title: Interleukin 6 production by lipopolysaccharide-stimulated human fibroblasts is potently inhibited by naphthoquinone (vitamin K) compounds.
abstract: Naphthoquinone vitamins (vitamins K) are widely recognized for their role in the gamma-carboxylation of specific glutamyl residues in coagulation, anti-coagulation and extra-hepatic proteins. Recently, however, there have been reports that these compounds can exert actions other than those normally associated with protein gamma-carboxylation. These observations suggest that naphthoquinones may have effects on the production of inflammatory mediators including cytokines. Fibroblasts are now recognized as a rich source of cytokines and we have examined the effect of various naphthoquinones on the production of interleukin 6 (IL-6) by lipopolysaccharide-stimulated human gingival fibroblasts. Compounds examined in this study include: phylloquinone (K1), menaquinone-4 (K2), menadione (K3), 2,3-dimethoxy-1,4-naphthoquinone (DMK) and a synthetic product of vitamin K catabolism, 2-methyl, 3-(2'methyl)-hexanoic acid-1,4-naphthoquinone (KCAT). All of these compounds are capable of inhibiting IL-6 production with a rank order of potency: KCAT > K3 > DMK > K2 > K1. The most potent compound, KCAT, inhibited IL-6 production with an IC50 of 3 x 10(-7)M. The mechanism of action of these naphthoquinones on fibroblast IL-6 production is unknown. Given that K3 and KCAT are inactive in the gamma-carboxylation reaction, we suggest that this activity is not essential for the inhibition of IL-6 production and that activity may be related to the redox capacity of these naphthoquinones.
authors.affiliation: Department of Oral and Maxillofacial Surgery, Eastman Dental Institute for Oral Healthcare Sciences, London.
authors.forename: K
authors.initials: K
authors.lastname: Reddi
authors.forename: B
authors.initials: B
authors.lastname: Henderson
authors.forename: S
authors.initials: S
authors.lastname: Meghji
authors.forename: M
authors.initials: M
authors.lastname: Wilson
authors.forename: S
authors.initials: S
authors.lastname: Poole
authors.forename: C
authors.initials: C
authors.lastname: Hopper
authors.forename: M
authors.initials: M
authors.lastname: Harris
authors.forename: S J
authors.initials: SJ
authors.lastname: Hodges
mesh_terms: D002478:Cells, Cultured; D005347:Fibroblasts / Q000187:drug effects*; D005881:Gingiva / Q000166:cytology / Q000187:drug effects / Q000378:metabolism; D006801:Humans; D015850:Interleukin-6 / Q000096:biosynthesis*; D008070:Lipopolysaccharides / Q000037:antagonists & inhibitors / Q000494:pharmacology*; D013268:Stimulation, Chemical; D014812:Vitamin K / Q000494:pharmacology*
chemical_list: D015850:Interleukin-6; D008070:Lipopolysaccharides; D014812:Vitamin K