipopolysaccharide (LPS), have been implicated in the activation of coagulation in sepsis and endotoxemia. In monocytes LPS induces the synthesis of tissue factor (TF) which, assembled with factor VII, initiates the blood coagulation cascades. In this study we investigated the mechanism of LPS recognition by monocytes, and the consequent expression of TF mRNA and TF activity. We also studied the inhibition of these effects of LPS by rBPI23, a 23-kD recombinant fragment of bactericidal/permeability increasing protein, which has been shown to antagonize LPS in vitro and in vivo. Human peripheral blood mononuclear cells, or monocytes isolated by adherence, were stimulated with Escherichia coli O113 LPS at physiologically relevant concentrations (> or = 10 pg/mL). The effect of LPS was dependent on the presence of the serum protein LBP (lipopolysaccharide-binding protein), as shown by the potentiating effect of human recombinant LBP or serum. Furthermore, recognition of low amounts of LPS by monocytes was also dependent on CD14 receptors, because monoclonal antibodies against CD14 greatly reduced the LPS sensitivity of monocytes in the presence of serum or rLBP. Induction of TF activity and mRNA expression by LPS were inhibited by rBPI23. The expression of tumor necrosis factor showed qualitatively similar changes. Considering the involvement of LPS-induced TF in the potentially lethal intravascular coagulation in sepsis, inhibition of TF induction by rBPI23 may be of therapeutic benefit.

scholarly journals Cloning of mouse ptx3, a new member of the pentraxin gene family expressed at extrahepatic sites

Blood ◽  
1996 ◽  
Vol 87 (5) ◽  
pp. 1862-1872 ◽  
Author(s):  
M Introna ◽  
VV Alles ◽  
M Castellano ◽  
G Picardi ◽  
L De Gioia ◽  
...  
Keyword(s):  
Gene Family ◽  
Tertiary Structure ◽  
Helical Structure ◽  
Distinct Pattern ◽  
Mononuclear Phagocytes ◽  
Acute Phase Reactants ◽  
Inflammatory Reactions ◽  
Reactive Protein

Abstract Pentraxins, which include C reactive protein (CRP) and serum amyloid P component (SAP), are prototypic acute phase reactants that serve as indicators of inflammatory reactions. Here we report genomic and cDNA cloning of mouse ptx3 (mptx3), a member of the pentraxin gene family and characterize its extrahepatic expression in vitro and in vivo. mptx3 is organized into three exons on chromosome 3: the first (43 aa) and second exon (175 aa) code for the signal peptide and for a protein portion with no high similarity to known sequences the third (203 aa) for a domain related to classical pentraxins, which contains the “pentraxin family signature.” Analysis of the N terminal portion predicts a predominantly alpha helical structure, while the pentraxin domain of ptx3 is accommodated comfortably in the tertiary structure fold of SAP. Normal and transformed fibroblasts, undifferentiated and differentiated myoblasts, normal endothelial cells, and mononuclear phagocytes express mptx3 mRNA and release the protein in vitro on exposure to interleukin-1beta (IL-1beta) and tumor necrosis factor (TNF)alpha. mptx3 was induced by bacterial lipopolysaccharide in vivo in a variety of organs and, most strongly, in the vascular endothelium of skeletal muscle and heart. Thus, mptx3 shows a distinct pattern of in vivo expression indicative of a significant role in cardiovascular and inflammatory pathology.

scholarly journals LASS3 (longevity assurance homologue 3) is a mainly testis-specific (dihydro)ceramide synthase with relatively broad substrate specificity

2006 ◽  
Vol 398 (3) ◽  
pp. 531-538 ◽  
Author(s):  
Yukiko Mizutani ◽  
Akio Kihara ◽  
Yasuyuki Igarashi
Keyword(s):  
Amino Acid ◽  
Substrate Specificity ◽  
Family Members ◽  
Fatty Acyl ◽  
Ceramide Synthase ◽  
Broad Substrate Specificity ◽  
Acid Protein ◽  
Amino Acid Protein

The LASS (longevity assurance homologue) family members are highly conserved from yeasts to mammals. Five mouse and human LASS family members, namely LASS1, LASS2, LASS4, LASS5 and LASS6, have been identified and characterized. In the present study we cloned two transcriptional variants of hitherto-uncharacterized mouse LASS3 cDNA, which encode a 384-amino-acid protein (LASS3) and a 419-amino-acid protein (LASS3-long). In vivo, [3H]dihydrosphingosine labelling and electrospray-ionization MS revealed that overproduction of either LASS3 isoform results in increases in several ceramide species, with some preference toward those having middle- to long-chain-fatty acyl-CoAs. A similar substrate preference was observed in an in vitro (dihydro)ceramide synthase assay. These results indicate that LASS3 possesses (dihydro)ceramide synthesis activity with relatively broad substrate specificity. We also found that, except for a weak display in skin, LASS3 mRNA expression is limited almost solely to testis, implying that LASS3 plays an important role in this gland.

