scholarly journals Connexin 43 Communication Channels in Follicular Dendritic Cell Development and in Follicular Lymphomas

2015 ◽  
Vol 2015 ◽  
pp. 1-10 ◽  
Author(s):  
Hajnalka Rajnai ◽  
Ivett Teleki ◽  
Gergo Kiszner ◽  
Nora Meggyesházi ◽  
Peter Balla ◽  
...  
Keyword(s):  
Cell Proliferation ◽  
B Cell ◽  
Connexin 43 ◽  
Ex Vivo ◽  
Bone Marrow Involvement ◽  
Germinal Centers ◽  
Cx43 Expression ◽  
Cx43 Protein ◽  
Follicular Dendritic ◽  
Follicular Lymphomas

Follicular dendritic cells (FDC) show homo- and heterocellular metabolic coupling through connexin 43 (Cx43) gap junctions and support B cell selection and maturation in germinal centers. In follicular lymphomas B cells escape apoptosis while FDC develop abnormally. Here we tested Cx43 channels in reactive FDC development and follicular lymphomas. In culture, the treatment of FDC-B cell clusters (resembling to “ex vivo” germinal centers) with Gap27 peptide, mimicking the 2nd extracellular loop of Cx43 protein, significantly impaired FDC-B cell cluster formation and cell survival. In untreated cultures of intact clusters, cell proliferation showed a moderate reduction. In tissues, Cx43 protein levels run parallel with the density of FDC both in reactive germinal centers and in malformed follicles of follicular lymphomas and showed strong upregulation in newly generated and/or degrading bi-/multinuclear FDC of rudimentary processes. However, the inverse correlation between Cx43 expression and B cell proliferation seen in reactive germinal centers was not detected in follicular lymphomas. Furthermore, Cx43 levels were not associated with either lymphoma grade or bone marrow involvement. Our results suggest that Cx43 channels are critical in FDC and “ex vivo” germinal center development and in the persistence of FDC in follicular lymphomas but do not affect tumor progression.

CX43 expression, phosphorylation, and distribution in the normal and autoimmune orchitic testis with a look at gap junctions joining germ cell to germ cell

2011 ◽  
Vol 300 (1) ◽  
pp. R121-R139 ◽  
Author(s):  
R.-Marc Pelletier ◽  
Casimir D. Akpovi ◽  
Li Chen ◽  
Robert Day ◽  
María L. Vitale
Keyword(s):  
Cell Differentiation ◽  
Gap Junctions ◽  
Germ Cell ◽  
Sertoli Cell ◽  
Sertoli Cells ◽  
Seminiferous Tubule ◽  
Connexin 43 ◽  
Cx43 Expression ◽  
Cx43 Protein ◽  
Cx43 Mrna

Spermatogenesis requires connexin 43 (Cx43).This study examines normal gene transcription, translation, and phosphorylation of Cx43 to define its role on germ cell growth and Sertoli cell's differentiation, and identifies abnormalities arising from spontaneous autoimmune orchitis (AIO) in mink, a seasonal breeder and a natural model for autoimmunity. Northern blot analysis detected 2.8- and a 3.7-kb Cx43 mRNA bands in seminiferous tubule-enriched fractions. Cx43 mRNA increased in seminiferous tubule-enriched fractions throughout development and then seasonally with the completion of spermatogenesis. Cx43 protein levels increased transiently during the colonization of the tubules by the early-stage spermatocytes. Cx43 phosphorylated (PCx43) and nonphosphorylated (NPCx43) in Ser368 decreased during the periods of completion of meiosis and Sertoli cell differentiation, while Cx43 mRNA remained elevated throughout. PCx43 labeled chiefly the plasma membrane except by stage VII when vesicles were also labeled in Sertoli cells. Vesicles and lysosomes in Sertoli cells and the Golgi apparatus in the round spermatids were NPCx43 positive. A decrease in Cx43 gene expression was matched by a Cx43 protein increase in the early, not the late, phase of AIO. Total Cx43 and PCx43 decreased with the advance of orchitis. The study makes a novel finding of gap junctions connecting germ cells. The data indicate that Cx43 protein expression and phosphorylation in Ser368 are stage-specific events that may locally influence the acquisition of meiotic competence and the Sertoli cell differentiation in normal testis. AIO modifies Cx43 levels, suggesting changes in Cx43-mediated intercommunication and spermatogenic activity in response to cytokines imbalances in Sertoli cells.

