THE INVOLVEMENT OF KAV001 IN INHIBITION OF LPS/P. GINGIVALIS-INDUCED CYTOKINES

Abstract

TNF-a is an important cytokine mediator of inflammation which suggests that inhibition of TNF-a activity may provide potential for clinical application. Recent data indicated that treatment of both human and mouse cells with Kavain significantly modulates P. gingivalis- and LPS-induced TNF-α expression. In order to obtain a selective analog with optimized biological activity and structural physico-chemical properties of Kavain, Kavain analogs were designed and synthesized and found one Kavain analogue (named Kav001) that is similar to Kavain but soluble and does not induce a significant toxicity. Both studies in vitro and in vivo treatment by Kav001 showed stronger biological function as compared to Kavain. Furthermore, most mouse bone marrow macrophages up-regulated Bcl-6 while down-regulating LITAF expression after treatment with Kav001 for 36 h. Consequently, this led to an extension of macrophage pseudopods due to its immune response to P.g. infection/ LPS stimulation. we further found that Kav001 not only inhibits TNF-α, but also IL-1β, IL-6, caspase 1 and neutrophil infiltration in response to LPS. However, this phenomenon cannot be observed when macrophages were treated with LPS plus Kavain. We believe that Kav001 may mediate a novel link between Kav001 and LPS-induced vi inflammation and may be used as a key inhibitor to LPS-induced inflammation/inflammatory disease.