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  • 1
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    Selective oral ROCK2 inhibitor down-regulates IL-21 and IL-17 secretion in human T cells via STAT3-dependent mechanism (2014)
    National Academy of Sciences
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    Publication Date: 2014-11-10
    Print ISSN: 0027-8424
    Electronic ISSN: 1091-6490
    Topics: Biology , Medicine , Natural Sciences in General
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  • 2
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    Scaffold protein Disc large homolog 1 is required for T-cell receptor-induced activation of regulatory T-cell function (2012)
    National Academy of Sciences
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    Publication Date: 2012-01-17
    Print ISSN: 0027-8424
    Electronic ISSN: 1091-6490
    Topics: Biology , Medicine , Natural Sciences in General
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  • 3
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    ROCK2 controls IL-21 and IL-17 secretion in humans [Immunology and Inflammation] (2014)
    National Academy of Sciences
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    Publication Date: 2014-11-26
    Description: Rho-associated kinase 2 (ROCK2) regulates the secretion of proinflammatory cytokines and the development of autoimmunity in mice. Data from a phase 1 clinical trial demonstrate that oral administration of KD025, a selective ROCK2 inhibitor, to healthy human subjects down-regulates the ability of T cells to secrete IL-21 and IL-17 by...
    Print ISSN: 0027-8424
    Electronic ISSN: 1091-6490
    Topics: Biology , Medicine , Natural Sciences in General
    Published by National Academy of Sciences
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  • 4
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    Scaffold protein Disc large homolog 1 is required for T-cell receptor-induced activation of regulatory T-cell function [Immunology] (2012)
    National Academy of Sciences
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    Publication Date: 2012-02-01
    Description: Foxp3+CD4+CD25high regulatory T cell (Treg) suppression of inflammation depends on T-cell receptor-mediated Nuclear Factor of Activated T cells c1 (NFATc1) activation with reduced Akt activity. We investigated the role of the scaffold protein Disc large homolog 1 (Dlgh1) in linking the T-cell receptor to this unique signaling outcome. The Treg immunological synapse (IS) recruited fourfold more Dlgh1 than conventional CD4+ T-cell IS. Tregs isolated from patients with active rheumatoid arthritis, or treated with tumor necrosis factor-α, displayed reduced function and diminished Dlgh1 recruitment to the IS. Furthermore, Dlgh1 silencing abrogated Treg function, impaired NFATc1 activation, reduced phosphatase and tensin homolog levels, and increased Akt activation. Dlgh1 operates independently of the negative feedback pathway mediated by the related adapter protein Carma1 and thus presents an array of unique targets to selectively manipulate Treg function.
    Print ISSN: 0027-8424
    Electronic ISSN: 1091-6490
    Topics: Biology , Medicine , Natural Sciences in General
    Published by National Academy of Sciences
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  • 5
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    The growth factor progranulin binds to TNF receptors and is therapeutic against inflammatory arthritis in mice (2011)
    American Association for the Advancement of Science (AAAS)
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    Publication Date: 2011-03-12