DETERIORATION OF B CELL PROLIFERATION CORRELATES WITH DENDRITIC RETICULUM CELL DESTRUCTION IN GERMINAL CENTERS OF AN AIDS PATIENT. Case Study

1988 ◽  
Vol 38 (9) ◽  
pp. 1205-1214
Author(s):  
Shigeo Mori ◽  
Yukiyoshi Ezaki ◽  
Mayumi Mori ◽  
Muneharu Takahashi ◽  
Mari Teshima ◽  
...  
Keyword(s):  
Cell Proliferation ◽  
B Cell ◽  
Germinal Centers ◽  
Reticulum Cell ◽  
Patient Case ◽  
Cell Destruction ◽  
Dendritic Reticulum Cell

scholarly journals Connexin 43 and Sonic Hedgehog Pathway Interplay in Glioblastoma Cell Proliferation and Migration

Biology ◽  
2021 ◽  
Vol 10 (8) ◽  
pp. 767
Author(s):  
Filippo Torrisi ◽  
Cristiana Alberghina ◽  
Debora Lo Furno ◽  
Agata Zappalà ◽  
Samuel Valable ◽  
...  
Keyword(s):  
Cell Proliferation ◽  
Sonic Hedgehog ◽  
Intercellular Communication ◽  
Connexin 43 ◽  
Cx43 Expression ◽  
Close Link ◽  
Shh Pathway ◽  
Cell Proliferation And Migration ◽  
And Migration ◽  
Proliferation And Migration

Glioblastoma (GBM) represents the most common primary brain tumor within the adult population. Current therapeutic options are still limited by high rate of recurrences and signalling axes that promote GBM aggressiveness. The contribution of gap junctions (GJs) to tumor growth and progression has been proven by experimental evidence. Concomitantly, tumor microenvironment has received increasing interest as a critical process in dysregulation and homeostatic escape, finding a close link between molecular mechanisms involved in connexin 43 (CX43)-based intercellular communication and tumorigenesis. Moreover, evidence has come to suggest a crucial role of sonic hedgehog (SHH) signalling pathway in GBM proliferation, cell fate and differentiation. Herein, we used two human GBM cell lines, modulating SHH signalling and CX43-based intercellular communication in in vitro models using proliferation and migration assays. Our evidence suggests that modulation of the SHH effector smoothened (SMO), by using a known agonist (i.e., purmorphamine) and a known antagonist (i.e., cyclopamine), affects the CX43 expression levels and therefore the related functions. Moreover, SMO activation also increased cell proliferation and migration. Importantly, inhibition of CX43 channels was able to prevent SMO-induced effects. SHH pathway and CX43 interplay acts inducing tumorigenic program and supporting cell migration, likely representing druggable targets to develop new therapeutic strategies for GBM.

scholarly journals Effects of Orally Administered ViableLactobacillus rhamnosus GG and Propionibacterium freudenreichii subsp. shermanii JS on Mouse Lymphocyte Proliferation

1999 ◽  
Vol 6 (6) ◽  
pp. 799-802 ◽  
Author(s):  
Pirkka V. Kirjavainen ◽  
Hani S. ElNezami ◽  
Seppo J. Salminen ◽  
Jorma T. Ahokas ◽  
Paul F. A. Wright
Keyword(s):  
Cell Proliferation ◽  
T Cell ◽  
B Cell ◽  
Proliferative Activity ◽  
Ex Vivo ◽  
Lactobacillus Rhamnosus ◽  
Time Profile ◽  
T Cell Proliferation ◽  
High Dose ◽  
Propionibacterium Freudenreichii

ABSTRACT Immunomodulation by probiotics is a subject of growing interest, but the knowledge of dose response and time profile relationships is minimal. In this study we examined the effects of Lactobacillus rhamnosus GG (LGG) and Propionibacterium freudenreichii subsp. shermanii JS (PJS) on the proliferative activity of murine lymphocytes ex vivo. Dose dependency was assessed by treating animals perorally with a low or a high dose (i.e., 109 or 1012 viable bacteria/kg of body weight) for 7 days. The lower dose levels of each strain appeared to enhance T-cell proliferation at the optimal concanavalin A (ConA) concentration (by 69 to 84%) and B-cell proliferation at the optimal and supraoptimal concentrations of lipopolysaccharide (by 57 to 82%). B-cell proliferation was also enhanced by the high LGG dose (by 32 to 39%) but was accompanied by a marginal decrease in T-cell proliferation (by 8%) at the optimal ConA concentration. The time profiles of the immune responses were assessed after daily treatment with the higher dose for 3, 7, and 14 days. A significant decrease in basal lymphoproliferation (by 32 to 42%) was observed with PJS treatment after the 3- and 7-day periods; however, this activity returned to control levels after 14 days of treatment, which also resulted in significantly enhanced T-cell proliferation at optimal and supraoptimal ConA concentrations (by 24 to 80%). The 14-day LGG treatment also enhanced the latter activity (by 119%). In conclusion, LGG and PJS have specific dose- and duration-dependent immunomodulatory effects on the proliferative activity of B and T lymphocytes and may also reduce lymphocyte sensitivity to the cytotoxic effects of lectin mitogens.

