scholarly journals Tofacitinib Suppresses Several JAK-STAT Pathways in Rheumatoid Arthritis In Vivo and Baseline Signaling Profile Associates With Treatment Response

2021 ◽  
Vol 12 ◽  
Author(s):  
Maaria Palmroth ◽  
Krista Kuuliala ◽  
Ritva Peltomaa ◽  
Anniina Virtanen ◽  
Antti Kuuliala ◽  
...  
Keyword(s):  
Rheumatoid Arthritis ◽  
T Cells ◽  
Treatment Response ◽  
Peripheral Blood ◽  
Janus Kinase ◽  
Cytokine Signaling ◽  
Stat3 Phosphorylation ◽  
Stat Pathway

ObjectiveCurrent knowledge on the actions of tofacitinib on cytokine signaling pathways in rheumatoid arthritis (RA) is based on in vitro studies. Our study is the first to examine the effects of tofacitinib treatment on Janus kinase (JAK) - signal transducer and activator of transcription (STAT) pathways in vivo in patients with RA.MethodsSixteen patients with active RA, despite treatment with conventional synthetic disease-modifying antirheumatic drugs (csDMARDs), received tofacitinib 5 mg twice daily for three months. Levels of constitutive and cytokine-induced phosphorylated STATs in peripheral blood monocytes, T cells and B cells were measured by flow cytometry at baseline and three-month visits. mRNA expression of JAKs, STATs and suppressors of cytokine signaling (SOCS) were measured from peripheral blood mononuclear cells (PBMCs) by quantitative PCR. Association of baseline signaling profile with treatment response was also investigated.ResultsTofacitinib, in csDMARDs background, decreased median disease activity score (DAS28) from 4.4 to 2.6 (p < 0.001). Tofacitinib treatment significantly decreased cytokine-induced phosphorylation of all JAK-STAT pathways studied. However, the magnitude of the inhibitory effect depended on the cytokine and cell type studied, varying from 10% to 73% inhibition following 3-month treatment with tofacitinib. In general, strongest inhibition by tofacitinib was observed with STAT phosphorylations induced by cytokines signaling through the common-γ-chain cytokine receptor in T cells, while lowest inhibition was demonstrated for IL-10 -induced STAT3 phosphorylation in monocytes. Constitutive STAT1, STAT3, STAT4 and STAT5 phosphorylation in monocytes and/or T cells was also downregulated by tofacitinib. Tofacitinib treatment downregulated the expression of several JAK-STAT pathway components in PBMCs, SOCSs showing the strongest downregulation. Baseline STAT phosphorylation levels in T cells and monocytes and SOCS3 expression in PBMCs correlated with treatment response.ConclusionsTofacitinib suppresses multiple JAK-STAT pathways in cytokine and cell population specific manner in RA patients in vivo. Besides directly inhibiting JAK activation, tofacitinib downregulates the expression of JAK-STAT pathway components. This may modulate the effects of tofacitinib on JAK-STAT pathway activation in vivo and explain some of the differential findings between the current study and previous in vitro studies. Finally, baseline immunological markers associate with the treatment response to tofacitinib.

scholarly journals AB0250 TOFACITINIB SUPPRESSES SEVERAL JAK-STAT PATHWAYS IN RHEUMATOID ARTHRITIS AND BASELINE SIGNALING PROFILE ASSOCIATES WITH TREATMENT RESPONSE

2021 ◽  
Vol 80 (Suppl 1) ◽  
pp. 1150.2-1151
Author(s):  
M. Palmroth ◽  
K. Kuuliala ◽  
R. Peltomaa ◽  
A. Virtanen ◽  
A. Kuuliala ◽  
...  
Keyword(s):  
Rheumatoid Arthritis ◽  
T Cells ◽  
Treatment Response ◽  
Peripheral Blood ◽  
Janus Kinase ◽  
Cytokine Signaling ◽  
Type I ◽  
Research Support ◽  
Mediators Of Inflammation