scholarly journals Short-Form Bomanins Mediate Humoral Immunity in Drosophila

2018 ◽  
Vol 10 (4) ◽  
pp. 306-314 ◽  
Author(s):  
Scott A. Lindsay ◽  
Samuel J.H. Lin ◽  
Steven A. Wasserman
Keyword(s):  
Humoral Immunity ◽  
Short Form ◽  
Family Members ◽  
Gene Encoding ◽  
Vitro Assay ◽  
Gram Positive Bacteria ◽  
Toll Receptor ◽  
Secreted Peptides

The Bomanins (Boms) are a family of a dozen secreted peptides that mediate the innate immune response governed by the Drosophila Toll receptor. We recently showed that deleting a cluster of 10 Bom genes blocks Toll-mediated defenses against a range of fungi and gram-positive bacteria. Here, we characterize the activity of individual Bom family members. We provide evidence that the Boms overlap in function and that a single Bom gene encoding a mature peptide of just 16 amino acids can act largely or entirely independent of other family members to provide phenotypic rescue in vivo. We further demonstrate that the Boms function in Drosophila humoral immunity, mediating the killing of the fungal pathogen Candida glabrata in an in vitro assay of cell-free hemolymph. In addition, we find that the level of antifungal activity both in vivo and in vitro is linked to the level of Bom gene expression. Although Toll dictates expression of the antimicrobial peptides (AMPs) drosomycin and metchnikowin, we find no evidence that Boms act by modifying the expression of the mature forms of these antifungal AMPs.

FOR MODULATION AS A MEANS OF ELEVATING THE PLATELET COUNT IN ITP

1987 ◽  
Author(s):  
J Bussel
Keyword(s):  
Monoclonal Antibody ◽  
Platelet Count ◽  
Immune Complex ◽  
Vinca Alkaloid ◽  
Natural Killer Activity ◽  
Mononuclear Phagocytes ◽  
Similar Degree ◽  
Killer Activity

ITP is an autoantibody-mediated disease which would logically be treated by decreasing the level of autoantibody. However, the most exciting developments in understanding the pathophysiology of the thrombocytopenia and its treatment involve a better understanding of the MPS FcR system and ways in which it can be modulated. This work has focussed on phagocytic paralysis or FcR blockade (FcRBl): the slowing of destruction of antibody-coated platelets despite the persistent presence of antibody on the surface of the platelet.Several areas have been explored in learning about the MPS system. Investigation by Kurlander among others have revealed that at least 2 FcR's exist on mononuclear phagocytes: one with high and one with low affinity for monomeric IgG. Study of the high affinity FcR expressed by circulating monocytes, by Schreiber among others, has explored the effect of Danazol to decrease the expression of this FcR. The clinical relevance of this receptor is uncertain however because it is saturated in vitro by physiologic concentrations of IgG. Unkeless defined the properties of the low affinity "immune complex" FcR, expressed on macrophages and neutrophils, via monoclonal antibody 3G8 (see below) which blocks ligand binding to this FcR. The exact roles of these two, and possibly more, FcR's are being explored. Another still unsolved controversy involves whether the interaction Fc portions of antibodies coating particles with FcR's is mediated by a conformational change of the Fc portion or by a multipoint attachment of several Fc parts.Studies by Mollison in the 60's demonstrated that the MPS had a limited capacity for removal of antibody-coated (red) cells. Shulman pursued MPS modulation by exploring the inhibition of thrombocytopenia caused by infusion of ITP plasma into normals. Kelton demonstrated that "compensated" ITP may be caused by a decreased clearance of antibody-coated cells and that the rate of clearance of antibody-coated cells may be correlated with rate of clearance of antibody-coated cells may be correlated with the intrinsic levels of IgG. Stossel investigated FcRBl as a mechanism of effect of corticosteroids and related it clinically. Subsequently intravenous gammaglobulin (IVGG) was introducedas a treatment of ITP and Fehr et al first demonstrated FcRBl as the mechanism of effect of IVGG. Exploration of the mechanism of the FcRBl caused by IVGGled Salama and Mueller-Eckhardt to demonstrate the therapeutic effect of I anti-D, which apparentlycoats RBC with antibody and causes their destruction atthe coats RBC with antibody and causes their destruction at the expense of antibody-coated platelets. A similar degree of FcRBl has been shown for aldometrelated to the development of antibody on RBC.Our studies, including Drs. Clarkson, Kimberly, Nachman, and Unkeless, have focussed on the role of the low affinity or "Immune complex" FcR by using monoclonal antibody 3G8 in vivo. An infusion of 1 mg/kg of 3G8 in chimpanzees caused a reproducible FcRBl demonstrable by a slowing of the destruction of antibody-coated RBC for > 10 days (JEM, 1986). Less effect of 3G8 to inhibit CIC removal was seen using DNA-anti-DNA as the immune complex. In view of the wel1-documented effects of IVGG infusion to create FcRBl, we infused 3G8 into 6 adults with refractory ITP (NEJM, 1986). Specifically these patients were refractory to all forms of conventional therapy including splenectomy, steroids, vinca alkaloid infusion, immunosuppressives and danazol . 3 of the 6 patients had peak platelet responses to >80,000/ul. The other 3 had short-lived platelet increases from 10 to 30,000/ul. These responses confirmed the effect of FcRBl, specifically of the low affinity FcR, to underlie a dramatic platelet increase in therapy of ITP. Surprisingly 3 of the patients had apparent longterm effects of this therapy demonstrable in 2 cases as a maintenance of the platelet count >20,0C0/ul without any further therapy and in 1 case as a clearly enhanced responsiveness to other therapies following 3G8 infusion. Since Natural Killer activity was (transiently) ablated by 3G8 infusion, we speculate that an alternation of regulation of (auto) antibody production by NK cells may be responsible for this effect and that FcR interactions include regulatory roles in addition to their primary function of removal of CIC.

