title: A dual character of flavonoids in influenza A virus replication and spread through modulating cell-autonomous immunity by MAPK signaling pathways.
abstract: Flavonoids are well known as a large class of polyphenolic compounds, which have a variety of physiological activities, including anti-influenza virus activity. The influenza A/WSN/33 infected A549 cells have been used to screen anti-influenza virus drugs from natural flavonoid compounds library. Unexpectedly, some flavonoid compounds significantly inhibited virus replication, while the others dramatically promoted virus replication. In this study, we attempted to understand these differences between flavonoid compounds in their antivirus mechanisms. Hesperidin and kaempferol were chosen as representatives of both sides, each of which exhibited the opposite effects on influenza virus replication. Our investigation revealed that the opposite effects produced by hesperidin and kaempferol on influenza virus were due to inducing the opposite cell-autonomous immune responses by selectively modulating MAP kinase pathways: hesperidin up-regulated P38 and JNK expression and activation, thus resulting in the enhanced cell-autonomous immunity; while kaempferol dramatically down-regulated p38 and JNK expression and activation, thereby suppressing cell-autonomous immunity. In addition, hesperidin restricted RNPs export from nucleus by down-regulating ERK activation, but kaempferol promoted RNPs export by up-regulating ERK activation. Our findings demonstrate that a new generation of anti-influenza virus drugs could be developed based on selective modulation of MAP kinase pathways to stimulate cell-autonomous immunity.
authors.affiliation: Protein &Peptide Pharmaceutical Laboratory, Institute of Biophysics, Chinese Academy of Science, Beijing 100101, China.
authors.forename: Wenjuan
authors.initials: W
authors.lastname: Dong
authors.affiliation: Protein &Peptide Pharmaceutical Laboratory, Institute of Biophysics, Chinese Academy of Science, Beijing 100101, China.
authors.forename: Xiuli
authors.initials: X
authors.lastname: Wei
authors.affiliation: Protein &Peptide Pharmaceutical Laboratory, Institute of Biophysics, Chinese Academy of Science, Beijing 100101, China.
authors.forename: Fayun
authors.initials: F
authors.lastname: Zhang
authors.affiliation: Facility of pathology, Institute of Biophysics, Chinese Academy of Science, Beijing 100101, China.
authors.forename: Junfeng
authors.initials: J
authors.lastname: Hao
authors.affiliation: Protein &Peptide Pharmaceutical Laboratory, Institute of Biophysics, Chinese Academy of Science, Beijing 100101, China.
authors.forename: Feng
authors.initials: F
authors.lastname: Huang
authors.affiliation: Protein &Peptide Pharmaceutical Laboratory, Institute of Biophysics, Chinese Academy of Science, Beijing 100101, China.
authors.forename: Chunling
authors.initials: C
authors.lastname: Zhang
authors.affiliation: Protein &Peptide Pharmaceutical Laboratory, Institute of Biophysics, Chinese Academy of Science, Beijing 100101, China.
authors.forename: Wei
authors.initials: W
authors.lastname: Liang
mesh_terms: D000818:Animals; D004261:DNA Replication / Q000187:drug effects; D004285:Dogs; D005419:Flavonoids / Q000494:pharmacology*; D006569:Hesperidin / Q000494:pharmacology; D006801:Humans; D007109:Immunity / Q000187:drug effects*; D009980:Influenza A virus / Q000187:drug effects*; D007251:Influenza, Human / Q000188:drug therapy* / Q000378:metabolism / Q000821:virology; D048031:JNK Mitogen-Activated Protein Kinases / Q000378:metabolism; D044949:Kaempferols / Q000494:pharmacology; D061985:Madin Darby Canine Kidney Cells; D020928:Mitogen-Activated Protein Kinases / Q000378:metabolism*; D009976:Orthomyxoviridae Infections / Q000188:drug therapy / Q000378:metabolism / Q000821:virology; D015398:Signal Transduction / Q000187:drug effects*; D014779:Virus Replication / Q000187:drug effects*; D048051:p38 Mitogen-Activated Protein Kinases / Q000378:metabolism
chemical_list: D005419:Flavonoids; D044949:Kaempferols; C006552:kaempferol; D006569:Hesperidin; D048031:JNK Mitogen-Activated Protein Kinases; D020928:Mitogen-Activated Protein Kinases; D048051:p38 Mitogen-Activated Protein Kinases