scholarly journals Sympathetic Overactivity in CKD Disrupts Buffering of Neurotransmission by Endothelium-Derived Hyperpolarizing Factor and Enhances Vasoconstriction

2020 ◽  
Vol 31 (10) ◽  
pp. 2312-2325
Author(s):  
Wei Cao ◽  
Liling Wu ◽  
Xiaodong Zhang ◽  
Jing Zhou ◽  
Jian Wang ◽  
...  
Keyword(s):  
Gap Junction ◽  
Vascular Resistance ◽  
Connexin 43 ◽  
Structural Changes ◽  
Ex Vivo ◽  
Resistance Arteries ◽  
Cx43 Expression ◽  
Neurovascular Transmission

BackgroundHypertension commonly complicates CKD. Vascular smooth muscle cells (VSMCs) of resistance arteries receive signals from the sympathetic nervous system that induce an endothelial cell (EC)–dependent anticontractile response that moderates vasoconstriction. However, the specific role of this pathway in the enhanced vasoconstriction in CKD is unknown.MethodsA mouse model of CKD hypertension generated with 5/6-nephrectomy (5/6Nx) was used to investigate the hypothesis that an impaired anticontractile mechanism enhances sympathetic vasoconstriction. In vivo, ex vivo (isolated mesenteric resistance arteries), and in vitro (VSMC and EC coculture) models demonstrated neurovascular transmission and its contribution to vascular resistance.ResultsBy 4 weeks, 5/6Nx mice (versus sham) had augmented increases in mesenteric vascular resistance and mean arterial pressure with carotid artery occlusion, accompanied by decreased connexin 43 (Cx43) expression at myoendothelial junctions (MEJs), impaired gap junction function, decreased EC-dependent hyperpolarization (EDH), and enhanced contractions. Exposure of VSMCs to NE for 24 hours in a vascular cell coculture decreased MEJ Cx43 expression and MEJ gap junction function. These changes preceded vascular structural changes evident only at week 8. Inhibition of central sympathetic outflow or transfection of Cx43 normalized neurovascular transmission and vasoconstriction in 5/6Nx mice.Conclusions5/6Nx mice have enhanced neurovascular transmission and vasoconstriction from an impaired EDH anticontractile component before vascular structural changes. These neurovascular changes depend on an enhanced sympathetic discharge that impairs the expression of Cx43 in gap junctions at MEJs, thereby interrupting EDH responses that normally moderate vascular tone. Dysregulation of neurovascular transmission may contribute to the development of hypertension in CKD.

Follicular dendritic cells restrict interleukin-4 availability in germinal centers and foster memory B cell generation

Immunity ◽  
2021 ◽  
Vol 54 (10) ◽  
pp. 2256-2272.e6
Author(s):  
Lihui Duan ◽  
Dan Liu ◽  
Hsin Chen ◽  
Michelle A. Mintz ◽  
Marissa Y. Chou ◽  
...  
Keyword(s):  
Dendritic Cells ◽  
B Cell ◽  
Germinal Centers ◽  
Cell Generation ◽  
Interleukin 4 ◽  
Follicular Dendritic Cells ◽  
Memory B Cell ◽  
Follicular Dendritic

Cyclin D3 Is Required for Peritoneal B-1a Lymphocyte Proliferation.

Blood ◽  
2005 ◽  
Vol 106 (11) ◽  
pp. 1353-1353
Author(s):  
Jennifer M. Mataraza ◽  
Joseph R. Tumang ◽  
Thomas L. Rothstein ◽  
Thomas C. Chiles
Keyword(s):  
Cell Proliferation ◽  
B Cells ◽  
B Cell ◽  
Ex Vivo ◽  
Cell Cycle Control ◽  
Lymphocytic Leukemia ◽  
Cyclin D3 ◽  
Minor Amount ◽  
Cyclin D2 ◽  
Stimulation Of

