scholarly journals The two-pore domain K2P channel TASK2 drives human NK-cell proliferation and cytolytic function

2015 ◽  
Vol 45 (9) ◽  
pp. 2602-2614 ◽  
Author(s):  
Andreas Schulte-Mecklenbeck ◽  
Stefan Bittner ◽  
Petra Ehling ◽  
Frank Döring ◽  
Erhard Wischmeyer ◽  
...  
Keyword(s):  
Cell Proliferation ◽  
Nk Cell ◽  
K2p Channel ◽  
Cytolytic Function ◽  
Pore Domain

Natural Killer Cell Cytolytic Function in Korean Patients with Adult-onset Still’s Disease

2012 ◽  
Vol 39 (10) ◽  
pp. 2000-2007 ◽  
Author(s):  
JEONG HA PARK ◽  
HEE-SUN KIM ◽  
JIN SOOK LEE ◽  
JIN JU KIM ◽  
KYONG-HEE JUNG ◽  
...  
Keyword(s):  
Nk Cells ◽  
Natural Killer ◽  
Nk Cell ◽  
Adult Onset Still’S Disease ◽  
Adult Onset ◽  
Still’S Disease ◽  
Cytolytic Function ◽  
Cell Proportion ◽  
Cytotoxic Function ◽  
Adult Onset Still's Disease

Objective.To investigate natural killer (NK) cell proportions, NK cell cytotoxicity, and interleukin 18 (IL-18) expression, in patients with adult-onset Still’s disease (AOSD).Methods.Forty-five patients with AOSD (active = 22, inactive = 23) and 32 healthy controls were included. The proportions of NK cells among peripheral blood mononuclear cells were assessed by flow cytometry. IL-18 and IL-18-binding protein (IL-18BP) concentrations were measured by ELISA. Twenty-four patients with AOSD and 18 controls were examined for cytotoxic activity of NK cells by co-incubating NK cells with NK-sensitive K562 cells. The association of NK cell function with clinical and laboratory measures was investigated.Results.The proportions of NK cells were significantly lower in patients with active AOSD than in patients with inactive disease and controls. NK cell cytotoxic function was significantly lower in patients with AOSD than in controls. NK cell proportions and cytotoxic functions were reexamined in 11 and 6 patients, respectively, after treatment. Low NK cell proportion and cytotoxic dysfunction were improved with clinical improvements of the patients. IL-18 and IL-18BP levels were much higher in patients with active AOSD than in controls. NK cell cytotoxic functions were consistently low and IL-18 and IL-18BP levels were constantly high in patients with AOSD, regardless of disease activity.Conclusion.Low NK cell proportion, defective cytotoxic function, and elevated IL-18 levels may be significant features of AOSD. After resolution of the acute phase, low NK cell proportion was recovered and NK cell cytolytic function was restored along with clinical improvement. These findings possibly contribute to immunologic abnormalities in AOSD.

scholarly journals A Deafness Associated Protein TMEM43 Interacts with KCNK3 (TASK-1) Two-pore Domain K+ (K2P) Channel in the Cochlea

2021 ◽  
Vol 30 (5) ◽  
pp. 319-328
Author(s):  
Minwoo Wendy Jang ◽  
Tai Young Kim ◽  
Kushal Sharma ◽  
Jea Kwon ◽  
Eunyoung Yi ◽  
...  
Keyword(s):  
K2p Channel ◽  
Pore Domain

Tandem Pore Domain Potassium Channels

2019 ◽  
Author(s):  
Douglas A. Bayliss
Keyword(s):  
Single Channel ◽  
Resting Membrane Potential ◽  
K2p Channel ◽  
Physiological Processes ◽  
System A ◽  
Wide Range ◽  
K2p Channels ◽  
To Come ◽  
A Site ◽  
Pore Domain

