Curcumin inhibits activation of Vgamma9Vdelta2 T cells by phosphoantigens and induces apoptosis involving apoptosis-inducing factor and large scale DNA fragmentation.
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.
Cipriani
B
B
Department of Pathology, Albert Einstein College of Medicine, Bronx, NY 10461, USA. cipriani@aecon.yu.edu
Borsellino
G
G
Knowles
H
H
Tramonti
D
D
Cavaliere
F
F
Bernardi
G
G
Battistini
L
L
Brosnan
C F
CF
D000328:Adult; D000590:Amino Acid Chloromethyl Ketones / Q000494:pharmacology; D017304:Annexin A5 / Q000032:analysis; D000894:Anti-Inflammatory Agents, Non-Steroidal / Q000494:pharmacology*; D000942:Antigens, Bacterial / Q000276:immunology*; D000970:Antineoplastic Agents / Q000494:pharmacology; D017209:Apoptosis / Q000187:drug effects*; D053148:Caspase 3; D020169:Caspases / Q000378:metabolism; D054407:Chemokine CCL4; D018946:Chemokine CCL5 / Q000378:metabolism; D003474:Curcumin / Q000494:pharmacology*; D003513:Cycloheximide / Q000494:pharmacology; D015853:Cysteine Proteinase Inhibitors / Q000494:pharmacology; D053938:DNA Fragmentation / Q000187:drug effects*; D004587:Electrophoresis, Agar Gel; D016521:Electrophoresis, Gel, Pulsed-Field; D004789:Enzyme Activation / Q000187:drug effects; D005434:Flow Cytometry; D045782:Hemiterpenes; D006801:Humans; D020287:In Situ Nick-End Labeling; D019409:Interleukin-15 / Q000494:pharmacology; D007376:Interleukin-2 / Q000494:pharmacology; D008213:Lymphocyte Activation / Q000187:drug effects*; D019402:Macrophage Inflammatory Proteins / Q000378:metabolism; D008970:Molecular Weight; D016328:NF-kappa B / Q000037:antagonists & inhibitors / Q000378:metabolism; D009943:Organophosphorus Compounds / Q000037:antagonists & inhibitors / Q000276:immunology* / Q000494:pharmacology; D010766:Phosphorylation; D011500:Protein Synthesis Inhibitors / Q000494:pharmacology; D016692:Receptors, Antigen, T-Cell, gamma-delta / Q000032:analysis*; D016176:T-Lymphocyte Subsets / Q000187:drug effects* / Q000276:immunology; D018808:Transcription Factor AP-1 / Q000037:antagonists & inhibitors / Q000378:metabolism; D014409:Tumor Necrosis Factor-alpha / Q000494:pharmacology
D000590:Amino Acid Chloromethyl Ketones; D017304:Annexin A5; D000894:Anti-Inflammatory Agents, Non-Steroidal; D000942:Antigens, Bacterial; D000970:Antineoplastic Agents; D054407:Chemokine CCL4; D018946:Chemokine CCL5; D015853:Cysteine Proteinase Inhibitors; D045782:Hemiterpenes; D019409:Interleukin-15; D007376:Interleukin-2; D019402:Macrophage Inflammatory Proteins; D016328:NF-kappa B; D009943:Organophosphorus Compounds; D011500:Protein Synthesis Inhibitors; D016692:Receptors, Antigen, T-Cell, gamma-delta; D018808:Transcription Factor AP-1; D014409:Tumor Necrosis Factor-alpha; C096713:benzyloxycarbonylvalyl-alanyl-aspartyl fluoromethyl ketone; C004809:isopentenyl pyrophosphate; D003513:Cycloheximide; C505407:CASP3 protein, human; D053148:Caspase 3; D020169:Caspases; D003474:Curcumin