Chemically Modified Curcumins Suppress Human Mononuclear Cell Cytokines

Objective: To determine the effect of curcumin and chemically modified curcumin compound (CMC-2.5) on the production of cytokines (TNF-α, MIP-1α, IL-1β, and IL-6) and MMP-9 in cultured human mononuclear cells treated with endotoxin (lipopolysaccharide, LPS) produced by P. gingivalis, a periodontal-relevant cell culture model. Methods: Human monocytes, isolated and purified by density gradient centrifugation, were cultured in serum-free media for 18 hours in the absence or presence of LPS (50 ng/ml). Cells were treated with 2μm, 5μm curcumin or CMC-2.5. The conditioned media was analyzed for cytokine levels with ELISA. MMP-9 levels were measured using gelatin zymography. Results: MMP-9 levels were reduced more by CMC-2.5 than by curcumin when compared to cells with LPS only. TNF-α levels were reduced by 13% and 46% with 2 or 5 μM curcumin; and the reduction was 45% and 79% with 2 or 5 μM of CMC-2.5. Similarly, IL-1β levels were reduced by 57% and 83% with 2 or 5 μM curcumin, and both 2 and 5 μM of CMC-2.5 decreased IL-1β levels by more than 90%, essentially back to non-LPS values. Curcumin at both concentrations and 2 μM CMC-2.5 did not have significant effects on IL-6 and MIP-1α levels. However, 5 μM CMC reduced both IL-6 and MIP-1α levels by 33% and 19% respectively. Conclusion: Curcumin is a highly pleiotropic anti-inflammatory molecule with poor solubility and systemic bioavailability. Our lab has developed novel curcumin derivatives with increased solubility and retained/enhanced therapeutic effects. We have demonstrated that CMC-2.5 has significant inhibitory effect, better than its mother compound curcumin, on inflammatory cytokines and MMP-9. The therapeutic potential of these drugs may help to prevent tissue damage and bone loss in patients with periodontal disease or other inflammatory diseases. Supported by NYSTAR grant #A43273 from CAT, SBU, Chem-Master Intl., Inc., and SB-Summer-Research-Fellowship-Program.