scholarly journals Differences in Shedding of the Interleukin-11 Receptor by the Proteases ADAM9, ADAM10, ADAM17, Meprin α, Meprin β and MT1-MMP

2019 ◽  
Vol 20 (15) ◽  
pp. 3677 ◽  
Author(s):  
Sammel ◽  
Peters ◽  
Lokau ◽  
Scharfenberg ◽  
Werny ◽  
...  
Keyword(s):  
Biologically Active ◽  
Target Cells ◽  
Matrix Metalloprotease ◽  
Bone Homeostasis ◽  
Inflammatory Conditions ◽  
Stat3 Phosphorylation ◽  
Membrane Bound ◽  
The Difference ◽  
Membrane Type ◽  
Interleukin 11

Interleukin-11 (IL-11) has been associated with inflammatory conditions, bone homeostasis, hematopoiesis, and fertility. So far, these functions have been linked to classical IL-11 signaling via the membrane bound receptor (IL-11R). However, a signaling cascade via the soluble IL-11R (sIL-11R), generated by proteolytic cleavage, can also be induced. This process is called IL-11 trans-signaling. A disintegrin and metalloprotease 10 (ADAM10) and neutrophil elastase were described as ectodomain sheddases of the IL-11R, thereby inducing trans-signaling. Furthermore, previous studies employing approaches for the stimulation and inhibition of endogenous ADAM-proteases indicated that ADAM10, but not ADAM17, can cleave the IL-11R. Herein, we show that several metalloproteases, namely ADAM9, ADAM10, ADAM17, meprin β, and membrane-type 1 matrix metalloprotease/matrix metalloprotease-14 (MT1-MMP/MMP-14) when overexpressed are able to shed the IL-11R. All sIL-11R ectodomains were biologically active and capable of inducing signal transducer and activator of transcription 3 (STAT3) phosphorylation in target cells. The difference observed for ADAM10/17 specificity compared to previous studies can be explained by the different approaches used, such as stimulation of protease activity or making use of cells with genetically deleted enzymes.

scholarly journals Cathepsin S provokes interleukin-6 (IL-6) trans-signaling through cleavage of the IL-6 receptor in vitro

2020 ◽  
Vol 10 (1) ◽  
Author(s):  
Charlotte M. Flynn ◽  
Yvonne Garbers ◽  
Stefan Düsterhöft ◽  
Rielana Wichert ◽  
Juliane Lokau ◽  
...  
Keyword(s):  
Interleukin 6 ◽  
Cleavage Site ◽  
Serum Levels ◽  
Biologically Active ◽  
Cathepsin S ◽  
Target Cells ◽  
Membrane Bound ◽  
Pleiotropic Functions

AbstractThe cytokine interleukin-6 (IL-6) fulfills its pleiotropic functions via different modes of signaling. Regenerative and anti-inflammatory activities are mediated via classic signaling, in which IL-6 binds to the membrane-bound IL-6 receptor (IL-6R). For IL-6 trans-signaling, which accounts for the pro-inflammatory properties of the cytokine, IL-6 activates its target cells via soluble forms of the IL-6R (sIL-6R). We have previously shown that the majority of sIL-6R in human serum originates from proteolytic cleavage and mapped the cleavage site of the IL-6R. The cleavage occurs between Pro-355 and Val-356, which is the same cleavage site that the metalloprotease ADAM17 uses in vitro. However, sIL-6R serum levels are unchanged in hypomorphic ADAM17ex/ex mice, making the involvement of ADAM17 questionable. In order to identify other proteases that could be relevant for sIL-6R generation in vivo, we perform a screening approach based on the known cleavage site. We identify several candidate proteases and characterize the cysteine protease cathepsin S (CTSS) in detail. We show that CTSS is able to cleave the IL-6R in vitro and that the released sIL-6R is biologically active and can induce IL-6 trans-signaling. However, CTSS does not use the Pro-355/Val-356 cleavage site, and sIL-6R serum levels are not altered in Ctss−/− mice. In conclusion, we identify a novel protease of the IL-6R that can induce IL-6 trans-signaling, but does not contribute to steady-state sIL-6R serum levels.