    Description: The growth factor progranulin (PGRN) has been implicated in embryonic development, tissue repair, tumorigenesis, and inflammation, but its receptors remain unidentified. We report that PGRN bound directly to tumor necrosis factor receptors (TNFRs) and disturbed the TNFalpha-TNFR interaction. PGRN-deficient mice were susceptible to collagen-induced arthritis, and administration of PGRN reversed inflammatory arthritis. Atsttrin, an engineered protein composed of three PGRN fragments, exhibited selective TNFR binding. PGRN and Atsttrin prevented inflammation in multiple arthritis mouse models and inhibited TNFalpha-activated intracellular signaling. Collectively, these findings demonstrate that PGRN is a ligand of TNFR, an antagonist of TNFalpha signaling, and plays a critical role in the pathogenesis of inflammatory arthritis in mice. They also suggest new potential therapeutic interventions for various TNFalpha-mediated pathologies and conditions, including rheumatoid arthritis.〈br /〉〈br /〉〈a href="https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3104397/" target="_blank"〉〈img src="https://static.pubmed.gov/portal/portal3rc.fcgi/4089621/img/3977009" border="0"〉〈/a〉   〈a href="https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3104397/" target="_blank"〉This paper as free author manuscript - peer-reviewed and accepted for publication〈/a〉〈br /〉〈br /〉〈span class="detail_caption"〉Notes: 〈/span〉Tang, Wei -- Lu, Yi -- Tian, Qing-Yun -- Zhang, Yan -- Guo, Feng-Jin -- Liu, Guang-Yi -- Syed, Nabeel Muzaffar -- Lai, Yongjie -- Lin, Edward Alan -- Kong, Li -- Su, Jeffrey -- Yin, Fangfang -- Ding, Ai-Hao -- Zanin-Zhorov, Alexandra -- Dustin, Michael L -- Tao, Jian -- Craft, Joseph -- Yin, Zhinan -- Feng, Jian Q -- Abramson, Steven B -- Yu, Xiu-Ping -- Liu, Chuan-ju -- AI43542/AI/NIAID NIH HHS/ -- AR040072/AR/NIAMS NIH HHS/ -- AR050620/AR/NIAMS NIH HHS/ -- AR053210/AR/NIAMS NIH HHS/ -- GM061710/GM/NIGMS NIH HHS/ -- R01 AI030165/AI/NIAID NIH HHS/ -- R01 AI030165-20/AI/NIAID NIH HHS/ -- R01 GM061710/GM/NIGMS NIH HHS/ -- R01 GM061710-08/GM/NIGMS NIH HHS/ -- New York, N.Y. -- Science. 2011 Apr 22;332(6028):478-84. doi: 10.1126/science.1199214. Epub 2011 Mar 10.〈br /〉〈span class="detail_caption"〉Author address: 〈/span〉Department of Orthopaedic Surgery, New York University School of Medicine and NYU Hospital for Joint Diseases, New York, NY 10003, USA.〈br /〉〈span class="detail_caption"〉Record origin:〈/span〉 〈a href="http://www.ncbi.nlm.nih.gov/pubmed/21393509" target="_blank"〉PubMed〈/a〉
    Keywords: Adolescent ; Adult ; Aged ; Animals ; Anti-Inflammatory Agents, Non-Steroidal/metabolism/pharmacology/therapeutic use ; Arthritis, Experimental/*drug therapy/*immunology/pathology/physiopathology ; Cartilage, Articular/metabolism/pathology ; Female ; Humans ; Intercellular Signaling Peptides and ; Proteins/chemistry/genetics/*metabolism/therapeutic use ; Ligands ; Male ; Mice ; Mice, Inbred Strains ; Mice, Knockout ; Mice, Transgenic ; Middle Aged ; Protein Interaction Domains and Motifs ; Receptors, Tumor Necrosis Factor, Type I/genetics/*metabolism ; Receptors, Tumor Necrosis Factor, Type II/genetics/*metabolism ; Recombinant Fusion Proteins/metabolism/pharmacology/therapeutic use ; Recombinant Proteins/therapeutic use ; Signal Transduction ; T-Lymphocytes, Regulatory/immunology/physiology ; Tumor Necrosis Factor-alpha/*metabolism ; Young Adult
    Print ISSN: 0036-8075
    Electronic ISSN: 1095-9203
    Topics: Biology , Chemistry and Pharmacology , Computer Science , Medicine , Natural Sciences in General , Physics
    Published by American Association for the Advancement of Science (AAAS)
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  • 6
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    Protein kinase C-theta mediates negative feedback on regulatory T cell function (2010)
    American Association for the Advancement of Science (AAAS)
    Details