The KCNK gene family encodes two-pore-domain potassium (K2P) channels, which generate the background (“leak”) K+ currents that establish a negative resting membrane potential in cells of the nervous system. A pseudotetrameric K+-selective pore is formed by pairing channel subunits, each with two pore-domains, in homo- or heterodimeric conformations. Unique features apparent from high-resolution K2P channel structures include a domain-swapped extracellular cap domain, a lateral hydrophobic-lined fenestration connecting the lipid bilayer to the channel vestibule, and an antiparallel proximal C-terminal region that links the paired subunits and provides a site for polymodal channel modulation. Individual channels transition between open and closed states, with the channel gate located at the selectivity filter. In general, K2P channels display relatively modest voltage- and time-dependent gating, together with distinct single-channel rectification properties, that conspire to yield characteristic weakly rectifying macroscopic currents over a broad range of membrane potentials (i.e., background K+ currents). Of particular note, K2P channel activity can be regulated by a wide range of physicochemical factors, neuromodulators, and clinically useful drugs; a distinct repertoire of activators and inhibitors for different K2P channel subtypes endows each with unique modulatory potential. Thus, by mediating background currents and serving as targets for multiple modulators, K2P channels are able to dynamically regulate key determinants of cell-intrinsic electroresponsive properties. The roles of specific K2P channels in various physiological processes and pathological conditions are now beginning to come into focus, and this may portend utility for these channels as potential therapeutic targets.

CFSE dilution to study human T and NK cell proliferation in vitro

2020 ◽  
pp. 239-255 ◽  
Author(s):  
Iñigo Terrén ◽  
Ane Orrantia ◽  
Joana Vitallé ◽  
Olatz Zenarruzabeitia ◽  
Francisco Borrego
Keyword(s):  
Cell Proliferation ◽  
Nk Cell ◽  
Cfse Dilution ◽  
Proliferation In Vitro

The Ability of NK Cell and Granulocyte Forms of CD 16 to Trigger Cytolytic Function

2015 ◽  
pp. 50-54
Author(s):  
Olli Carp�n ◽  
Periasamy Selvaraj ◽  
Margaret L. Hibbs ◽  
Timothy A. Springer
Keyword(s):  
Nk Cell ◽  
Cytolytic Function

scholarly journals P460 Evaluation of potential mechanisms underlying the safety observations of filgotinib in clinical studies in rheumatoid arthritis

2020 ◽  
Vol 14 (Supplement_1) ◽  
pp. S409-S409
Author(s):  
A Clarke ◽  
J Di Paolo ◽  
B Downie ◽  
A Meng ◽  
N Mollova ◽  
...  
Keyword(s):  
Rheumatoid Arthritis ◽  
Cell Proliferation ◽  
Clinical Studies ◽  
Nk Cell ◽  
Janus Kinase ◽  
Jak Inhibitor ◽  
Jak Inhibitors ◽  
Erythroid Progenitor ◽  
Cell Counts