Background:Cytokines are important mediators of inflammation and tissue destruction in rheumatoid arthritis (RA) 1. Several cytokines involved in RA pathogenesis act through Janus kinase (JAK)-signal transducer and activator of transcription (STAT) pathway 2. The effects of JAK-inhibitor tofacitinib on cytokine signaling in vitro are well established, while in vivo evidence in patients remains scarce.Objectives:To investigate in vivo in rheumatoid arthritis patients i) which JAK-STAT pathways are inhibited by tofacitinib and ii) if baseline signaling profile is associated with the treatment response.Methods:Sixteen patients with active RA, despite treatment with conventional synthetic disease-modifying antirheumatic drugs (csDMARDs), received tofacitinib 5 mg twice daily for three months. Levels of basal and cytokine-induced phosphorylated STATs and total STAT1 and STAT3 in peripheral blood monocytes, T cells and B cells were measured by flow cytometry. mRNA expression of JAKs, STATs and suppressors of cytokine signaling (SOCS) were measured from peripheral blood mononuclear cells (PBMCs) by quantitative PCR. Association of baseline signaling profile with treatment response (the change from baseline in disease activity score (DAS28)) was studied by calculating correlation coefficients.Results:Treatment with tofacitinib and csDMARDs decreased median DAS28 from 4.4 to 2.6 (p < 0.001). Tofacitinib significantly decreased cytokine-induced phosphorylation of all JAK-STAT pathways studied. Basal STAT1, STAT3, STAT4 and STAT5 phosphorylation in monocytes and/or T cells was downregulated by tofacitinib. No changes were observed in STAT1 and STAT3 protein levels, while gene expression of STAT3, STAT4, STAT5A, JAK1, JAK3 and all studied SOCSs was significantly suppressed. Baseline STAT phosphorylation levels in T cells and monocytes and SOCS3 expression in PBMCs correlated with treatment response.Conclusion:Tofacitinib suppresses multiple JAK-STAT pathways in RA patients in vivo. Baseline JAK-STAT signaling profile may be applicable as a prognostic marker for treatment response to tofacitinib.References:[1]McInnes, I. B., Buckley, C. D. & Isaacs, J. D. Cytokines in rheumatoid arthritis-shaping the immunological landscape. Nature Reviews Rheumatology vol. 12 63–68 (2016).[2]Schwartz, D. M., Bonelli, M., Gadina, M. & O’Shea, J. J. Type I/II cytokines, JAKs, and new strategies for treating autoimmune diseases. Nat. Rev. Rheumatol.12, 25–36 (2016).Acknowledgements:This study was supported by Pfizer Inc.Disclosure of Interests:Maaria Palmroth Consultant of: Pfizer and from 1/21 a part-time employee of MedEngine and consultant for Pfizer, Krista Kuuliala Grant/research support from: Pfizer, Ritva Peltomaa Speakers bureau: Boehringer Ingelmheim, Pfizer, Sanofi, Paid instructor for: Boehringer Ingelheim, Eli Lilly and Company, Janssen, Abbvie, UCB Pharma, Anniina Virtanen: None declared, Antti Kuuliala: None declared, Antti Kurttila: None declared, Anna Kinnunen: None declared, Marjatta Leirisalo-Repo: None declared, Olli Silvennoinen Speakers bureau: Pfizer, AbbVie, Pia Isomäki Speakers bureau: Abbvie, Eli Lilly and Company, Pfizer, Roche, Paid instructor for: Abbvie, Eli Lilly and Company, Pfizer, Roche, Grant/research support from: Pfizer

scholarly journals Quercetin Preservesβ-Cell Mass and Function in Fructose-Induced Hyperinsulinemia through Modulating Pancreatic Akt/FoxO1 Activation

2013 ◽  
Vol 2013 ◽  
pp. 1-12 ◽  
Author(s):  
Jian-Mei Li ◽  
Wei Wang ◽  
Chen-Yu Fan ◽  
Ming-Xing Wang ◽  
Xian Zhang ◽  
...  
Keyword(s):  
Serum Insulin ◽  
Cell Mass ◽  
Janus Kinase ◽  
Cytokine Signaling ◽  
Akt Phosphorylation ◽  
High Fructose ◽  
Stat3 Phosphorylation ◽  
And Function

