title: Daidzein enhances efferocytosis via transglutaminase 2 and augmentation of Rac1 activity.
abstract: Clearance of apoptotic cells, termed "efferocytosis", is the mechanism required to prevent secondary necrosis and release of proinflammatory cytokines. Defective efferocytosis is cumulatively regarded as one of mechanisms in the development of autoimmune and chronic inflammatory diseases. Our previous finding showed that ethanolic extract from Glycine tomentella Hayata (GTH) can enhance mouse macrophage RAW264.7 efferocytosis (clearance of apoptotic cells). We have demonstrated that the major components of GTH are daidzein, catechin, epicatechin and naringin. Here, we explore the potential of each component in modulating efferocytic capability. For this, RAW264.7 cells were cultured with CFDA-stained apoptotic cells and assayed by flow cytometry. We found that daidzein is the main component of GTH, and it can enhance RAW264.7 efferocytosis dose-dependently. Moreover, the enhancive effect of daidzein on macrophage efferocytic capability is accompanied by increased transglutaminase 2 (TG2) at both mRNA and protein levels. TG2 knockdown attenuated daidzein increased macrophage efferocytic capability. After treatment with daidzein, increased phosphorylation was observed in Erk, but not in p38 and JNK. Finally, we report that after daidzein treatment, Rac1 activity was markedly increased and the mitochondrial membrane potential was decreased, which may contribute to efferocytosis. Taken together, these data suggest that enhancement of macrophage efferocytic capability by daidzein treatment was mainly through up-regulation of TG2 expression and Rac1 activity. Daidzein may have the therapeutical potential in the treatment of inflammatory diseases.
authors.affiliation: Institute of Microbiology and Immunology, Chung Shan Medical University, Taichung, Taiwan.
authors.forename: Jia-Hau
authors.initials: JH
authors.lastname: Yen
authors.affiliation: School of Health Diet and Industry Management, Chung Shan Medical University, Taichung, Taiwan.
authors.forename: Deng-Jye
authors.initials: DJ
authors.lastname: Yang
authors.affiliation: Institute of Microbiology and Immunology, Taiwan.
authors.forename: Meng-Chi
authors.initials: MC
authors.lastname: Chen
authors.affiliation: Department of Medical Laboratory Science and Biotechnology, China Medical University and Hospital, Taichung, Taiwan.
authors.forename: Wu
authors.initials: W
authors.lastname: Yi-Ying
authors.affiliation: Institute of Microbiology and Immunology, Taiwan.
authors.forename: Yu-Fan
authors.initials: YF
authors.lastname: Hsieh
authors.affiliation: Institute of Microbiology and Immunology, Taiwan.
authors.forename: Yueh-Mei
authors.initials: YM
authors.lastname: Cheng
authors.affiliation: Department of Allergy, Immunology and Rheumatology, Taichung Veterans General Hospital, Taiwan.
authors.forename: Wen-Nan
authors.initials: WN
authors.lastname: Huang
authors.affiliation: Department of Biochemistry and Molecular Biology, Apoptosis and Genomics Research Group, Hungarian Academy of Sciences, Debrecen, Hungary.
authors.forename: Zsuzsa
authors.initials: Z
authors.lastname: Szondy
authors.affiliation: Institute of Microbiology and Immunology, Taiwan; Department of Internal Medicine, Chung Shan Medical University Hospital, Taichung, Taiwan. Electronic address: gjt@csmu.edu.tw.
authors.forename: Gregory J
authors.initials: GJ
authors.lastname: Tsay
mesh_terms: D000818:Animals; D002460:Cell Line; D019204:GTP-Binding Proteins / Q000378:metabolism*; D006801:Humans; D007529:Isoflavones / Q000494:pharmacology*; D020935:MAP Kinase Signaling System / Q000187:drug effects; D053078:Membrane Potential, Mitochondrial / Q000187:drug effects; D051379:Mice; D010587:Phagocytosis / Q000187:drug effects*; D010766:Phosphorylation / Q000187:drug effects; D000091345:Protein Glutamine gamma Glutamyltransferase 2; D011503:Transglutaminases / Q000378:metabolism*; D015854:Up-Regulation / Q000187:drug effects; D020830:rac1 GTP-Binding Protein / Q000378:metabolism*
chemical_list: D007529:Isoflavones; C004742:daidzein; D000091345:Protein Glutamine gamma Glutamyltransferase 2; D011503:Transglutaminases; D019204:GTP-Binding Proteins; D020830:rac1 GTP-Binding Protein
keywords: Daidzein; Efferocytosis; Erk; Mitochondrial membrane potential; Rac1