scholarly journals Characterization of calcium- and integrin-binding protein 1 (CIB1) knockout platelets: Potential compensation by CIB family members

2008 ◽  
Vol 100 (05) ◽  
pp. 847-856 ◽  
Author(s):  
Brenda R. Temple ◽  
Holly R. Gentry ◽  
Jan C. DeNofrio ◽  
Weiping Yuan ◽  
Leslie V. Parise
Keyword(s):  
Thrombus Formation ◽  
Mrna Level ◽  
Family Members ◽  
Cytoplasmic Tail ◽  
Binding Pocket ◽  
Vitro Binding ◽  
Cytoplasmic Tails ◽  
Hydrophobic Binding

SummaryPlatelet aggregation requires activation of the αIIbβ3 integrin,an event regulated by the integrin cytoplasmic tails. CIB1 binds to the cytoplasmic tail of the integrin αIIb subunit. Previous overexpression and knockdown studies in murine megakaryocytes demonstrated that CIB1 inhibits integrin αIIbβ3 activation.Here we analyzed Cib1-/- mice to determine the function of CIB1 in platelets in vitro and in vivo. We found that although these mice had no overt platelet phenotype, mRNA level of CIB1 homolog CIB3 was increased in Cib1-/- megakaryocytes. In vitro binding experiments showed that recombinant CIB1, -2 and -3 bound specifically to an αIIb cytoplasmic tail peptide. Subsequent protein modeling experiments indicated that CIBs 1–3 each have a highly conserved hydrophobic binding pocket. Therefore, the potential exists for compensation for the loss of CIB1 by these CIB family members, thereby preventing pathologic thrombus formation in Cib1-/- mice.

scholarly journals Increased in vitro and in vivo generation of procoagulant activity (tissue factor) by mononuclear phagocytes after intralipid infusion in rabbits

Blood ◽  
1985 ◽  
Vol 65 (6) ◽  
pp. 1391-1395 ◽  
Author(s):  
P Montemurro ◽  
A Lattanzio ◽  
G Chetta ◽  
L Lupo ◽  
L Caputi-Iambrenghi ◽  
...  
Keyword(s):  
Tissue Factor ◽  
Mononuclear Cells ◽  
Mononuclear Phagocyte ◽  
Mononuclear Phagocytes ◽  
Procoagulant Activity ◽  
Sterile Saline ◽  
Functional Changes ◽  
Before And After

Abstract Intralipid, a fat emulsion widely used in parenteral nutrition, can produce marked functional changes of the mononuclear phagocyte system. We investigated the effect of Intralipid administration on the generation of procoagulant activity by rabbit mononuclear phagocytes. Two groups of ten rabbits given either a single infusion of Intralipid 10% or a similar volume of sterile saline were studied before and after infusion. Procoagulant activity was measured on isolated blood mononuclear cells after incubation with and without endotoxin, using a one-stage clotting assay. Cells from animals infused with Intralipid produced significantly more procoagulant activity than controls (P less than .01). Results were similar when freshly collected whole blood was incubated with and without endotoxin, and procoagulant activity was measured on subsequently isolated mononuclear cells (P less than .01). In addition, when rabbits were given a single injection of endotoxin, blood and spleen mononuclear cells harvested 50 to 60 minutes after the injection from animals pretreated with Intralipid expressed five to seven times more procoagulant activity than did cells from animals pretreated with saline. In all instances, procoagulant activity was identified as tissue factor. These findings suggest that Intralipid may cause functional changes in mononuclear phagocytes, resulting in increased production of tissue factor on incubation in short-term culture in vitro and in response to endotoxin in vivo.