    Publication Date: 2010-03-27
    Description: T cell receptor (TCR)-dependent regulatory T cell (Treg) activity controls effector T cell (Teff) function and is inhibited by the inflammatory cytokine tumor necrosis factor-alpha (TNF-alpha). Protein kinase C-theta (PKC-theta) recruitment to the immunological synapse is required for full Teff activation. In contrast, PKC-theta was sequestered away from the Treg immunological synapse. Furthermore, PKC-theta blockade enhanced Treg function, demonstrating PKC-theta inhibits Treg-mediated suppression. Inhibition of PKC-theta protected Treg from inactivation by TNF-alpha, restored activity of defective Treg from rheumatoid arthritis patients, and enhanced protection of mice from inflammatory colitis. Treg freed of PKC-theta-mediated inhibition can function in the presence of inflammatory cytokines and thus have therapeutic potential in control of inflammatory diseases.〈br /〉〈br /〉〈a href="https://www.ncbi.nlm.nih.gov/pmc/articles/PMC2905626/" target="_blank"〉〈img src="https://static.pubmed.gov/portal/portal3rc.fcgi/4089621/img/3977009" border="0"〉〈/a〉   〈a href="https://www.ncbi.nlm.nih.gov/pmc/articles/PMC2905626/" target="_blank"〉This paper as free author manuscript - peer-reviewed and accepted for publication〈/a〉〈br /〉〈br /〉〈span class="detail_caption"〉Notes: 〈/span〉Zanin-Zhorov, Alexandra -- Ding, Yi -- Kumari, Sudha -- Attur, Mukundan -- Hippen, Keli L -- Brown, Maryanne -- Blazar, Bruce R -- Abramson, Steven B -- Lafaille, Juan J -- Dustin, Michael L -- P01 AI056299/AI/NIAID NIH HHS/ -- PN2 EY016586/EY/NEI NIH HHS/ -- PN2 EY016586-06/EY/NEI NIH HHS/ -- R01 AI055037/AI/NIAID NIH HHS/ -- R01 AI055037-06A1/AI/NIAID NIH HHS/ -- R01 AI43542/AI/NIAID NIH HHS/ -- R01 HL056067/HL/NHLBI NIH HHS/ -- R37 AI043542/AI/NIAID NIH HHS/ -- R37 AI043542-12/AI/NIAID NIH HHS/ -- New York, N.Y. -- Science. 2010 Apr 16;328(5976):372-6. doi: 10.1126/science.1186068. Epub 2010 Mar 25.〈br /〉〈span class="detail_caption"〉Author address: 〈/span〉Molecular Pathogenesis Program, Helen and Martin Kimmel Center for Biology and Medicine, Skirball Institute of Biomolecular Medicine, Department of Pathology, New York University School of Medicine, New York, NY 10016, USA.〈br /〉〈span class="detail_caption"〉Record origin:〈/span〉 〈a href="http://www.ncbi.nlm.nih.gov/pubmed/20339032" target="_blank"〉PubMed〈/a〉
    Keywords: Adolescent ; Adult ; Aged ; Animals ; Arthritis, Rheumatoid/immunology ; Colitis/immunology/prevention & control ; Enzyme Inhibitors/pharmacology ; Feedback, Physiological ; Humans ; Immunological Synapses/*immunology ; Inflammation/*immunology ; Interferon-gamma/metabolism ; Isoenzymes/antagonists & inhibitors/*metabolism ; Lymphocyte Activation ; Mice ; Mice, Inbred C57BL ; Middle Aged ; Protein Kinase C/antagonists & inhibitors/*metabolism ; Receptors, Antigen, T-Cell/immunology/metabolism ; Signal Transduction ; T-Lymphocyte Subsets/*immunology/metabolism ; T-Lymphocytes, Regulatory/*immunology/metabolism ; Tumor Necrosis Factor-alpha/metabolism ; Young Adult
    Print ISSN: 0036-8075
    Electronic ISSN: 1095-9203
    Topics: Biology , Chemistry and Pharmacology , Computer Science , Medicine , Natural Sciences in General , Physics
    Published by American Association for the Advancement of Science (AAAS)
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  • 7
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    Targeted Rho-associated kinase 2 inhibition suppresses murine and human chronic GVHD through a Stat3-dependent mechanism (2016)
    American Society of Hematology
    Details
    Publication Date: 2016-04-28
    Description: Key Points The ROCK2 inhibitor, KD025, decreases chronic GVHD pathology in multiple murine models. KD025 inhibits STAT3 phosphorylation to decrease RORγt and Bcl6 expression in both murine and human cells.