Abstract Cyclins D2 and D3 are coordinately induced in response to mitogenic stimulation of splenic B-2 lymphocytes. It is recognized that the cyclin D2:cdk4:pRb pathway plays an essential role in B-2 cell proliferation. By contrast, little is known about the function of cyclin D3 in B cells. Peritoneal CD5+ B-1 cells represent a distinct subset of B lymphocytes and exhibit several unique phenotypic and functional characteristics, which distinguish them from B-2 cells. B-1 cells are associated with several human disease states characterized by B-cell expansion. Notably, B-1 cells represent the normal counterpart for a subset of human chronic lymphocytic leukemia (CLL), the cells of which express CD5. In mice, monoclonal expansions of CD5+ B-1 cells, that resemble CLL, develop as a function of age. These associations with malignant diseases impel the necessity to understand cell cycle control in B-1 cells. In contrast to splenic B-2 cells, stimulation of ex vivo B-1 cells results in an early and transient induction of cyclin D2; however, cyclin D2 complexes account for a relatively minor amount of the total pRb phosphorylation. Evidence for a second cyclin functioning in this capacity is supported by the finding that stimulated cdk4/6-mediated phosphorylation of pRb increases dramatically in mid-to-late G1-phase coincident with the induction of cyclin D3. Thus, in contrast to B-2 cells, the non-overlapping expression of cyclins D2 and D3 points to distinct roles for these D-type cyclins in B-1 cells. We hypothesize that the timing and duration of cyclin D3 induction suggest a unique role in mediating the G1/S transition in B-1 cells. To investigate this possibility, we transduced TAT-p16 peptidyl mimetics into ex vivo B-1 cells immediately prior to cyclin D3 induction to specifically target and inactivate cyclin D3-cdk complexes. We report here that transduction of TAT-p16 mimetics selectively disrupted cyclin D3-cdk4 complexes, whereas cdk2-containing complexes remained intact. Transduction of wild-type TAT-p16 mimetics, but not mutant TAT-p16 mimetics blocked S-phase entry in response to several B-cell mitogens. In addition, we found that transduction of TAT-p16 peptidyl mimetics inhibited pRb phosphorylation by D-type cyclin-cdk4/6 holoenzymes in B-1 cells stimulated with PMA, LPS or CD40L. These results provide the first evidence of a subset-specific functional role for cyclin D3 in B cells and suggest that cyclin D3, in its capacity as a regulator of cdk4/6-mediated pRb phosphorylation, is required for B-1 cell proliferation.

BTK Inhibition Targets in Vivo CLL Proliferation Through Its Effects On B-Cell Receptor Signaling Activity.

Blood ◽  
2012 ◽  
Vol 120 (21) ◽  
pp. 2903-2903
Author(s):  
Y. Lynn Wang ◽  
Shuhua Cheng ◽  
Jiao Ma ◽  
Ailin Guo ◽  
Pin Lu ◽  
...  
Keyword(s):  
Cell Proliferation ◽  
B Cells ◽  
B Cell ◽  
Ex Vivo ◽  
Cell Receptor ◽  
B Cell Receptor ◽  
B Cell Receptor Signaling ◽  
Serial Samples ◽  
Cell Receptor Signaling

Abstract Abstract 2903 Purpose: Bruton tyrosine kinase (BTK) is a component of the B-cell receptor signaling pathway. Ibrutinib (previously known as PCI-32765), a first in class, covalent BTK inhibitor, has demonstrated significant clinical activity against CLL in early clinical trials. Understanding the molecular mechanisms of action would shed light on CLL pathophysiology and provide additional opportunities for the development of new therapies. Experimental Design: The anti-tumor activity of ibrutinib in CLL has been investigated previously using either an ex vivo approach or a mouse model (Herman et.al, Blood. 2011;117:6287–96 and Ponader et.al, Blood. 2012;119:1182–9). In this study, we have chosen, instead, a patient-oriented in vivo approach by using samples from an ongoing phase 1b trial of ibrutinib (NCT01105247). We prospectively collected serial samples from CLL patients (n=14) before and at several time points after the initiation of therapy and analyzed them for cellular and molecular signaling events. Results: We demonstrated that levels of the phosphorylated BTK protein (p-BTK) in CLL cells from treatment-naïve patients were significantly higher than in normal B cells, explaining why CLL cells are more susceptible to BCR inhibition than normal B cells. Response assessments, performed at the end of cycle 2 (∼Day 56), demonstrated nodal responses in all patients by CT scan. Ex vivo apoptosis did occur but required high concentrations of ibrutinib (>500 nM). In addition, in vivo apoptosis was rarely observed in serial peripheral blood samples collected from treated patients. With these serial samples, we found that the population of Ki67+ cells were gradually decreased over a 28-day ibrutinib treatment course. Using a newly established co-culture system that induces CLL proliferation in vitro, the analysis of several parameters, including Ki-67 expression, cell growth and bromodeoxyuridine (BrdU) incorporation (shown in the figure), revealed that the proliferation of CLL cells was directly inhibited by ibrutinib (200 nM). Furthermore, activities of BTK and downstream signaling events, such as the phosphorylation of PLCg2, AKT and ERK, were all suppressed over time in ibrutinib-treated patients. Conclusions: With primarily an in vivo approach, we have demonstrated that the blockage of cell proliferation was a major effect of ibrutinib against leukemic CLL cells. Blocking cell proliferation via inhibition of BTK-mediated signaling concurs with clinical responses in ibrutinib-treated CLL patients. Disclosures: Leonard: Pharmacyclics Inc.: Consultancy, Honoraria. Buggy:Pharmacyclics: Employment, Equity Ownership.

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