Lactoferrin in Bone Tissue Regeneration

2020 ◽  
Vol 27 (6) ◽  
pp. 838-853 ◽  
Author(s):  
Madalina Icriverzi ◽  
Valentina Dinca ◽  
Magdalena Moisei ◽  
Robert W. Evans ◽  
Mihaela Trif ◽  
...  
Keyword(s):  
Bone Tissue ◽  
Tissue Regeneration ◽  
Bone Cells ◽  
Bone Diseases ◽  
Biologically Active Compounds ◽  
Biologically Active ◽  
Bone Tissue Regeneration ◽  
Bone Homeostasis ◽  
Active Compounds

: Among the multiple properties exhibited by lactoferrin (Lf), its involvement in bone regeneration processes is of great interest at the present time. A series of in vitro and in vivo studies have revealed the ability of Lf to promote survival, proliferation and differentiation of osteoblast cells and to inhibit bone resorption mediated by osteoclasts. Although the mechanism underlying the action of Lf in bone cells is still not fully elucidated, it has been shown that its mode of action leading to the survival of osteoblasts is complemented by its mitogenic effect. Activation of several signalling pathways and gene expression, in an LRPdependent or independent manner, has been identified. Unlike the effects on osteoblasts, the action on osteoclasts is different, with Lf leading to a total arrest of osteoclastogenesis. : Due to the positive effect of Lf on osteoblasts, the potential use of Lf alone or in combination with different biologically active compounds in bone tissue regeneration and the treatment of bone diseases is of great interest. Since the bioavailability of Lf in vivo is poor, a nanotechnology- based strategy to improve the biological properties of Lf was developed. The investigated formulations include incorporation of Lf into collagen membranes, gelatin hydrogel, liposomes, loading onto nanofibers, porous microspheres, or coating onto silica/titan based implants. Lf has also been coupled with other biologically active compounds such as biomimetic hydroxyapatite, in order to improve the efficacy of biomaterials used in the regulation of bone homeostasis. : This review aims to provide an up-to-date review of research on the involvement of Lf in bone growth and healing and on its use as a potential therapeutic factor in bone tissue regeneration.

scholarly journals The “Vesicular Intelligence” Strategy of Blood Cancers

Genes ◽  
2021 ◽  
Vol 12 (3) ◽  
pp. 416
Author(s):  
Dorian Forte ◽  
Martina Barone ◽  
Francesca Palandri ◽  
Lucia Catani
Keyword(s):  
Clonal Evolution ◽  
Biological Properties ◽  
Hemopoietic Stem Cell ◽  
Target Cells ◽  
Cancer Cell Growth ◽  
Cell Compartment ◽  
Blood Cancer ◽  
Non Invasive ◽  
Membrane Bound ◽  
Immune Potential

Blood cancers are a heterogeneous group of disorders including leukemia, multiple myeloma, and lymphoma. They may derive from the clonal evolution of the hemopoietic stem cell compartment or from the transformation of progenitors with immune potential. Extracellular vesicles (EVs) are membrane-bound nanovesicles which are released by cells into body fluids with a role in intercellular communication in physiology and pathology, including cancer. EV cargos are enriched in nucleic acids, proteins, and lipids, and these molecules can be delivered to target cells to influence their biological properties and modify surrounding or distant targets. In this review, we will describe the “smart strategy” on how blood cancer-derived EVs modulate tumor cell development and maintenance. Moreover, we will also depict the function of microenvironment-derived EVs in blood cancers and discuss how the interplay between tumor and microenvironment affects blood cancer cell growth and spreading, immune response, angiogenesis, thrombogenicity, and drug resistance. The potential of EVs as non-invasive biomarkers will be also discussed. Lastly, we discuss the clinical application viewpoint of EVs in blood cancers. Overall, blood cancers apply a ‘vesicular intelligence’ strategy to spread signals over their microenvironment, promoting the development and/or maintenance of the malignant clone.

scholarly journals THU0236 EFFICACY AND SAFETY OF NON-MITOGENIC ANTICD3 ANTIBODY ADMINISTRATION IN THE TREATMENT OF LUPUS-PRONE MICE