Fructose-induced hyperinsulinemia is associated with insulin compensative secretion and predicts the onset of type 2 diabetes. In this study, we investigated the preservation of dietary flavonoid quercetin on pancreaticβ-cell mass and function in fructose-treated rats and INS-1β-cells. Quercetin was confirmed to reduce serum insulin and leptin levels and blockade islet hyperplasia in fructose-fed rats. It also prevented fructose-inducedβ-cell proliferation and insulin hypersecretion in INS-1β-cells. High fructose increased forkhead box protein O1 (FoxO1) expressionsin vivoandin vitro, which were reversed by quercetin. Quercetin downregulated Akt and FoxO1 phosphorylation in fructose-fed rat islets and increased the nuclear FoxO1 levels in fructose-treated INS-1β-cells. The elevated Akt phosphorylation in fructose-treated INS-1β-cells was also restored by quercetin. Additionally, quercetin suppressed the expression of pancreatic and duodenal homeobox 1 (Pdx1) and insulin gene (Ins1 and Ins2)in vivoandin vitro. In fructose-treated INS-1β-cells, quercetin elevated the reduced janus kinase 2/signal transducers and activators of transcription 3 (Jak2/Stat3) phosphorylation and suppressed the increased suppressor of cytokine signaling 3 (Socs3) expression. These results demonstrate that quercetin protectsβ-cell mass and function under high-fructose induction through improving leptin signaling and preserving pancreatic Akt/FoxO1 activation.

scholarly journals THU0067 JAK SELECTIVITY AND THE IMPACT ON CYTOKINE SIGNALING INHIBITION AT CLINICAL RHEUMATOID ARTHRITIS DOSES

2020 ◽  
Vol 79 (Suppl 1) ◽  
pp. 246.1-246
Author(s):  
P. Gonzalez-Traves ◽  
B. Murray ◽  
F. Campigotto ◽  
A. Meng ◽  
J. A. DI Paolo
Keyword(s):  
Rheumatoid Arthritis ◽  
T Cells ◽  
Clinical Efficacy ◽  
Janus Kinase ◽  
Cytokine Signaling ◽  
Gm Csf ◽  
Time Profiles ◽  
Concentration Time ◽  
Mean Concentration

