Bisdemethoxycurcumin and Its Cyclized Pyrazole Analogue Differentially Disrupt Lipopolysaccharide Signalling in Human Monocyte-Derived Macrophages.

Several studies suggest that curcumin and related compounds possess antioxidant and anti-inflammatory properties including modulation of lipopolysaccharide- (LPS-) mediated signalling in macrophage cell models. We here investigated the effects of curcumin and the two structurally unrelated analogues GG6 and GG9 in primary human blood-derived macrophages as well as the signalling pathways involved. Macrophages differentiated from peripheral blood monocytes for 7 days were activated with LPS or selective Toll-like receptor agonists for 24 h. The effects of test compounds on cytokine production and immunophenotypes evaluated as CD80/CCR2 and CD206/CD163 subsets were examined by ELISA and flow cytometry. Signalling pathways were probed by Western blot. Curcumin (2.5-10 M) failed to suppress LPS-induced inflammatory responses. While GG6 reduced LPS-induced IB- degradation and showed a trend towards reduced interleukin-1 release, GG9 prevented the increase in proinflammatory CD80 macrophage subset, downregulation of the anti-inflammatory CD206/CD163 subset, increase in p38 phosphorylation, and increase in cell-bound and secreted interleukin-1 stimulated by LPS, at least in part through signalling pathways not involving Toll-like receptor 4 and nuclear factor-B. Thus, the curcumin analogue GG9 attenuated the LPS-induced inflammatory response in human blood-derived macrophages and may therefore represent an attractive chemical template for macrophage pharmacological targeting.