title: In Vitro and In Vivo Anti-Allergic and Anti-Inflammatory Effects of eBV, a Newly Developed Derivative of Bee Venom, through Modulation of IRF3 Signaling Pathway in a Carrageenan-Induced Edema Model.
abstract: BACKGROUND
  Bee venom (BV), a type of toxin extracted from honeybees (Apis mellifera), has been empirically and widely used to treat inflammatory diseases throughout Asia. Essential BV (eBV) was developed by removing phospholipase A2 (PLA2) and histamine to lower occurrence of allergic reaction. This study investigated the anti-allergic and anti-inflammatory activities of eBV in vitro and in vivo and its underlying mechanism of action.
  
  
  METHODS
  The anti-inflammatory potential of eBV was assessed in vivo using a carrageenan-induced paw edema model. To further investigate the mechanism by which eBV exerts anti-allergic and anti-inflammatory effects, compound 48/80-stimulated RBL-2H3 cells and lipopolysaccharide (LPS)-stimulated RAW 264.7 murine macrophage cells were studied in vitro.
  
  
  RESULTS
  Release of β-hexosaminidase and histamine was increased by eBV in a dose-dependent manner, but these levels were lower in eBV compared to original BV at the same concentration. In addition, eBV suppressed compound 48/80-induced expression of tumor necrosis factor-α (TNF-α) and interleukin-1β (IL-1β) in RBL-2H3 cells. eBV was also shown to suppress nitric oxide (NO) production by down-regulating mRNA expression and subsequent protein expression of inflammatory mediators in LPS-induced RAW 264.7 cells. Phosphorylation of activators and signal transducers of transcription 1/interferon regulatory factor 3 (STAT1/IRF3) was attenuated by eBV treatment. eBV significantly inhibited carrageenan-induced acute edema in vivo. Serum levels of prostaglandin E2 (PGE2), TNF-α, and IL-1β were also down-regulated by eBV.
  
  
  CONCLUSIONS
  These results demonstrate that eBV inhibits allergic and inflammatory response by reducing inflammatory mediator production via regulation of the STAT1/IRF3 signaling pathway, suggesting that eBV is a feasible candidate for regulation of allergic-inflammatory response in complementary and alternative medicine.
authors.affiliation: Jaseng Spine and Joint Research Institute, Jaseng Medical Foundation, Seoul, Republic of Korea.
authors.forename: Hwa-Jin
authors.initials: HJ
authors.lastname: Chung
authors.affiliation: Jaseng Spine and Joint Research Institute, Jaseng Medical Foundation, Seoul, Republic of Korea.
authors.forename: Jinho
authors.initials: J
authors.lastname: Lee
authors.affiliation: Jaseng Spine and Joint Research Institute, Jaseng Medical Foundation, Seoul, Republic of Korea.
authors.forename: Joon-Shik
authors.initials: JS
authors.lastname: Shin
authors.affiliation: Jaseng Spine and Joint Research Institute, Jaseng Medical Foundation, Seoul, Republic of Korea.
authors.forename: Me-Riong
authors.initials: MR
authors.lastname: Kim
authors.affiliation: Jaseng Spine and Joint Research Institute, Jaseng Medical Foundation, Seoul, Republic of Korea.
authors.forename: Wonil
authors.initials: W
authors.lastname: Koh
authors.affiliation: Jaseng Spine and Joint Research Institute, Jaseng Medical Foundation, Seoul, Republic of Korea.
authors.forename: Min-Jeong
authors.initials: MJ
authors.lastname: Kim
authors.affiliation: Jaseng Spine and Joint Research Institute, Jaseng Medical Foundation, Seoul, Republic of Korea.
authors.forename: Jae-Woong
authors.initials: JW
authors.lastname: Lee
authors.affiliation: Jaseng Spine and Joint Research Institute, Jaseng Medical Foundation, Seoul, Republic of Korea.
authors.forename: Eun Jee
authors.initials: EJ
authors.lastname: Kim
authors.affiliation: Jaseng Spine and Joint Research Institute, Jaseng Medical Foundation, Seoul, Republic of Korea.
authors.forename: In-Hee
authors.initials: IH
authors.lastname: Lee
authors.affiliation: College of Pharmacy, Natural Products Research Institute, Seoul National University, Seoul, Republic of Korea.
authors.forename: Won Kyung
authors.initials: WK
authors.lastname: Kim
authors.affiliation: Jaseng Spine and Joint Research Institute, Jaseng Medical Foundation, Seoul, Republic of Korea.
authors.forename: Yoon Jae
authors.initials: YJ
authors.lastname: Lee
authors.affiliation: College of Pharmacy, Natural Products Research Institute, Seoul National University, Seoul, Republic of Korea.
authors.forename: Sang Kook
authors.initials: SK
authors.lastname: Lee
authors.affiliation: Jaseng Spine and Joint Research Institute, Jaseng Medical Foundation, Seoul, Republic of Korea.
authors.forename: In-Hyuk
authors.identifier: http://orcid.org/0000-0002-5020-6723
authors.initials: IH
authors.lastname: Ha
mesh_terms: D000818:Animals; D001514:Bee Venoms / Q000627:therapeutic use*; D015153:Blotting, Western; D002351:Carrageenan / Q000494:pharmacology; D002851:Chromatography, High Pressure Liquid; D015232:Dinoprostone / Q000378:metabolism; D004195:Disease Models, Animal; D004487:Edema / Q000139:chemically induced / Q000188:drug therapy*; D006632:Histamine / Q000378:metabolism; D006967:Hypersensitivity / Q000188:drug therapy*; D007249:Inflammation / Q000188:drug therapy*; D050838:Interferon Regulatory Factor-3 / Q000037:antagonists & inhibitors*; D015847:Interleukin-4 / Q000378:metabolism; D008297:Male; D051379:Mice; D000067996:RAW 264.7 Cells / Q000187:drug effects; D051381:Rats; D017207:Rats, Sprague-Dawley; D060888:Real-Time Polymerase Chain Reaction; D050794:STAT1 Transcription Factor / Q000187:drug effects; D015398:Signal Transduction / Q000187:drug effects*; D014409:Tumor Necrosis Factor-alpha / Q000378:metabolism
chemical_list: D001514:Bee Venoms; D050838:Interferon Regulatory Factor-3; C494233:Irf3 protein, mouse; D050794:STAT1 Transcription Factor; C494080:Stat1 protein, mouse; D014409:Tumor Necrosis Factor-alpha; D015847:Interleukin-4; D006632:Histamine; D002351:Carrageenan; D015232:Dinoprostone