Background:Janus kinase 1 (JAK1) inhibitors are efficacious in rheumatoid arthritis (RA). Despite having similar efficacy, in vitro studies have shown differences in JAK selectivity profiles for the small-molecule JAK inhibitors (JAKi) baricitinib (BARI), tofacitinib (TOFA), and upadacitinib (UPA).1For example, BARI and UPA are JAK1/JAK2 selective, while TOFA is JAK1/JAK3 selective, but each JAKi has some activity against other JAKs. As JAKs form signaling pairs, differences in selectivity could lead to distinct pharmacologic profiles that may impact clinical efficacy and safety.Objectives:As a first step to understand the basis of potential differences at therapeutic doses, we compared the selectivity and potency of filgotinib (FIL) and its major metabolite (MET) to those of BARI, TOFA, and UPA in cytokine-stimulated peripheral blood mononuclear cells (PBMCs) and whole blood (WB).Methods:PBMCs and WB from healthy donors were incubated in vitro with 8 doses of each JAKi, and levels of signal transducer and activator of transcription phosphorylation (pSTAT) were measured following cytokine stimulation. Half maximal inhibitory concentration (IC50) values were calculated in phenotypically sorted leukocyte populations by flow cytometry. Therapeutic dose relevance of the in vitro analyses was assessed using calculated mean concentration-time profiles from JAKi population pharmacokinetic data in RA subjects. For each JAKi, the time above IC50and average daily pSTAT inhibition were calculated for each cytokine/STAT pair in B cells, CD4+ T cells, CD8+ T cells, monocytes, and/or NK cells.Results:Cellular assays in PBMCs and WB showed dose-dependent inhibition of cytokine-induced pSTATs with all JAKi (correlation between the protein-adjusted IC50values from PBMCs and IC50values from WB, r2=0.98). Among the most potently inhibited pathways were JAK1/TYK2-dependent cytokine, interferon alpha (IFNα), and the JAK1/2-dependent cytokine, interleukin (IL)-6. FIL and MET had weaker potencies against JAK2/TYK2 (G-CSF/pSTAT3), JAK1/2 (IFNƴ/pSTAT1), and JAK2/2 (granulocyte-macrophage colony-stimulating factor [GM-CSF])-dependent pathways compared to JAK1/TYK2 (IFNα/pSTAT5). FIL and MET showed the greatest selectivity vs the JAK2/2 pathway (GM-CSF/pSTAT3) in monocytes.The mean concentration-time profiles and time above IC50over 24 hr for each cytokine/STAT pathway showed that JAK1/2 (IL-6/pSTAT1) and JAK1/TYK2 (IFNα/pSTAT1) pathways were strongly modulated with all tested JAKi. FIL (200 mg) showed similar activity in average target coverage and time above IC50to the approved low doses of TOFA (5 mg) and UPA (15 mg); conversely, FIL had reduced mean average inhibition and time above IC50levels against JAK1/2 (IFNƴ/pSTAT1), JAK1/3-dependent cytokines (IL-2, -4, and -15), JAK2/TYK2 (G-CSF/pSTAT3), and JAK2/2 (GM-CSF/pSTAT5)-dependent pathways compared to TOFA and UPA, and in certain cases to BARI (2 mg).Conclusion:Different JAKi modulate distinct cytokine pathways to varying degrees, and no agent potently and continuously inhibited an individual cytokine signaling pathway throughout the dosing interval. FIL (200 mg) showed a similar inhibition profile to TOFA, BARI, and UPA against the JAK1/TYK2- (IFNα/pSTAT1) or JAK1/2-dependent (IL-6/pSTAT1) responses, consistent with the role of these pathways in clinical efficacy.2However, FIL displayed a differentiated pharmacologic profile from the other JAKi, showing biologically reduced activity on the JAK1/2 (IFNγ)-, JAK1/3 (IL-2, -4 and -15)-, JAK2/TYK2 (G-CSF)-, and JAK2/2 (GM-CSF)-dependent pathways, which play important roles in hematopoiesis and immune function. These data suggest that FIL (200 mg) may have less impact on a subset of homeostatic immune functions signaling via JAK2 and JAK3 than those observed at the clinically approved doses of TOFA (5 mg and 10 mg), UPA (15 mg), and BARI (4 mg).References:[1]McInnes IB, et al. Arthritis Res Ther. 2019;21:183.[2]Banerjee S, et al. Drugs. 2017;77:521-546.Disclosure of Interests:Paqui Gonzalez-Traves Employee of: Gilead, Bernard Murray Employee of: Gilead, Federico Campigotto Employee of: Gilead, Amy Meng Shareholder of: Gilead Sciences, Employee of: Gilead, Julie A. Di Paolo Employee of: Gilead

Inhibition of JAK2/STAT Signaling by Degrasyn through a Novel Mechanism.

Blood ◽  
2006 ◽  
Vol 108 (11) ◽  
pp. 3423-3423
Author(s):  
Vaibhav Kapuria ◽  
Geoffrey Bartholomeusz ◽  
William Bornmann ◽  
Ling Y. Kong ◽  
Moshe Talpaz ◽  
...  
Keyword(s):  
Kinase Inhibitor ◽  
Sh2 Domain ◽  
Janus Kinase ◽  
Cytokine Receptor ◽  
In Vivo Studies ◽  
Pcr Analysis ◽  
Stat3 Phosphorylation ◽  
Stat Pathway