2020 ◽  
Vol 79 (Suppl 1) ◽  
pp. 345.1-345
Author(s):  
M. Morita ◽  
S. Masuyama ◽  
M. Mizui ◽  
Y. Isaka
Keyword(s):  
T Cells ◽  
Antibody Titer ◽  
Cell Function ◽  
Cell Subpopulation ◽  
Target Cells ◽  
Therapeutic Effects ◽  
Autoantibody Production ◽  
Rate Of Increase ◽  
Dsdna Antibody ◽  
The Difference

Background:Systemic lupus erythematosus (SLE) is a multisystem autoimmune disease characterized by the production of autoantibody and systemic tissue damages including glomerulonephritis. Immune responses mediated by autoreactive T-cells, as well as by autoantibody, is involved in the development and progression of end-organ damages1. Biologic agents which manipulate T-cell function such as CTLA4-Ig and anti-CD40L have been revisited and tried to treat human SLE, however, both of them failed to demonstrate efficacy.A mouse specific anti-CD3ε mAb, clone 145-2C11 (2C11) is known to be immunosuppressive by down-modulation of TCR and depletion of T-cells2. Administration of Fc-deleted 145-2C11 F(ab’)2to lupus-prone mice was reported to reduce lymphadenopathy and prolong survival, but had no significant effect on anti-DNA antibody titer3. The mechanisms by which 2C11 ameliorates lupus are still unclear.In this study, we used non-mitogenic Fc-modified silent 145-2c11 (2C11S), which disables interaction between target cells and Fc receptor-bearing cells, abolishes antibody directed cytotoxicity, and has longer half-life than F(ab’)2. 2C11S is expected to exert its effect in safe and stable as compared with functional parent-2C11 (2C11P) antibody.Objectives:The purpose of our study is to clarify the difference between 2C11S and 2C11P and to examine their therapeutic effects against murine lupus-prone (NZB/W F1) mice.Methods:20 μg of 2C11P (absolute antibody), 2C11S (absolute antibody), or isotype control immunoglobulin G1 κ (IC)(BioLegend) were administered intraperitoneally to C57BL6 mice. The difference of their action on T-cells were evaluated in a time series from peripheral blood. Plasma cytokine levels were measured within 24 hours after antibody administration.In NZB/W F1 mice from weeks 10 or 20, 2C11P, 2C11S, and IC were administered (100 μg / week, 4 times, intraperitoneally). Plasma anti-dsDNA antibody titer, spleen and kidney blood cell subpopulation, and histology of renal tissue were evaluated before and/or after treatment.Results:Duration of reduced TCR expression in 2C11S group was approximately twice as long as that in 2C11P group, and the levels of plasma TNF-α was not increased in 2C11S group while significant increase was observed in 2C11P group (IC; mean 48.3 ± SD 16.7 pg/ml, 2C11S; 57.9 ± 6.12, 2C11P; 168 ± 50.6, IC VS 2C11S; p>0.99, IC VS 2C11P; p=0.03, ANOVA).In NZB/W F1 mice, the number of follicular helper T (Tfh) cells in spleen significantly decreased in 2C11S group (IC; median 9.0*104[interquartile range 8.5*104], 2C11S; 1.8*104[1.0*104], 2C11P; 1.0*105[9.4*104], IC VS 2C11S; p=0.03, IC VS 2C11P; p>0.99, Kruskal-Wallis). The number of germinal center B (GCB) cells in spleen also decreased in 2C11S group (IC; 1.2*105[1.7*105], 2C11S; 9.0*103[2.3*104], 2C11P; 8.0*104[2.3*105], IC VS 2C11S; p=0.03, IC VS 2C11P; p>0.99). The number of infiltrating CD4+T-cells in kidney significantly reduced in 2C11S group (IC; 3.4*103[1.0*104], 2C11S; 6.4*102[8.8*102], 2C11P; 1.2*103[4.4*103], IC VS 2C11S; p=0.048, IC VS 2C11P; p=0.23). In addition, the rate of increase in anti-dsDNA IgG titers significantly decreased in 2C11S group (IC; 2.3 [1.3], 2C11S; 0.9 [1.0], 2C11P; 1.3 [1.4], IC VS 2C11S; p=0.03, IC VS 2C11P; p=0.24). Finally, glomerular hypercellularity was markedly alleviated only in 2C11S group (IC; 4.4*10 [8.4], 2C11S; 3.8*10 [1.1], 2C11P; 3.9*10 [8.2], IC VS 2C11S; p=0.02, IC VS 2C11P; p=0.57).Conclusion:2C11S did not induce cytokine release with maintaining longer effect on TCR down-modulation. 2C11S reduced autoantibody production by suppressing GCB differentiation, possibly through down-regulation of Tfh cell number. Consequently, 2C11S ameliorated lupus nephritis. On the other hand, 2C11P did not show therapeutic effect.References:[1]George C Tsokos. et al. Nat. Rev. Rheum (2016) 12: 716-730.[2]Kuhn C. et al. Immunotherapy (2016) 8: 889-906.[3]Henrickson M. et al. Arthritis Rheum (1994) 37: 587-589.Disclosure of Interests: :None declared