Multinucleated rat alveolar macrophages express functional receptors for calcitonin

1991 ◽  
Vol 261 (6) ◽  
pp. F1026-F1032 ◽  
Author(s):  
A. Vignery ◽  
M. J. Raymond ◽  
H. Y. Qian ◽  
F. Wang ◽  
S. A. Rosenzweig
Keyword(s):  
Plasma Membrane ◽  
Alveolar Macrophages ◽  
Giant Cells ◽  
Mononuclear Phagocytes ◽  
Inflammatory Reactions ◽  
Calcitonin Gene ◽  
Novel Model

The fusion of mononuclear phagocytes occurs spontaneously in vivo and leads to the differentiation of either multinucleated giant cells or osteoclasts in chronic inflammatory sites or in bone, respectively. Although osteoclasts are responsible for resorbing bone, the functional role of giant cells in chronic inflammatory reactions and tumors remains poorly understood. We recently reported that the plasma membrane of multinucleated macrophages is, like that of osteoclasts, enriched in Na-K-adenosinetriphosphatases (ATPases). We also observed that the localization of their Na-K-ATPases is restricted to the nonadherent domain of the plasma membrane of cells both in vivo and in vitro, thus imposing a functional polarity on their organization. By following this observation, we wished to investigate whether these cells also expressed, like osteoclasts, functional receptors for calcitonin (CT). To this end, alveolar macrophages were fused in vitro, and both their structural and functional association with CT was analyzed and compared with those of mononucleated peritoneal and alveolar macrophages. Evidence is presented that multinucleated alveolar macrophages express a high copy number of functional receptors for CT. Our results also indicate that alveolar macrophages, much like peritoneal, express functional receptors for calcitonin gene-related peptide. It is suggested that multinucleated rat alveolar macrophages offer a novel model system to study CT receptors and that calcitonin may control local immune reactions where giant cells differentiate.

scholarly journals Interferon (IFN)-α Activation of Human Blood Mononuclear Cells In Vitro and In Vivo for Nitric Oxide Synthase (NOS) Type 2 mRNA and Protein Expression: Possible Relationship of Induced NOS2 to the Anti–Hepatitis C Effects of IFN-α In Vivo

1997 ◽  
Vol 186 (9) ◽  
pp. 1495-1502 ◽  
Author(s):  
Ala I. Sharara ◽  
Douglas J. Perkins ◽  
Mary A. Misukonis ◽  
Stanley U. Chan ◽  
Jason A. Dominitz ◽  
...  
Keyword(s):  
Hepatitis C ◽  
Mononuclear Cell ◽  
Mononuclear Cells ◽  
Mononuclear Phagocytes ◽  
No Production ◽  
Hepatitis C Infection ◽  
Serum Alanine Aminotransferase

Although researchers have noted high level activation of rodent mononuclear phagocytes for nitric oxide (NO) synthase type 2 (S2) expression and NO production with a variety of agents such as interferon (IFN) γ and endotoxin, it has been difficult to demonstrate activation of human mononuclear phagocytes. The purpose of this study was to determine if IFN-α serves as an activator in vitro and in vivo in humans. Treatment of normal monocytes or mononuclear cells in vitro with IFN-α caused a dose-dependent increase in monocyte NOS2 activity and NO production, and increased expression of NOS2 protein and mRNA expression. To determine if in vivo administration of IFN-α also modulated NOS2, we studied blood cells from patients with hepatitis C before and after IFN-α therapy. Untreated patients with chronic hepatitis C virus infection had levels of NOS activity and NOS2 antigen in freshly isolated mononuclear cells similar to those of healthy subjects, and they expressed minimal or no NOS2 mRNA. However, IFN-α treatment of patients with hepatitis C infection was associated with a significant elevation in mononuclear cell NOS activity, NOS2 antigen content, and NOS2 mRNA content. IFN-α–treated patients had significant decreases in levels of serum alanine aminotransferase and plasma hepatitis C mRNA. The degree of IFN-α–enhanced mononuclear cell NOS2 antigen content correlated significantly with the degree of reduction in serum alanine aminotransferase levels. Thus, IFN-α treatment of cells in vitro or administration of IFN-α to hepatitis C patients in vivo increases expression of mononuclear cell NOS2 mRNA expression, NOS activity, NOS2 antigen expression, and NO production. Since NO has been reported to have antiviral activity for a variety of viruses, we speculate that induced NO production may be related to the antiviral action(s) of IFN-α in hepatitis C infection.

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