Abstract Janus Kinase 2 (JAK2) is a cytokine receptor associated tyrosine kinase. Cytokine stimulation results in JAK2 activation and tyrosine phosphorylation of the cytokine receptor. Cytosolic SH2 domain containing proteins, such as the signal transducer and activator of transcription 3 (STAT3) are recruited to phospho-tyrosine residues on the activated cytokine receptor, and phosphorylated by JAK2 to form stable dimers, followed by their translocation to the nucleus where they function as transcription factors. Deregulation of the JAK-STAT pathway is seen in several epithelial tumors and many hematological malignancies. Recent studies demonstrate that an activating mutation in the pseudokinase domain of JAK2 (V617F) underlies hematological disorders like polycythemia vera. Therefore, inhibition of JAK2 may have therapeutic significance in many cancers. The tryphostin AG490 is the most widely studied inhibitor of JAK2, which inhibits tumor cell growth and increases sensitivity to apoptotic stimuli in vitro. However, in vivo studies with AG490 have been less promising due to its poor pharmacology and requirement for high concentrations to achieve significant anti-tumor activity. To identify a more effective inhibitor of the JAK2-STAT pathway, we screened over 300 analogues of AG490 for their ability to inhibit IL-6 dependent activation of STAT3. A lead compound, Degrasyn (WP1130), was identified from this screen that inhibited IL-6 mediated STAT3 activation at low microM concentrations. Preliminary studies using in vitro kinase assays revealed that Degrasyn is a weak JAK2 kinase inhibitor despite being a strong suppressor of STAT3 activation, suggesting a different mechanism of inhibition of the JAK2-STAT pathway. We show that Degrasyn inhibits STAT3 phosphorylation by inducing the down-regulation of JAK2 protein without affecting STAT3. The loss of JAK2 protein via Degrasyn is a rapid and irreversible process. A decrease in JAK2 protein levels is observed as early as 30 minutes after treatment with near complete loss of JAK2 after 2 hours of Degrasyn incubation. While other tyrosine kinases are not affected, both wild type and mutant (V617F) forms of JAK2 are equally down-regulated by Degrasyn. Loss of JAK2 protein by Degrasyn is not blocked by inhibition of calpain or serine/threonine proteases or by inhibition of the proteosomal or lysosomal pathway. Real-Time PCR analysis of JAK2 transcript levels after Degrasyn treatment showed no significant change, suggesting a direct effect of Degrasyn on the JAK2 protein itself. Recent studies suggest that Degrasyn alters the cytoplasmic compartmentalization of JAK2, sequestering the kinase in an insoluble fraction. In vivo studies show that Degrasyn has significant anti-tumor effects against models of leukemia and lymphoma. These results suggest that Degrasyn induces JAK2 degradation by a unique mechanism and may be useful in treating tumors and diseases where the JAK2 kinase plays a pivotal role.

Comparison of In Vitro and In Vivo Effects of Infliximab on Cytokine Production in Proliferating CD4+ T Cells in Patients with Rheumatoid Arthritis

2015 ◽  
Vol 1 (2) ◽  
pp. 122-128
Author(s):  
Syuichi Koarada ◽  
Yuri Sadanaga ◽  
Natsumi Nagao ◽  
Satoko Tashiro ◽  
Rie Suematsu ◽  
...  
Keyword(s):  
Rheumatoid Arthritis ◽  
T Cells ◽  
Cd4 T Cells ◽  
Cytokine Production

scholarly journals Preferential and persistent impact of acute HIV-1 infection on CD4+ iNKT cells in colonic mucosa

2021 ◽  
Vol 118 (46) ◽  
pp. e2104721118
Author(s):  
Dominic Paquin-Proulx ◽  
Kerri G. Lal ◽  
Yuwadee Phuang-Ngern ◽  
Matthew Creegan ◽  
Andrey Tokarev ◽  
...  
Keyword(s):  
T Cells ◽  
Peripheral Blood ◽  
Colonic Mucosa ◽  
Inkt Cells ◽  
Elevated Expression ◽  
Acute Hiv ◽  
The Impact ◽  
Hiv 1

Acute HIV-1 infection (AHI) results in the widespread depletion of CD4+ T cells in peripheral blood and gut mucosal tissue. However, the impact on the predominantly CD4+ immunoregulatory invariant natural killer T (iNKT) cells during AHI remains unknown. Here, iNKT cells from peripheral blood and colonic mucosa were investigated during treated and untreated AHI. iNKT cells in blood were activated and rapidly depleted in untreated AHI. At the time of peak HIV-1 viral load, these cells showed the elevated expression of cell death–associated transcripts compared to preinfection. Residual peripheral iNKT cells suffered a diminished responsiveness to in vitro stimulation early into chronic infection. Additionally, HIV-1 DNA, as well as spliced and unspliced viral RNA, were detected in iNKT cells isolated from blood, indicating the active infection of these cells in vivo. The loss of iNKT cells occurred from Fiebig stage III in the colonic mucosa, and these cells were not restored to normal levels after initiation of ART during AHI. CD4+ iNKT cells were depleted faster and more profoundly than conventional CD4+ T cells, and the preferential infection of CD4+ iNKT cells over conventional CD4+ T cells was confirmed by in vitro infection experiments. In vitro data also provided evidence of latent infection in iNKT cells. Strikingly, preinfection levels of peripheral blood CD4+ iNKT cells correlated directly with the peak HIV-1 load. These findings support a model in which iNKT cells are early targets for HIV-1 infection, driving their rapid loss from circulation and colonic mucosa.

