title: Curcumin blocks interleukin (IL)-2 signaling in T-lymphocytes by inhibiting IL-2 synthesis, CD25 expression, and IL-2 receptor signaling.
abstract: Curcumin (diferulomethane) is the principal curcuminoid in the spice tumeric and a potent inhibitor of activation-induced T-lymphocyte proliferation; however, the molecular basis of this immunosuppressive effect has not been well studied. Here we show that micromolar concentrations of curcumin inhibited DNA synthesis by mouse CD4(+) T-lymphocytes, as well as interleukin-2 (IL-2) and CD25 (α chain of the high affinity IL-2 receptor) expression in response to antibody-mediated cross-linking of CD3 and CD28. Curcumin acted downstream of protein kinase C activation and intracellular Ca(2+) release to inhibit IκB phosphorylation, which is required for nuclear translocation of the transcription factor NFκB. In addition, IL-2-dependent DNA synthesis by mouse CTLL-2 cells, but not constitutive CD25 expression, was impaired in the presence of curcumin, which demonstrated an inhibitory effect on IL-2 receptor (IL-2R) signaling. IL-2-induced phosphorylation of STAT5A and JAK3, but not JAK1, was diminished in the presence of curcumin, indicating inhibition of critical proximal events in IL-2R signaling. In line with the inhibitory action of curcumin on IL-2R signaling, pretreatment of CD4(+)CD25(+) regulatory T-cells with curcumin downregulated suppressor function, as well as forkhead box p3 (Foxp3) expression. We conclude that curcumin inhibits IL-2 signaling by reducing available IL-2 and high affinity IL-2R, as well as interfering with IL-2R signaling.
authors: Department of Microbiology and Immunology, Dalhousie University, Halifax, Nova Scotia, Canada.
authors: Nicholas A
authors: NA
authors: Forward
authors: David M
authors: DM
authors: Conrad
authors: Melanie R
authors: MR
authors: Power Coombs
authors: Carolyn D
authors: CD
authors: Doucette
authors: Suzanne J
authors: SJ
authors: Furlong
authors: Tong-Jun
authors: TJ
authors: Lin
authors: David W
authors: DW
authors: Hoskin
mesh_terms: D000818:Animals; D049109:Cell Proliferation / Q000187:drug effects; D002470:Cell Survival / Q000187:drug effects; D003474:Curcumin / Q000494:pharmacology*; D005260:Female; D007166:Immunosuppressive Agents / Q000494:pharmacology*; D007376:Interleukin-2 / Q000037:antagonists & inhibitors* / Q000096:biosynthesis; D053645:Interleukin-2 Receptor alpha Subunit / Q000037:antagonists & inhibitors* / Q000096:biosynthesis; D053616:Janus Kinase 3 / Q000378:metabolism; D051379:Mice; D008810:Mice, Inbred C57BL; D015375:Receptors, Interleukin-2 / Q000037:antagonists & inhibitors*; D050799:STAT5 Transcription Factor / Q000378:metabolism; D015398:Signal Transduction / Q000187:drug effects; D013601:T-Lymphocytes / Q000187:drug effects* / Q000276:immunology
chemical_list: D007166:Immunosuppressive Agents; D007376:Interleukin-2; D053645:Interleukin-2 Receptor alpha Subunit; D015375:Receptors, Interleukin-2; D050799:STAT5 Transcription Factor; C507935:Jak3 protein, mouse; D053616:Janus Kinase 3; D003474:Curcumin