title: Phytocomponent 4-hydroxy-3-methoxycinnamaldehyde ablates T-cell activation by targeting protein kinase C-θ and its downstream pathways.
abstract: Autoreactive T-cell responses have a crucial role in the pathology and clinical course of autoimmune diseases. Therefore, controlling the activation of these cells is an important strategy for developing therapies and therapeutics. Here, we identified that 4-hydroxy-3-methoxycinnamaldehyde (4H3MC) has a therapeutic potential for T-cell activation by modulating protein kinase C-θ (PKCθ) and its downstream pathways. Pre- and post-treatment with 4H3MC prevented IL-2 release from human transformed and untransformed T cells at the micromolar concentrations without any cytotoxic effects, in fact more efficiently than its structural analogue 4-hydroxycinnamic acid-a previously reported T-cell inhibitor. In silico analysis showed that 4H3MC is a potential inhibitor of PKC isotypes, including PKCθ-a crucial PKC isotype in T cells. Consistently, 4H3MC significantly blocked PKC activity in vitro and also inhibited the phosphorylation of PKCθ in T cells. 4H3MC had no effect on TCR-mediated membrane-proximal-signalling events such as phosphorylation of Zap70. Instead, it attenuated the phosphorylation of mitogen-activated protein kinases (ERK and p38) and promoter activities of NF-κB, AP-1 and NFAT. Taken together, our results provide the evidences that 4H3MC may have curative potential as a novel immune modulator in a broad range of immunopathological disorders by modulating PKCθ activity.
authors: School of Life Sciences, Immune Synapse Research Center and Cell Dynamics Research Center, Gwangju Institute of Science and Technology, Gwangju 500-712, Korea.
authors: Uroos
authors: U
authors: Akber
authors: School of Life Sciences, Immune Synapse Research Center and Cell Dynamics Research Center, Gwangju Institute of Science and Technology, Gwangju 500-712, Korea.
authors: Bo-Ra
authors: BR
authors: Na
authors: Yoo-Seung
authors: YS
authors: Ko
authors: School of Life Sciences, Immune Synapse Research Center and Cell Dynamics Research Center, Gwangju Institute of Science and Technology, Gwangju 500-712, Korea.
authors: You-Seung
authors: YS
authors: Ko
authors: School of Life Sciences, Immune Synapse Research Center and Cell Dynamics Research Center, Gwangju Institute of Science and Technology, Gwangju 500-712, Korea.
authors: Hyun-Su
authors: HS
authors: Lee
authors: School of Life Sciences, Immune Synapse Research Center and Cell Dynamics Research Center, Gwangju Institute of Science and Technology, Gwangju 500-712, Korea.
authors: Hye-Ran
authors: HR
authors: Kim
authors: School of Life Sciences, Immune Synapse Research Center and Cell Dynamics Research Center, Gwangju Institute of Science and Technology, Gwangju 500-712, Korea.
authors: Min-Sung
authors: MS
authors: Kwon
authors: School of Life Sciences, Immune Synapse Research Center and Cell Dynamics Research Center, Gwangju Institute of Science and Technology, Gwangju 500-712, Korea.
authors: Zee-Yong
authors: ZY
authors: Park
authors: Division of Sport Science, College of Natural Sciences, Konkuk University, Chungbuk 380-702, Korea.
authors: Eun-Ju
authors: EJ
authors: Choi
authors: Department of Pathology, Wonkwang University School of Medicine, Iksan, Chonbuk 570-749, Korea.
authors: Weon-Cheol
authors: WC
authors: Han
authors: College of Pharmacy, Yeungnam University, Gyeongsan 712-749, Korea.
authors: Seung-Ho
authors: SH
authors: Lee
authors: Bioindustrial Process Research Center, KRIBB, Jeongeup 580-185, Korea. Electronic address: ohhm@kribb.re.kr.
authors: Hyun-Mee
authors: HM
authors: Oh
authors: School of Life Sciences, Immune Synapse Research Center and Cell Dynamics Research Center, Gwangju Institute of Science and Technology, Gwangju 500-712, Korea. Electronic address: cdjun@gist.ac.kr.
authors: Chang-Duk
authors: CD
authors: Jun
mesh_terms: D000097:Acetonitriles / Q000737:chemistry / Q000494:pharmacology*; D003373:Coumaric Acids / Q000494:pharmacology; D048049:Extracellular Signal-Regulated MAP Kinases / Q000378:metabolism; D006801:Humans; D007527:Isoenzymes / Q000378:metabolism*; D019169:Jurkat Cells; D008213:Lymphocyte Activation / Q000187:drug effects; D016328:NF-kappa B / Q000235:genetics / Q000378:metabolism; D050778:NFATC Transcription Factors / Q000235:genetics / Q000378:metabolism; D010766:Phosphorylation / Q000187:drug effects; D011401:Promoter Regions, Genetic / Q000235:genetics; D011422:Propionates; D011493:Protein Kinase C / Q000378:metabolism*; D000074121:Protein Kinase C-theta; D015398:Signal Transduction / Q000187:drug effects; D013601:T-Lymphocytes / Q000187:drug effects* / Q000276:immunology; D018808:Transcription Factor AP-1 / Q000235:genetics / Q000378:metabolism; D048051:p38 Mitogen-Activated Protein Kinases / Q000378:metabolism
chemical_list: D000097:Acetonitriles; D003373:Coumaric Acids; D007527:Isoenzymes; D016328:NF-kappa B; D050778:NFATC Transcription Factors; D011422:Propionates; D018808:Transcription Factor AP-1; C419311:hydroxy-3-phenoxybenzeneacetonitrile; C076233:PRKCQ protein, human; D011493:Protein Kinase C; D000074121:Protein Kinase C-theta; D048049:Extracellular Signal-Regulated MAP Kinases; D048051:p38 Mitogen-Activated Protein Kinases; C495469:p-coumaric acid
keywords: 4-Hydroxy-3-methoxycinnamaldehyde; IL-2; Immunosuppression; MAP kinase; PKCθ; T-cell activation