    Print ISSN: 0006-4971
    Electronic ISSN: 1528-0020
    Topics: Biology , Medicine
    Published by American Society of Hematology
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  • 8
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    KD025-208: A Phase 2a Study of KD025 for Patients with Chronic Graft Versus Host Disease (cGVHD) — Pharmacodynamics and Updated Results (2018)
    American Society of Hematology
    Details
    Publication Date: 2018-11-29
    Description: Introduction: cGVHD remains a leading cause of post-transplant morbidity / mortality, exhibiting features of both autoimmune and fibrotic diseases across multiple organ systems. cGVHD is characterized by an imbalance between effector and regulatory arms of the immune system that results in over production of inflammatory cytokines including IL-17 and IL-21. Moreover, a persistent reduction in the number of regulatory T (Treg) cells limits the ability of the immune system to re-calibrate this pro-inflammatory environment. KD025 is an orally available Rho-associated coiled-coil kinase 2 (ROCK2) selective inhibitor. In vitro data have demonstrated that KD025 (1) attenuates IL-21 and IL-17 secretion in human CD4+ T cells via STAT3, IRF4 and RORγt regulation, and (2) leads to increased percentages of Foxp3+ CD4+ T cells via a STAT5-dependent mechanism and upregulates the suppressive function of human Tregs. These MOA suggest that KD025 modulates immune homeostasis by shifting the Th17/Treg balance towards a Treg phenotype. No studies have examined KD025 effects in patients with dysregulation associated with high Th17 and low Tregs. Methods: KD025-208 enrolled 3 cohorts (C1: 200 mg QD, C2: 200 mg BID, and C3: 400 mg QD) of patients (pts) with cGVHD after 1-3 prior lines of systemic therapy. Treatment is in 28-Day cycles until disease progression or unacceptable toxicity. The primary endpoint is the overall response rate (ORR) (% pts achieving partial response (PR) or complete response (CR)) as per 2014 NIH response criteria. Secondary endpoints include duration of response (DOR) and corticosteroid (CS) dose reductions. Exploratory endpoints include Lee Symptom Scale (LSS) score and pharmacodynamics (PD). Peripheral blood samples were collected from all pts at Cycle 1 Day 1 (C1D1), C2D1, C4D1 and C6D25, and shipped at ambient temperature. PBMC were isolated and kept frozen until analysis. The intracellular expression of IL-17A and FOXP3 on viable CD3+ CD4+ cells was determined by using multicolor flow cytometry. Results: Data as of 6-June-2018 for C1 and C2 are included; C3 data will be available 4Q18. 17 and 16 pts were enrolled in C1 and C2 with median age 52 years, median time from cGVHD diagnosis to KD025 treatment of 19 months, and a median of 3 prior treatment regimens. Median duration of treatment was 37 (C1) and 33 (C2) weeks (wks). KD025 demonstrated an ORR of 65% in C1 and 63% in C2. ORR in key subgroups is shown below. Responses were rapid (76% achieved at first assessment at 8 wks) and durable with 82% (C1) and 50% (C2) of responders sustaining response for ≥20 wks. Responses including CRs were observed across all affected organ systems except lung (mouth, eyes, joints/ fascia, skin, upper GI, lower GI, esophagus, liver). A previously reported lung PR was deemed on review to be IPF with no cGVHD involvement. During treatment with KD025, median CS dose was reduced by 44% (C1) and 26% (C2). 76% and 56% of pts achieved CS dose reductions. 5/33 (15%) pts discontinued CS. 65% (C1) and 50% (C2) achieved a meaningful improvement (≥7 point reduction) in the LSS score, including both responders (67%) and non-responders (42%). KD025 has been well tolerated. AEs reported were generally consistent with those expected in pts with advanced cGVHD treated with CS. Common AEs were increased LFTs (42%), URI (33%), anemia (27%), nausea (24%), diarrhea (24%) and fatigue (21%). Increased LFTs did not lead to treatment discontinuation, commonly occurred prior to KD025 dosing and were often considered attributable to cGVHD. Grade 3+ LFT increases were reported for 6 (18%) pts. 2 pts discontinued treatment due to AEs possibly related to KD025 (headache, diarrhea). SAEs were reported for 11/33 (33%) pts, none considered related to