curcumin and isopentenyl-pyrophosphate

Curcumin, in addition to its role as a spice, has been used for centuries to treat inflammatory disorders. Although the mechanism of action remains unclear, it has been shown to inhibit the activation of NF-kappaB and AP-1, transcription factors required for induction of many proinflammatory mediators. Due to its low toxicity it is currently under consideration as a broad anti-inflammatory, anti-tumor cell agent. In this study we investigated whether curcumin inhibited the response of gammadelta T cells to protease-resistant phosphorylated derivatives found in the cell wall of many pathogens. The results showed that curcumin levels > or =30 microM profoundly inhibited isopentenyl pyrophosphate-induced release of the chemokines macrophage inflammatory protein-1alpha and -1beta and RANTES. Curcumin also blocked isopentenyl pyrophosphate-induced activation of NF-kappaB and AP-1. Commencing around 16 h, treatment with curcumin lead to the induction of cell death that could not be reversed by APC, IL-15, or IL-2. This cytotoxicity was associated with increased annexin V reactivity, nuclear expression of active caspase-3, cleavage of poly(ADP-ribose) polymerase, translocation of apoptosis-inducing factor to the nucleus, and morphological evidence of nuclear disintegration. However, curcumin led to only large scale DNA chromatolysis, as determined by a combination of TUNEL staining and pulse-field and agarose gel electrophoresis, suggesting a predominantly apoptosis-inducing factor-mediated cell death process. We conclude that gammadelta T cells activated by these ubiquitous Ags are highly sensitive to curcumin, and that this effect may contribute to the anti-inflammatory properties of this compound.

Topics: Adult; Amino Acid Chloromethyl Ketones; Annexin A5; Anti-Inflammatory Agents, Non-Steroidal; Antigens, Bacterial; Antineoplastic Agents; Apoptosis; Caspase 3; Caspases; Chemokine CCL4; Chemokine CCL5; Curcumin; Cycloheximide; Cysteine Proteinase Inhibitors; DNA Fragmentation; Electrophoresis, Agar Gel; Electrophoresis, Gel, Pulsed-Field; Enzyme Activation; Flow Cytometry; Hemiterpenes; Humans; In Situ Nick-End Labeling; Interleukin-15; Interleukin-2; Lymphocyte Activation; Macrophage Inflammatory Proteins; Molecular Weight; NF-kappa B; Organophosphorus Compounds; Phosphorylation; Protein Synthesis Inhibitors; Receptors, Antigen, T-Cell, gamma-delta; T-Lymphocyte Subsets; Transcription Factor AP-1; Tumor Necrosis Factor-alpha