title: Sulforaphane and its methylcarbonyl analogs inhibit the LPS-stimulated inflammatory response in human monocytes through modulating cytokine production, suppressing chemotactic migration and phagocytosis in a NF-κB- and MAPK-dependent manner.
abstract: Sulforaphane [SF; 1-isothiocyanato-4-(methylsulfinyl)-butane], an aliphatic isothiocyanate (ITC) naturally derived from cruciferous vegetables and largely known for its chemopreventive potential also appears to possess anti-inflammatory potential. In this study, structural analogs of SF {compound 1 [1-isothiocyanato-4-(methylcarbonyl)-butane] and 2 [1-isothiocyanato-3-(methylcarbonyl)-propane]} containing a carbonyl group in place of the sulfinyl group in SF, were evaluated for their anti-inflammatory activities. In RAW 264.7 cells, the ITCs at non-toxic concentrations caused an inhibition of NO and prostaglandin E2 (PGE2) release through suppressing expression of inducible nitric oxide synthase (iNOS) and cyclooxygenase-2 (COX-2), as well as a reduction in matrix metalloproteinase-9 (MMP-9) expression, secretion and gelatinolytic activity. Further work performed on human monocytes isolated from blood of healthy donors revealed that the ITCs not only suppressed the expression and release of pro-inflammatory mediators IL-1β, IL-6, TNF-α and MMP-9, but also suppressed their antibody-independent phagocytic and chemotactic migratory abilities. These anti-inflammatory activities were mediated through suppression of the NF-κB and MAPK signaling pathways. In addition, the ITCs were revealed to interact with the cysteines in inhibitor of nuclear factor-κB kinase β subunit (IKKβ), which could contribute at least partly to the suppression of NF-κB signaling. In conclusion, results obtained in this study provide deeper insights into the anti-inflammatory properties of SF and its methylcarbonyl analogs and the underlying mechanisms. These compounds thus serve as promising candidates for clinical applications in controlling inflammatory conditions.
authors.affiliation: Department of Pharmacy, Faculty of Science, National University of Singapore, Republic of Singapore.
authors.forename: Shridhivya A
authors.initials: SA
authors.lastname: Reddy
authors.affiliation: Department of Pharmacy, Faculty of Science, National University of Singapore, Republic of Singapore.
authors.forename: Sandeep B
authors.initials: SB
authors.lastname: Shelar
authors.affiliation: SIgN (Singapore Immunology Network), A*STAR (Agency for Science, Technology and Research), Biopolis, Republic of Singapore.
authors.forename: Truong-Minh
authors.initials: TM
authors.lastname: Dang
authors.affiliation: Department of Pharmacy, Faculty of Science, National University of Singapore, Republic of Singapore.
authors.forename: Baxter Neng-Cun
authors.initials: BN
authors.lastname: Lee
authors.affiliation: Department of Pharmacy, Faculty of Science, National University of Singapore, Republic of Singapore.
authors.forename: Hong
authors.initials: H
authors.lastname: Yang
authors.affiliation: SIgN (Singapore Immunology Network), A*STAR (Agency for Science, Technology and Research), Biopolis, Republic of Singapore.
authors.forename: Siew-Min
authors.initials: SM
authors.lastname: Ong
authors.affiliation: Department of Pharmacy, Faculty of Science, National University of Singapore, Republic of Singapore.
authors.forename: Hui-Li
authors.initials: HL
authors.lastname: Ng
authors.affiliation: Department of Pharmacy, Faculty of Science, National University of Singapore, Republic of Singapore.
authors.forename: Wai-Keung
authors.initials: WK
authors.lastname: Chui
authors.affiliation: SIgN (Singapore Immunology Network), A*STAR (Agency for Science, Technology and Research), Biopolis, Republic of Singapore.
authors.forename: Siew-Cheng
authors.initials: SC
authors.lastname: Wong
authors.affiliation: Department of Pharmacy, Faculty of Science, National University of Singapore, Republic of Singapore. Electronic address: phaceh@nus.edu.sg.
authors.forename: Eng-Hui
authors.initials: EH
authors.lastname: Chew
mesh_terms: D000818:Animals; D000893:Anti-Inflammatory Agents / Q000494:pharmacology*; D002460:Cell Line; D002465:Cell Movement / Q000187:drug effects; D002470:Cell Survival / Q000187:drug effects; D002478:Cells, Cultured; D051546:Cyclooxygenase 2 / Q000235:genetics / Q000378:metabolism; D016207:Cytokines / Q000235:genetics / Q000378:metabolism; D015232:Dinoprostone / Q000378:metabolism; D057809:HEK293 Cells; D006801:Humans; D051550:I-kappa B Kinase / Q000378:metabolism; D017879:Isothiocyanates / Q000494:pharmacology*; D008070:Lipopolysaccharides; D020780:Matrix Metalloproteinase 9 / Q000378:metabolism; D051379:Mice; D020928:Mitogen-Activated Protein Kinases / Q000378:metabolism; D009000:Monocytes / Q000187:drug effects* / Q000378:metabolism / Q000502:physiology; D016328:NF-kappa B / Q000378:metabolism; D052247:Nitric Oxide Synthase Type II / Q000235:genetics / Q000378:metabolism; D009573:Nitrites / Q000378:metabolism; D010587:Phagocytosis / Q000187:drug effects; D013454:Sulfoxides
chemical_list: D000893:Anti-Inflammatory Agents; D016207:Cytokines; D017879:Isothiocyanates; D008070:Lipopolysaccharides; D016328:NF-kappa B; D009573:Nitrites; D013454:Sulfoxides; D052247:Nitric Oxide Synthase Type II; C496317:Nos2 protein, mouse; C077623:Ptgs2 protein, mouse; D051546:Cyclooxygenase 2; D051550:I-kappa B Kinase; D020928:Mitogen-Activated Protein Kinases; C579270:MMP9 protein, human; D020780:Matrix Metalloproteinase 9; C501830:Mmp9 protein, mouse; C016766:sulforaphane; D015232:Dinoprostone
keywords: Human monocytes; Inflammation; Isothiocyanates; MAPK; NF-κB