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      Immunosuppressive Activity of Daphnetin, One of Coumarin Derivatives, Is Mediated through Suppression of NF-κB and NFAT Signaling Pathways in Mouse T Cells

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          Abstract

          Daphnetin, a plant-derived dihydroxylated derivative of coumarin, is an effective compound extracted from a plant called Daphne Korean Nakai. Coumarin derivates were known for their antithrombotic, anti-inflammatory, and antioxidant activities. The present study was aimed to determine the immunosuppressive effects and the underlying mechanisms of daphnetin on concanavalin A (ConA) induced T lymphocytes in mice. We showed that, in vitro, daphnetin suppressed ConA-induced splenocyte proliferation, influenced production of the cytokines and inhibited cell cycle progression through the G0/G1 transition. The data also revealed that daphnetin could down-regulate activation of ConA induced NF-κB and NFAT signal transduction pathways in mouse T lymphocyte. In vivo, daphnetin treatment significantly inhibited the 2, 4- dinitrofluorobenzene (DNFB) -induced delayed type hypersensitivity (DTH) reactions in mice. Collectively, daphnetin had strong immunosuppressive activity both in vitro and in vivo, suggesting a potential role for daphnetin as an immunosuppressive agent, and established the groundwork for further research on daphnetin.

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          Metabolism in T cell activation and differentiation.

          Erika L Pearce (2010)
          When naïve or memory T cells encounter foreign antigen along with proper co-stimulation they undergo rapid and extensive clonal expansion. In mammals, this type of proliferation is fairly unique to cells of the adaptive immune system and requires a considerable expenditure of energy and cellular resources. While research has often focused on the roles of cytokines, antigenic signals, and co-stimulation in guiding T cell responses, data indicate that, at a fundamental level, it is cellular metabolism that regulates T cell function and differentiation and therefore influences the final outcome of the adaptive immune response. This review will focus on some earlier fundamental observations regarding T cell bioenergetics and its role in regulating cellular function, as well as recent work that suggests that manipulating the immune response by targeting lymphocyte metabolism could prove useful in treatments against infection and cancer. Copyright 2010 Elsevier Ltd. All rights reserved.
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            Protein Kinase C θ Affects Ca2+ Mobilization and NFAT Activation in Primary Mouse T Cells

            Christa Pfeifhofer-Obermair, Kurt Kofler, Thomas Gruber … (2003)
            Protein kinase C (PKC)θ is an established component of the immunological synapse and has been implicated in the control of AP-1 and NF-κB. To study the physiological function of PKCθ, we used gene targeting to generate a PKCθ null allele in mice. Consistently, interleukin 2 production and T cell proliferative responses were strongly reduced in PKCθ-deficient T cells. Surprisingly, however, we demonstrate that after CD3/CD28 engagement, deficiency of PKCθ primarily abrogates NFAT transactivation. In contrast, NF-κB activation was only partially reduced. This NFAT transactivation defect appears to be secondary to reduced inositol 1,4,5-trisphosphate generation and intracellular Ca2+ mobilization. Our finding suggests that PKCθ plays a critical and nonredundant role in T cell receptor–induced NFAT activation.
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              Ca2+/calmodulin-dependent protein kinase II (CaMKII) is activated by calmodulin with two bound calciums.

              Stephen Kennedy, Stephen Mayo, Stefan Mihalas … (2006)
              Changes in synaptic strength that underlie memory formation in the CNS are initiated by pulses of Ca2+ flowing through NMDA-type glutamate receptors into postsynaptic spines. Differences in the duration and size of the pulses determine whether a synapse is potentiated or depressed after repetitive synaptic activity. Calmodulin (CaM) is a major Ca2+ effector protein that binds up to four Ca2+ ions. CaM with bound Ca2+ can activate at least six signaling enzymes in the spine. In fluctuating cytosolic Ca2+, a large fraction of free CaM is bound to fewer than four Ca2+ ions. Binding to targets increases the affinity of CaM's remaining Ca2+-binding sites. Thus, initial binding of CaM to a target may depend on the target's affinity for CaM with only one or two bound Ca2+ ions. To study CaM-dependent signaling in the spine, we designed mutant CaMs that bind Ca2+ only at the two N-terminal or two C-terminal sites by using computationally designed mutations to stabilize the inactivated Ca2+-binding domains in the "closed" Ca2+-free conformation. We have measured their interactions with CaMKII, a major Ca2+/CaM target that mediates initiation of long-term potentiation. We show that CaM with two Ca2+ ions bound in its C-terminal lobe not only binds to CaMKII with low micromolar affinity but also partially activates kinase activity. Our results support the idea that competition for binding of CaM with two bound Ca2+ ions may influence significantly the outcome of local Ca2+ signaling in spines and, perhaps, in other signaling pathways.
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                Author and article information

                Contributors
                Jyothi Rengarajan: Role: Editor
                Journal
                Journal ID (nlm-ta): PLoS One
                Journal ID (iso-abbrev): PLoS ONE
                Journal ID (publisher-id): plos
                Journal ID (pmc): plosone
                Title: PLoS ONE
                Publisher: Public Library of Science (San Francisco, USA )
                ISSN (Electronic): 1932-6203
                Publication date Collection: 2014
                Publication date (Electronic): 6 May 2014
                Volume: 9
                Issue: 5
                Electronic Location Identifier: e96502
                Affiliations
                [1 ]Key Laboratory of Zoonosis, Ministry of Education, College of Veterinary Medicine, Jilin University, Changchun, People’s Republic of China
                [2 ]Department of Food Quality and Safety, College of Light Industry Economics and Management, Jilin University, Changchun, People’s Republic of China
                Emory University, United States of Amreica
                Author notes

                Competing Interests: The authors have declared that no competing interests exist.

                Conceived and designed the experiments: BCS XMD SG. Performed the experiments: BCS ZNW SSX GRH YX. Analyzed the data: YL SZ LLX. Wrote the paper: BCS SG.

                Article
                Publisher ID: PONE-D-13-49393
                DOI: 10.1371/journal.pone.0096502
                PMC ID: 4011761
                PubMed ID: 24800925
                SO-VID: 05add1f0-da7d-4348-b317-ec75dd57d6ca
                Copyright statement: Copyright @ 2014
                License:

                This is an open-access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited.

                History
                Date received : 25 November 2013
                Date accepted : 9 April 2014
                Page count
                Pages: 11
                Funding
                The authors are grateful for help received from the College of Veterinary Medicine of Jilin University. This study was supported by the National Nature Science Foundation of China (No . 31130053). The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript.
                Categories
                Subject: Research Article
                Subject: Physical Sciences
                Subject: Chemistry
                Subject: Phytochemistry
                Subject: Biology and Life Sciences
                Subject: Biochemistry
                Subject: Plant Biochemistry
                Subject: Phytochemicals
                Subject: Immunology
                Subject: Clinical Immunology
                Subject: Allergies
                Subject: Immunomodulation
                Subject: Toxicology
                Subject: Medicine and Health Sciences
                Subject: Clinical Medicine
                Subject: Research and Analysis Methods
                Subject: Model Organisms
                Subject: Animal Models
                Subject: Mouse Models

                ScienceOpen disciplines: Uncategorized
                Data availability:
                ScienceOpen disciplines: Uncategorized

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