scholarly journals Decreased MiR-128-3p alleviates the progression of rheumatoid arthritis by up-regulating the expression of TNFAIP3

2018 ◽  
Vol 38 (4) ◽  
Author(s):  
Zhongbin Xia ◽  
Fanru Meng ◽  
Ying Liu ◽  
Yuxuan Fang ◽  
Xia Wu ◽  
...  
Keyword(s):  
Rheumatoid Arthritis ◽  
T Cells ◽  
Peripheral Blood ◽  
Potential Role ◽  
Enzyme Linked Immunosorbent Assay ◽  
Normal Person ◽  
Synovial Joint ◽  
Peripheral Blood Mononuclear

Background: Rheumatoid arthritis (RA) is a inflammatory disease that characterized with the destruction of synovial joint, which could induce disability. Inflammatory response mediated the RA. It has been reported that MiR-128-3p is significantly increased in RA, while the potential role was still unclear. Methods: T cells in peripheral blood mononuclear cell (PBMC) were isolated from the peripheral blood from people of RA and normal person were used. Real-time PCR was performed to detect the expression of MiR-128-3p, while the protein expression of tumor necrosis factor-α-induced protein 3 (TNFAIP3) was determined using Western blot. The levels of IL-6 and IL-17 were measured using enzyme-linked immunosorbent assay (ELISA). The expression of CD69 and CD25 was detected using flow cytometry. The RA mouse model was constructed for verification of the role of MiR-128-3p. Results: The expression of MiR-128-3p was significantly increased, while TNFAIP3 was decreased, the levels of IL-6 and IL-17 were also increased in the T cells of RA patients. Down-regulated MiR-128-3p significantly suppressed the expression of p-IkBα and CD69, and CD25in T cells. MiR-128-3p targets TNFAIP3 to regulate its expression. MiR-128-3p knockdown significantly suppressed the activity of nuclear factor κB (NF-κB) and T cells by up-regulating TNFAIP3, while cells co-transfected with si-TNFAIP3 abolished the effects of MiR-128-3p knockdown. The in vivo experiments verified the potential role of MiR-128-3p on RA. Conclusion: Down-regulated MiR-128-3p significantly suppressed the inflammation response of RA through suppressing the activity of NF-κB pathway, which was mediated by TNFAIP3.

scholarly journals SOCS1/SOCS3 Immune Axis Modulates Synthetic Perturbations in IL6 Biological Circuit for Dynamical Cellular Response

2020 ◽  
Author(s):  
Bhavnita Soni ◽  
Shailza Singh
Keyword(s):  
Signaling Pathway ◽  
Cellular Response ◽  
Inflammatory Cytokine ◽  
Cytokine Expression ◽  
Janus Kinase ◽  
Cytokine Signaling ◽  
Macrophage Phenotype ◽  
Regulatory Circuit ◽  
Stat Pathway

AbstractMacrophage phenotype plays a crucial role in the pathogenesis of Leishmanial infection. Pro-inflammatory cytokines are the key regulators that eliminate the infection induced by Janus kinase/signal transducer and activator of transcription (JAK/STAT) pathway. Suppressor of cytokine signaling (SOCS) is a well-known negative feedback regulator of JAK/STAT pathway. However, change in expression levels of SOCS in correlation with the establishment of infection is not well understood. Mathematical modeling of IL6 signaling pathway have helped identified the role of SOCS1 in establishment of infection. Furthermore, the ratio of SOCS1 and SOCS3 has been quantified both in silico as well as in vitro, indicating an immune axis which governs the macrophage phenotype during L. major infection. The ability of SOCS1 protein to inhibit the JAK/STAT1 signaling pathway and thereby decreasing pro-inflammatory cytokine expression makes it a strong candidate for therapeutic intervention. Using synthetic biology approaches, peptide based immuno-regulatory circuit have been designed to target the activity of SOCS1 which can restore pro-inflammatory cytokine expression during infection.

