Aplotaxene blocks T cell activation by modulation of protein kinase C-θ-dependent pathway.
Aplotaxene, (8Z, 11Z, 14Z)-heptadeca-1, 8, 11, 14-tetraene, is one of the major components of essential oil obtained from Inula helenium root, which is used in Oriental medicine. However, the effects of aplotaxene on immunity have not been investigated. Here, we show that aplotaxene inhibits T cell activation in terms of IL-2 and CD69 expression. Aplotaxene, at a concentration that optimally inhibits IL-2 production, has little effect on apoptotic or necrotic cell death, suggesting that apoptosis is not a mechanism for aplotaxene-mediated inhibition of T cell activation. Aplotaxene affects neither superantigeninduced conjugate formation between Jurkat T cells and Raji B cells nor clustering of CD3 and LFA-1 at the immunological synapse. Aplotaxene significantly inhibits PKC-θ phosphorylation and translocation to the immunological synapse, and blocks PMA-induced T-cell receptor internalization. Furthermore, aplotaxene leads to inhibition of mitogen-activated protein kinases (JNK, ERK and p38) phosphorylation and NF-κB, NF-AT, and AP-1 promoter activities in Jurkat T cells. Taken together, our findings provide evidence for the immunosuppressive effect of aplotaxene on activated T cells through the modulation of the PKC-θ and MAPK pathways, suggesting that aplotaxene may be a novel immunotherapeutic agent for immunological diseases related to the overactivation of T cells.
School of Life Sciences, Immune Synapse Research Center and Cell Dynamics Research Center, Gwangju Institute of Science and Technology, Gwangju 500-712, Republic of Korea.
Bo-Ra
BR
Na
Hye-Ran
HR
Kim
Min-Sung
MS
Kwon
Hyun-Su
HS
Lee
Indre
I
Piragyte
Eun-Ju
EJ
Choi
Hyun-Kyu
HK
Choi
Weon-Cheol
WC
Han
Seung-Ho
SH
Lee
Chang-Duk
CD
Jun
D015703:Antigens, CD / Q000378:metabolism; D000945:Antigens, Differentiation, T-Lymphocyte / Q000378:metabolism; D017209:Apoptosis / Q000187:drug effects; D004305:Dose-Response Relationship, Drug; D006801:Humans; D007376:Interleukin-2 / Q000378:metabolism; D007527:Isoenzymes / Q000378:metabolism; D019169:Jurkat Cells / Q000187:drug effects / Q000276:immunology / Q000378:metabolism; D037181:Lectins, C-Type / Q000378:metabolism; D008213:Lymphocyte Activation / Q000187:drug effects*; D020928:Mitogen-Activated Protein Kinases / Q000378:metabolism; D016328:NF-kappa B / Q000378:metabolism; D050778:NFATC Transcription Factors / Q000378:metabolism; D010766:Phosphorylation / Q000187:drug effects; D011090:Polyenes / Q000494:pharmacology*; D011493:Protein Kinase C / Q000378:metabolism*; D021381:Protein Transport / Q000187:drug effects; D018808:Transcription Factor AP-1 / Q000378:metabolism; D000099192:CD69 Antigens
D015703:Antigens, CD; D000945:Antigens, Differentiation, T-Lymphocyte; D007376:Interleukin-2; D007527:Isoenzymes; D037181:Lectins, C-Type; D020928:Mitogen-Activated Protein Kinases; D016328:NF-kappa B; D050778:NFATC Transcription Factors; D011090:Polyenes; D011493:Protein Kinase C; D018808:Transcription Factor AP-1; D000099192:CD69 Antigens; C000597747:heptadeca-1,8,11,14-tetraene
AP-1; Aplotaxene; ERK; Extracellular signal-regulated kinase; IL-2; Immunosuppression; JNK; LFA-1; Lymphocyte function-associated antigen 1; MAPK; Mitogen-activated protein kinase; NF-AT; NF-κB; Nuclear factor of activated T-cells; PKC; PMA; Protein kinase C; Protein kinase C-θ; SMAC; Supramolecular activation complex; T cell activation; T cell receptor; TCR; activator protein 1; c-Jun N-terminal kinase; interleukin-2; nuclear factor kappa-light-chain-enhancer of activated B cells; phorbol 12-myristate 13-acetate