scholarly journals Detection of a latent soluble form of membrane type 1 matrix metalloprotease bound with tissue inhibitor of matrix metalloproteinases-2 in periprosthetic tissues and fluids from loose arthroplasty endoprostheses

FEBS Journal ◽  
2013 ◽  
Vol 280 (24) ◽  
pp. 6541-6555 ◽  
Author(s):  
Anna Niarakis ◽  
Eleftheria Giannopoulou ◽  
Panagiota Ravazoula ◽  
Elias Panagiotopoulos ◽  
Ioannis K. Zarkadis ◽  
...  
Keyword(s):  
Matrix Metalloproteinases ◽  
Soluble Form ◽  
Matrix Metalloprotease ◽  
Tissue Inhibitor ◽  
Membrane Type

scholarly journals Back to the future: a new look at ‘old’ vitamin D

2008 ◽  
Vol 198 (2) ◽  
pp. 261-269 ◽  
Author(s):  
Rene F Chun ◽  
John S Adams ◽  
Martin Hewison
Keyword(s):  
Vitamin D ◽  
Vitamin D Insufficiency ◽  
Target Cells ◽  
Bone Homeostasis ◽  
Immune Disorders ◽  
Factors Associated ◽  
Dihydroxyvitamin D ◽  
High Prevalence ◽  
Fresh Perspective ◽  
Vitamin D Signaling

Our perception of the vitamin D system continues to evolve. Recent studies have re-evaluated the parameters for adequate vitamin D status in humans, revealing a high prevalence of insufficiency in many populations throughout the world. Other reports have highlighted the potential consequences of vitamin D insufficiency beyond established effects on bone homeostasis. Most notably, there is now strong evidence of a role for vitamin D in modulating innate and adaptive immunities, with insufficiency being linked to infectious disease and other immune disorders. To date, signaling pathways for these new responses to vitamin D have been based on established endocrine models for active 1,25-dihydroxyvitamin D, despite present evidence for more localized, intracrine modes of action. In the following review, we provide a fresh perspective on vitamin D signaling in non-classical target cells such as macrophages by highlighting novel factors associated with the transport and action of this pluripotent secosteroid.

scholarly journals Subunit assembly of hemoglobin: an important determinant of hematologic phenotype

Blood ◽  
1987 ◽  
Vol 69 (1) ◽  
pp. 1-6 ◽  
Author(s):  
HF Bunn
Keyword(s):  
Electrostatic Interactions ◽  
Hemoglobin Concentration ◽  
Cytoskeletal Proteins ◽  
Membrane Receptors ◽  
Target Cells ◽  
Red Cell Membrane ◽  
Alpha Beta ◽  
The Difference ◽  
Polypeptide Chains ◽  
Positively Charged

