Abstract
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.
Publication types
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Research Support, Non-U.S. Gov't
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Research Support, U.S. Gov't, P.H.S.
MeSH terms
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Adult
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Amino Acid Chloromethyl Ketones / pharmacology
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Annexin A5 / analysis
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Anti-Inflammatory Agents, Non-Steroidal / pharmacology*
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Antigens, Bacterial / immunology*
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Antineoplastic Agents / pharmacology
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Apoptosis / drug effects*
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Caspase 3
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Caspases / metabolism
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Chemokine CCL4
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Chemokine CCL5 / metabolism
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Curcumin / pharmacology*
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Cycloheximide / pharmacology
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Cysteine Proteinase Inhibitors / pharmacology
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DNA Fragmentation / drug effects*
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Electrophoresis, Agar Gel
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Electrophoresis, Gel, Pulsed-Field
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Enzyme Activation / drug effects
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Flow Cytometry
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Hemiterpenes*
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Humans
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In Situ Nick-End Labeling
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Interleukin-15 / pharmacology
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Interleukin-2 / pharmacology
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Lymphocyte Activation / drug effects*
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Macrophage Inflammatory Proteins / metabolism
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Molecular Weight
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NF-kappa B / antagonists & inhibitors
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NF-kappa B / metabolism
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Organophosphorus Compounds / antagonists & inhibitors
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Organophosphorus Compounds / immunology*
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Organophosphorus Compounds / pharmacology
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Phosphorylation
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Protein Synthesis Inhibitors / pharmacology
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Receptors, Antigen, T-Cell, gamma-delta / analysis*
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T-Lymphocyte Subsets / drug effects*
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T-Lymphocyte Subsets / immunology
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Transcription Factor AP-1 / antagonists & inhibitors
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Transcription Factor AP-1 / metabolism
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Tumor Necrosis Factor-alpha / pharmacology
Substances
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Amino Acid Chloromethyl Ketones
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Annexin A5
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Anti-Inflammatory Agents, Non-Steroidal
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Antigens, Bacterial
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Antineoplastic Agents
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Chemokine CCL4
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Chemokine CCL5
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Cysteine Proteinase Inhibitors
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Hemiterpenes
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Interleukin-15
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Interleukin-2
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Macrophage Inflammatory Proteins
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NF-kappa B
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Organophosphorus Compounds
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Protein Synthesis Inhibitors
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Receptors, Antigen, T-Cell, gamma-delta
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Transcription Factor AP-1
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Tumor Necrosis Factor-alpha
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benzyloxycarbonylvalyl-alanyl-aspartyl fluoromethyl ketone
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isopentenyl pyrophosphate
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Cycloheximide
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CASP3 protein, human
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Caspase 3
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Caspases
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Curcumin