INTERLEUKIN-6 PRODUCTION BY LIPOPOLYSACCHARIDE-STIMULATED HUMAN FIBROBLASTS IS POTENTLY INHIBITED BY NAPHTHOQUINONE (VITAMIN-K) COMPOUNDS

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, Z-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 3x10(-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.