Hemoglobin's physiologic properties depend on the orderly assembly of its subunits in erythropoietic cells. The biosynthesis of alpha- and beta-globin polypeptide chains is normally balanced. Heme rapidly binds to the globin subunit, either during translation or shortly thereafter. The formation of the alpha beta-dimer is facilitated by electrostatic attraction of a positively charged alpha-subunit to a negatively charged beta-subunit. The alpha beta-dimer dissociates extremely slowly. The difference between the rate of dissociation of alpha beta- and alpha gamma-dimers with increasing pH explains the well-known alkaline resistance of Hb F. Two dimers combine to form the functioning alpha 2 beta 2-tetramer. This model of hemoglobin assembly explains the different levels of positively charged and negatively charged mutant hemoglobins that are encountered in heterozygotes and the effect of alpha-thalassemia and heme deficiency states in modifying the level of the variant hemoglobin as well as Hb A2. Electrostatic interactions also affect the binding of hemoglobin to the cytoplasmic surface of the red cell membrane and may underlie the formation of target cells. Enhanced binding of positively charged variants such as S and C trigger a normally dormant pathway for potassium and water loss. Thus, the positive charge on beta c is responsible for the two major contributors to the pathogenesis of Hb SC disease: increased proportion of Hb S and increased intracellular hemoglobin concentration. It is likely that electrostatic interactions play an important role in the assembly of a number of other multisubunit macromolecules, including membrane receptors, cytoskeletal proteins, and DNA binding proteins.

scholarly journals Membrane Specializations in the Form of Regular Membrane-to-Membrane Attachment Sites in Paramecium. A Correlated Freeze-Etching and Ultrathin-Sectioning Analysis

1973 ◽  
Vol 13 (3) ◽  
pp. 687-719
Author(s):  
H. PLATTNER ◽  
F. MILLER ◽  
L. BACHMANN
Keyword(s):  
Membrane Complex ◽  
Type D ◽  
Attachment Sites ◽  
Morphometric Analyses ◽  
Concentric Zone ◽  
Membrane Attachment ◽  
Ciliary Necklaces ◽  
Freeze Etching ◽  
Membrane Bound ◽  
Membrane Type

The outer membrane complex of Paramecium was investigated by ultrathin-sectioning techniques and by freeze-etching of unfixed cells without cryoprotectants. Granules were found in the freeze-etched cortical membrane complex in a highly ordered arrangement; morphometric analyses and partial disruption of this membrane complex showed that some of these granular membrane specializations (which we call types a, b, e, f, g) represent membrane-to-membrane attachment sites. Type a: granules arranged in rings (single or double), 300 nm in diameter, connect plasmalemma and alveolar membranes around trichocysts. Type b: within these a-type rings, a concentric zone (180 nm diameter) of granules connects plasma membrane and trichocyst membrane. Type c: the trichocyst membrane further contains a central ring or patch, 80 nm in diameter, of rather large granules where it is in contact with the crystalline trichocyst matrix. Type d: ‘ciliary necklaces’ are formed by groups of triple rows of 3-6, most frequently 5 granules, with 21-nm periodicity. Rows of granules also connect the alveolar membranes to the apical portion of the trichocyst membrane (type e) and the alveolar membrane to the plasmalemma around cilia (type f). Type g: the inner alveolar membrane displays an intense granularity and contains double rows of granules along alveolar septa at attachment sites between 2 alveolar membranes. Upon experimental discharge of the majority of trichocysts only the innermost concentric circles of membrane-bound granules of this region (b- and c-type) disappeared from the plasmalemma, while the outermost a-type rings of granules persisted for a longer time. Among other possible functions, these regular membrane-to-membrane attachments are likely to maintain the specific cellular shape.

scholarly journals A 15 amino acid fragment of influenza nucleoprotein synthesized in the cytoplasm is presented to class I-restricted cytotoxic T lymphocytes.

1989 ◽  
Vol 170 (3) ◽  
pp. 1051-1056 ◽  
Author(s):  
K Gould ◽  
J Cossins ◽  
J Bastin ◽  
G G Brownlee ◽  
A Townsend
Keyword(s):  
Cell Clone ◽  
Recombinant Vaccinia Virus ◽  
Class I ◽  
Peptide Transport ◽  
Cytotoxic T Cell ◽  
Target Cells ◽  
Recombinant Vaccinia ◽  
Acid Fragment ◽  
T Cell Clone ◽  
Membrane Bound

A recombinant vaccinia has been designed to express amino acids 366-379 of influenza nucleoprotein, previously shown to be the minimal epitope recognized by a class I-restricted cytotoxic T cell clone. Target cells infected with the recombinant vaccinia virus expressing this peptide are recognized by CTL as efficiently as target cells expressing the complete nucleoprotein. The results imply the existence of a peptide transport system that constitutively passes the products of degraded proteins from the cytoplasm into a membrane-bound compartment of the cell.

Sign in / Sign up

Export Citation Format

Share Document