Expression of CD10 by Human T Cells That Undergo Apoptosis Both In Vitro and In Vivo

Blood ◽  
1999 ◽  
Vol 94 (9) ◽  
pp. 3067-3076 ◽  
Author(s):  
Giovanna Cutrona ◽  
Nicolò Leanza ◽  
Massimo Ulivi ◽  
Giovanni Melioli ◽  
Vito L. Burgio ◽  
...  
Keyword(s):  
T Cells ◽  
Peripheral Blood ◽  
Ex Vivo ◽  
Lymphoid Cells ◽  
Normal Peripheral Blood ◽  
Apoptotic Process ◽  
Cd10 Expression ◽  
T Cell Lines

Abstract This study shows that human postthymic T cells express CD10 when undergoing apoptosis, irrespective of the signal responsible for initiating the apoptotic process. Cells from continuous T-cell lines did not normally express CD10, but became CD10+ when induced into apoptosis by human immunodeficiency virus (HIV) infection and exposure to CD95 monoclonal antibody, etoposide, or staurosporin. Inhibitors of caspases blocked apoptosis and CD10 expression. Both CD4+ and CD8+ T cells purified from normal peripheral blood expressed CD10 on apoptotic induction. CD10 was newly synthesized by the apoptosing cells because its expression was inhibited by exposure to cycloheximide and CD10 mRNA became detectable by reverse transcription-polymerase chain reaction in T cells cultured under conditions favoring apoptosis. To show CD10 on T cells apoptosing in vivo, lymph node and peripheral blood T cells from HIV+ subjects were used. These suspensions were composed of a substantial, although variable, proportion of apoptosing T cells that consistently expressed CD10. In contrast, CD10+ as well as spontaneously apoptosing T cells were virtually absent in peripheral blood from normal individuals. Collectively, these observations indicate that CD10 may represent a reliable marker for identifying and isolating apoptosing T cells in vitro and ex vivo and possibly suggest novel functions for surface CD10 in the apoptotic process of lymphoid cells.

scholarly journals Targeting JAK/STAT pathway in Takayasu’s arteritis

2020 ◽  
Vol 79 (7) ◽  
pp. 951-959 ◽  
Author(s):  
Paul Régnier ◽  
Alexandre Le Joncour ◽  
Anna Maciejewski-Duval ◽  
Anne-Claire Desbois ◽  
Cloé Comarmond ◽  
...  
Keyword(s):  
T Cells ◽  
Cd8 T Cells ◽  
Takayasu’S Arteritis ◽  
Signalling Pathway ◽  
Janus Kinase ◽  
Type I Interferons ◽  
Type I ◽  
Takayasu's Arteritis

ObjectiveTakayasu’s arteritis (TAK) is a large vessel vasculitis with important infiltration of proinflammatory T cells in the aorta and its main branches, but its aetiology is still unknown. Our work aims to explore the involvement of Janus Kinase/Signal Transducers and Activators of Transcription (JAK/STAT) signalling pathway in proinflammatory T cells differentiation and disease activity of TAK.MethodsWe analysed transcriptome and interferons gene signatures of fluorescence-activated cell sorting (FACS-sorted) CD4+ and CD8+ T cells from healthy donors (HD) and in 25 TAK (median age of 37.6 years including 21 active TAK with National Institutes of Health (NIH) score >1). Then we tested, in vitro and in vivo, the effects of JAK inhibitors (JAKinibs) in TAK.ResultsTranscriptome analysis showed 248 and 432 significantly dysregulated genes for CD4+ and CD8+ samples between HD and TAK, respectively. Among dysregulated genes, we highlighted a great enrichment for pathways linked to type I and type II interferons, JAK/STAT and cytokines/chemokines-related signalling in TAK. We confirmed by Real Time Reverse Transcription Polymerase Chain Reaction (RT-qPCR) the upregulation of type I interferons gene signature in TAK as compared with HD. JAKinibs induced both in vitro and in vivo a significant reduction of CD25 expression by CD4+ and CD8+ T cells, a significant decrease of type 1 helper T cells (Th1) and Th17 cells and an increase of Tregs cells in TAK. JAKinibs also decreased C reactive protein level, NIH score and corticosteroid dose in TAK patients.ConclusionsJAK/STAT signalling pathway is critical in the pathogenesis of TAK and JAKinibs may be a promising therapy.

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