Abstract Background Inhibitors of the Janus kinase-signal transducers and activators of transcription (JAK-STAT) pathway have demonstrated efficacy in the treatment of rheumatoid arthritis (RA) and inflammatory bowel disease (IBD). Differences in selectivity of JAK inhibitors for JAK1, JAK2, JAK3 and TYK2 may influence their respective safety profiles, and the mechanisms responsible are not currently known. Filgotinib (FIL), a JAK1 inhibitor, did not negatively impact haemoglobin, LDL:HDL ratios or natural killer (NK) cell counts in clinical trials. Here, we compare the in vitro mechanistic profiles of four JAK inhibitors at clinically relevant doses. Methods JAK inhibitors (FIL, FIL metabolite [GS-829845], baricitinib [BARI], tofacitinib [TOFA], and upadacitinib [UPA]) were evaluated in vitro in human-cell-based assays. Growth of erythroid progenitors from human cord blood CD34+ cells was assessed using a HemaTox™ liquid expansion assay, NK cell proliferation was induced by IL-15 and LXR agonist-induced cholesteryl ester transfer protein (CETP) expression was assessed in the hepatic cell line, HepG2. Using assay-generated IC50 values and the reported human plasma concentrations from clinical studies, we calculated the target coverage for each JAK inhibitor at clinically relevant doses. The activity of FIL in humans was based on PK/PD modelling of FIL + GS-829845. Results Inhibition of cellular activity was calculated for each JAK inhibitor based on in vitro dose-response data, human exposure data and modelled PK/PD relationships. At clinically relevant doses, FIL resulted in lower calculated inhibition of NK cell proliferation compared with other JAK inhibitors. FIL 100 mg and 200 mg also reduced CETP expression, whereas other JAK inhibitors had no effect. There was no difference in the effect of FIL vs. other JAK inhibitors on erythroid progenitor cell differentiation or maturation. Conclusion FIL, a JAK1 inhibitor, resulted in less inhibition of NK cell proliferation compared with BARI, TOFA, and UPA. FIL also reduced LXR agonist-induced CETP expression, while the other inhibitors did not alter these levels. These results provide a potential mechanistic link between the observed reduction of CETP concentration following FIL treatment and the previously observed reduction in the LDL:HDL ratio in RA patients.

Abstract 1524: CD137 (4-1BB) engagement fine-tunes the synergistic IL-15- and IL-21-driven NK cell proliferation

2019 ◽  
Author(s):  
Laurent Vidard ◽  
Christine Dureuil-Sizaire ◽  
Jérémy Baudhuin ◽  
Lionel Vescovi ◽  
Laurence Durand ◽  
...  
Keyword(s):  
Cell Proliferation ◽  
Nk Cell

scholarly journals Immunostimulatory Effects of Live Lactobacillus sakei K040706 on the CYP-Induced Immunosuppression Mouse Model

Nutrients ◽  
2020 ◽  
Vol 12 (11) ◽  
pp. 3573
Author(s):  
Seo-Yeon Kim ◽  
Ji-Sun Shin ◽  
Kyung-Sook Chung ◽  
Hee-Soo Han ◽  
Hwi-Ho Lee ◽  
...  
Keyword(s):  
Cell Proliferation ◽  
Molecular Mechanisms ◽  
Nk Cell ◽  
Cell Activity ◽  
Lactobacillus Sakei ◽  
Gm Csf ◽  
Positive Effects ◽  
Macrophage Colony Stimulating Factor ◽  
Macrophage Colony ◽  
Immunosuppressed Mice

Our previous studies have shown that heat-killed Lactobacillus sakei K040706 exerts immunostimulatory and anti-inflammatory activities in macrophages, cyclophosphamide (CYP)-treated mice, and dextran sulfate sodium–induced colitis mice. However, the immunostimulatory effects of live Lactobacillus sakei K040706 (live K040706) against CYP-induced immunosuppression and its underlying molecular mechanisms remain unknown. Therefore, we investigated the immunostimulatory effects of live K040706 (108 or 109 colony forming unit (CFU)/day, p.o.) in CYP-induced immunosuppressed mice. Oral administration of live K040706 prevented the CYP-induced decreases in body weight, thymus index, natural killer (NK) cell activity, T and B cell proliferation, and cytokine (interferon (IFN)-γ, interleukin (IL)-2, and IL-12) production. The administration of live K040706 also exerted positive effects on the gut microbiota of CYP-induced mice, resulting in a microbiota composition similar to that of normal mice. Moreover, live K040706 significantly enhanced IL-6 and granulocyte-macrophage colony-stimulating factor (GM-CSF) production in the splenocytes and Peyer’s patch (PP) cells of mice and increased bone marrow (BM) cell proliferation. Taken together, our data indicate that live K040706 may effectively accelerate recovery from CYP-induced immunosuppression, leading to activation of the immune system. Therefore, live K040706 may serve as a potential immunomodulatory agent against immunosuppression.

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