KD025 treatment. There was no apparent increased risk of infection. Exploratory PD analyses of PBMCs across C1 and C2 revealed an early increase in the percentage of CD4+ Treg cells by C2D1 of KD025 treatment with a simultaneous decrease in Th17 cells. The percentage of CD4+ Tregs continued to increase, and the Th17 cells continued to decrease through C4D1 and C6D25. Conclusion: Treatment with KD025 has demonstrated encouraging clinical responses in cGVHD pts with little toxicity. Responses have been clinically meaningful as evidenced by durability, reductions in CS doses and improvement in LSS score. Exploratory PD data indicate treatment with KD025 may modulate immune homeostasis by restoring the Th17/Treg balance. Figure. Figure. Disclosures Jagasia: Incyte Corporation: Membership on an entity's Board of Directors or advisory committees. Salhotra:Kadmon Corporation, LLC: Consultancy. Bachier:Sanofi: Speakers Bureau; Seattle Genetics: Speakers Bureau. Weisdorf:Seattle Genetics: Consultancy; Pharmacyclics: Consultancy; Equillium: Consultancy; SL Behring: Consultancy; FATE: Consultancy. Green:Kadmon Corporation, LLC: Employment. Schueller:Kadmon Corporation, LLC: Employment. Zanin-Zhorov:Kadmon Corporation, LLC: Employment. Weiss:Kadmon Corporation, LLC: Employment. Eiznhamer:Kadmon Corporation, LLC: Employment. Aggarwal:Kadmon Corporation, LLC: Employment. Blazar:Kadmon Corporation, LLC: Consultancy, Research Funding. Lee:Takeda: Research Funding; Kadmon: Research Funding; Amgen: Consultancy, Research Funding; Mallinckrodt: Honoraria; Incyte: Consultancy; Pfizer: Consultancy; Onyx: Research Funding.
    Print ISSN: 0006-4971
    Electronic ISSN: 1528-0020
    Topics: Biology , Medicine
    Published by American Society of Hematology
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  • 9
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    A Selective and Potent Rock 2 Inhibitor (KD025) Decreases Human STAT3-Dependent IL-21 and IL-17 Production and Experimental Chronic Graft-Versus-Host Disease (cGVHD) (2014)
    American Society of Hematology
    Details
    Publication Date: 2014-12-06
    Description: Pro-inflammatory IL-17-producing T cells termed Th17 are actively involved in the pathogenesis of GVHD. The development and function of Th17 cells is dependent on activation of STAT3, RORgt and IRF4 transcription factors. Aberrant activation of Rho-associated kinase 2 (ROCK2) leads to induction of IL-17 and IL-21 secretion via IRF4-dependent mechanism. KD025, is a potent and selective ROCK2 inhibitor, which when given to healthy human subjects down-regulated the ability of T cells to secrete IL-21 and IL-17, but not interferon (IFN)-g, in response to TCR stimulation in vitro (Figure 1). KD025 inhibits STAT3 phosphorylation which supports RORgt, Th17 generation, and IL-21 production. Concurrently, KD025 increases STAT5 phosphorylation and Treg suppressor function in a dose-responsive fashion. KD025 treatment therefore shifts Th17/Treg balance. Th17 cells have been linked to in vivo pro-inflammatory responses, antibody production, and fibrosis. Conversely, Tregs can offset these pathogenic responses. Given the profile of KD025, we tested the effects of this inhibitor on cGVHD pathogenesis in a multi-organ system rodent model of disease that is driven by IL-21 responses and is associated with lung, liver and intestinal fibrosis. We observed that Th17/Rorc deficient T cells are unable to mediate cGVHD pathogenesis. In mice with established cGVHD, therapy was initiated with 30, 100, or 150 mg/kg/dose of KD025 daily from d28-56. Treated mice had a dose dependent decrease in the development of pathogenic pulmonary function as determined by whole body plethysmography (Figure 2) which correlated with a marked reduction of antibody deposition in the lungs of treated mice to levels comparable to non-cGVHD controls. KD025 administration also resulted in a 2-fold decrease in collagen deposition in the lungs of mice treated with the highest dose of KD025. The spleens of mice treated with 150 mg/kg dose of KD025 had a decrease in the frequency of germinal centers compared to the vehicle treated mice. To determine the selective role of STAT3 on T cells, mice were transplanted with wildtype (WT) bone marrow (BM) and WT or inducible STAT3 deficient T cells. In parallel cohorts, the role of STAT3 in BM-derived B cells, precursors of germinal center B cells, was examined using WT vs inducible STAT3 deficient BM cells + WT T cells. We demonstrate here that mice transplanted with inducible STAT3 deficient T cells or BM cells had pulmonary function comparable to the healthy negative controls, suggesting that STAT3 is a potential therapeutic target in both T and B cells is necessary for the development of cGVHD and providing mechanistic insight into how KD025 may ameliorate active cGVHD. Studies are in progress to test KD025 administration in a murine scleroderma model using a minor histocompatibility antigen disparate donor-recipient strain that we have shown to be dependent upon STAT3 expressing donor T cells and a STAT3 inhibitor in both cGVHD models described here. Together, these data demonstrate that KD025 is effective at decreasing STAT3-dependent production of IL-21 and IL-17 and the use of KD025 is a potentially novel therapeutic intervention for the treatment of cGVHD. Fig 1 Oral administration of KD025 down-regulates the IL-17 and IL-21 secretion in human PBMCs upon stimulation ex vivo. Human PBMCs were purified from healthy human subjects before and after oral administration of KD025 at doses 40, 120, 240, 320 and stimulated ex vivo. Cytokine secretion was determined after 48 hours by ELISA. Fig 1. Oral administration of KD025 down-regulates the IL-17 and IL-21 secretion in human PBMCs upon stimulation ex vivo. Human PBMCs were purified from healthy human subjects before and after oral administration of KD025 at doses 40, 120, 240, 320 and stimulated ex vivo. Cytokine secretion was determined after 48 hours by ELISA. Fig 2 KD025 is an effective therapy for established murine cGVHD. Mice were given KD025 (150 mg/kg) d.28-56. PFTs indicate normal resistance, elastance and better compliance. Lung Ig deposition and fibrosis were comparable to BM controls. Fig 2. KD025 is an effective therapy for established murine cGVHD. Mice were given KD025 (150 mg/kg) d.28-56. PFTs indicate normal resistance, elastance and better compliance. Lung Ig deposition and fibrosis were comparable to BM controls. Disclosures No relevant conflicts of interest to declare.
    Print ISSN: 0006-4971
    Electronic ISSN: 1528-0020
    Topics: Biology , Medicine
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  • 10
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    Toll-like receptors and their ligands control mesenchymal stem cell functions (2006)
    American Society of Hematology
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    Publication Date: 2006-10-12
    Description: Mesenchymal stem cells (MSCs) are widespread in adult organisms and may be involved in tissue maintenance and repair as well as in the regulation of hematopoiesis and immunologic responses. Thus, it is important to discover the factors controlling MSC renewal and differentiation. Here we report that adult MSCs express functional Toll-like receptors (TLRs), confirmed by the responses of MSCs to TLR ligands. Pam3Cys, a prototypic TLR-2 ligand, augmented interleukin-6 secretion by MSC, induced nuclear factor κ B (NF-κB) translocation, reduced MSC basal motility, and increased MSC proliferation. The hallmark of MSC function is the capacity to differentiate into several mesodermal lineages. We show herein that Pam3Cys inhibited MSC differentiation into osteogenic, adipogenic, and chondrogenic cells while sparing their immunosuppressive effect. Our study therefore shows that a TLR ligand can antagonize MSC differentiation triggered by exogenous mediators and consequently maintains the cells in an undifferentiated and proliferating state in vitro. Moreover, MSCs derived from myeloid factor 88 (MyD88)–deficient mice lacked the capacity to differentiate effectively into osteogenic and chondrogenic cells. It appears that TLRs and their ligands can serve as regulators of MSC proliferation and differentiation and might affect the maintenance of MSC multipotency.
    Print ISSN: 0006-4971
    Electronic ISSN: 1528-0020
    Topics: Biology , Medicine
    Published by American Society of Hematology
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