title: Selective inhibition of JAK2/STAT1 signaling and iNOS expression mediates the anti-inflammatory effects of coniferyl aldehyde.
abstract: Urgent needs still exist for selective control of excessive inflammation. Despite the therapeutic potential of natural compounds against inflammation-associated chronic conditions, lack of specific molecular targets renders these bioactive compounds difficult for further development. Here we examined the bioactivity of coniferyl aldehyde (CA), a natural phenolic compound found in several dietary substances and medicinal plants, elucidating its efficacy both in vivo and in vitro with underlying molecular mechanisms. IFN-γ/TNF-α-stimulated human keratinocytes and lipopolysaccharide (LPS)-stimulated murine macrophages were used to examine the effect of CA in vitro and to elucidate the underlying mechanisms. In vivo models of phorbol 12-myristate 13-acetate (TPA)-induced ear edema and carrageenan (CRG)-induced paw edema were employed to investigate the topical and systemic anti-inflammatory effects of CA, respectively. CA significantly reduced nitric oxide (NO) production and inducible nitric oxide synthase (iNOS) expression in LPS-stimulated macrophages. While nuclear factor-κB (NF-κB) and mitogen-activated protein kinase (MAPKs) pathways, the representative cellular pathways for iNOS induction, were not affected by CA, phosphorylation of Janus kinase 2 (JAK2) and signal Transducers and Activators of Transcription 1 (STAT1) and subsequent nuclear translocation of p-STAT1 were significantly decreased by CA. The effect of CA on JAK2-STAT1-iNOS axis was also observed in human keratinocytes stimulated with IFN-γ/TNF-α. Topical application of CA to mice produced significant protection against TPA-induced ear edema along with suppressed epidermal hyperproliferation and leucocyte infiltration. Systemic administration of CA significantly reduced CRG-induced paw edema in rats, where CRG-induced iNOS expression and STAT1 phosphorylation were decreased by CA. In summary, CA has significant anti-inflammatory properties both in vitro and in vivo, mediated by significant selective inhibition of JAK2-STAT1-iNOS signaling. CA is an attractive novel candidate for treating inflammatory diseases associated with excessive production of NO.
authors.affiliation: College of Pharmacy Institute of Pharmaceutical Science and Technology, Hanyang University, Ansan, Republic of Korea.
authors.forename: Muhammad
authors.initials: M
authors.lastname: Akram
authors.affiliation: College of Pharmacy Institute of Pharmaceutical Science and Technology, Hanyang University, Ansan, Republic of Korea.
authors.forename: Kyeong-A
authors.initials: KA
authors.lastname: Kim
authors.affiliation: College of Pharmacy Institute of Pharmaceutical Science and Technology, Hanyang University, Ansan, Republic of Korea.
authors.forename: Eun-Sun
authors.initials: ES
authors.lastname: Kim
authors.affiliation: College of Pharmacy Institute of Pharmaceutical Science and Technology, Hanyang University, Ansan, Republic of Korea.
authors.forename: Young-Jun
authors.initials: YJ
authors.lastname: Shin
authors.affiliation: College of Pharmacy Institute of Pharmaceutical Science and Technology, Hanyang University, Ansan, Republic of Korea.
authors.forename: Dabi
authors.initials: D
authors.lastname: Noh
authors.affiliation: College of Pharmacy Institute of Pharmaceutical Science and Technology, Hanyang University, Ansan, Republic of Korea.
authors.forename: Eunji
authors.initials: E
authors.lastname: Kim
authors.affiliation: College of Pharmacy Institute of Pharmaceutical Science and Technology, Hanyang University, Ansan, Republic of Korea.
authors.forename: Jeong-Hyeon
authors.initials: JH
authors.lastname: Kim
authors.affiliation: Sheffield Institute for Translational Neuroscience, University of Sheffield, Sheffield, England, United Kingdom.
authors.forename: Arshad
authors.initials: A
authors.lastname: Majid
authors.affiliation: College of Pharmacy, Ajou University, Suwon, Republic of Korea.
authors.forename: Sun-Young
authors.initials: SY
authors.lastname: Chang
authors.affiliation: College of Pharmacy Institute of Pharmaceutical Science and Technology, Hanyang University, Ansan, Republic of Korea. Electronic address: jinkikim@hanyang.ac.kr.
authors.forename: Jin-Ki
authors.initials: JK
authors.lastname: Kim
authors.affiliation: College of Pharmacy Institute of Pharmaceutical Science and Technology, Hanyang University, Ansan, Republic of Korea. Electronic address: onbae@hanyang.ac.kr.
authors.forename: Ok-Nam
authors.initials: ON
authors.lastname: Bae
mesh_terms: D000171:Acrolein / Q000031:analogs & derivatives* / Q000494:pharmacology / Q000627:therapeutic use; D000818:Animals; D000893:Anti-Inflammatory Agents / Q000494:pharmacology / Q000627:therapeutic use*; D002351:Carrageenan; D002460:Cell Line; D015536:Down-Regulation / Q000187:drug effects*; D004423:Ear / Q000473:pathology; D004487:Edema / Q000139:chemically induced / Q000188:drug therapy* / Q000235:genetics / Q000276:immunology; D006801:Humans; D007249:Inflammation / Q000139:chemically induced / Q000188:drug therapy* / Q000235:genetics / Q000276:immunology; D053614:Janus Kinase 2 / Q000037:antagonists & inhibitors / Q000276:immunology*; D008070:Lipopolysaccharides / Q000276:immunology; D008264:Macrophages / Q000187:drug effects / Q000276:immunology; D008297:Male; D051379:Mice; D008813:Mice, Inbred ICR; D009569:Nitric Oxide / Q000276:immunology; D052247:Nitric Oxide Synthase Type II / Q000235:genetics* / Q000276:immunology; D000067996:RAW 264.7 Cells; D017207:Rats, Sprague-Dawley; D050794:STAT1 Transcription Factor / Q000037:antagonists & inhibitors / Q000276:immunology*; D015398:Signal Transduction / Q000187:drug effects; D013755:Tetradecanoylphorbol Acetate / Q000031:analogs & derivatives
chemical_list: D000893:Anti-Inflammatory Agents; D008070:Lipopolysaccharides; D050794:STAT1 Transcription Factor; C075384:coniferaldehyde; D009569:Nitric Oxide; C016658:phorbolol myristate acetate; D000171:Acrolein; D002351:Carrageenan; D052247:Nitric Oxide Synthase Type II; D053614:Janus Kinase 2; D013755:Tetradecanoylphorbol Acetate
keywords: Anti-inflammatory activity; Coniferyl aldehyde; JAK2-STAT1; Nitric oxide