Suppression of T cell signaling by polyunsaturated fatty acids: selectivity in inhibition of mitogen-activated protein kinase and nuclear factor activation.
Polyunsaturated fatty acids (PUFAs) are known to suppress inflammatory and autoimmune responses and, therefore, clinical applications of PUFAs as immunomodulatory substances are extensively studied. PUFAs are known to inhibit T cell responses, but with respect to TCR/CD3-mediated signal transduction only a block in CD3-induced phospholipase Cgamma1/calcium signaling has been shown so far. In this study, we investigated PUFA-mediated changes in downstream T cell signal transduction. We show that among the mitogen-activated protein kinase families activation of c-Jun NH(2)-terminal kinase, but not phosphorylation of extracellular signal-regulated kinase-1/-2 or p38 is inhibited. CD3/CD28-induced activity of NF-AT was markedly reduced by PUFA treatment, while activation of other nuclear receptors (AP-1 and NF-kappaB) remained unaltered. Furthermore, IL-2 promoter activity, IL-2 and IL-13 mRNA levels, IL-2 secretion, and IL-2R alpha-chain expression were significantly diminished by PUFA treatment, whereas the expression of IFN-gamma, IL-4, IL-10, and CD69 remained essentially unaffected by PUFAs. In conclusion, PUFA treatment of T cells inhibits selectively c-Jun NH(2)-terminal kinase and NF-AT activation, resulting in diminished production of IL-2 and IL-13.
Zeyda
Maximilian
M
Department of Internal Medicine III, Clinical Division of Endocrinology and Metabolism and Institute of Immunology, University of Vienna Medical School, Vienna, Austria.
Szekeres
Andreas B
AB
Säemann
Marcus D
MD
Geyeregger
René
R
Stockinger
Hannes
H
Zlabinger
Gerhard J
GJ
Waldhäusl
Werner
W
Stulnig
Thomas M
TM
D000276:Adjuvants, Immunologic / Q000494:pharmacology; D015536:Down-Regulation / Q000187:drug effects / Q000276:immunology; D004789:Enzyme Activation / Q000187:drug effects / Q000276:immunology; D005231:Fatty Acids, Unsaturated / Q000494:pharmacology*; D006801:Humans; D007166:Immunosuppressive Agents / Q000494:pharmacology*; D018793:Interleukin-13 / Q000037:antagonists & inhibitors / Q000096:biosynthesis; D007376:Interleukin-2 / Q000037:antagonists & inhibitors / Q000096:biosynthesis; D048031:JNK Mitogen-Activated Protein Kinases; D019169:Jurkat Cells; D008213:Lymphocyte Activation / Q000187:drug effects; D020928:Mitogen-Activated Protein Kinases / Q000037:antagonists & inhibitors* / Q000378:metabolism; D016328:NF-kappa B / Q000037:antagonists & inhibitors* / Q000378:metabolism; D021122:Protein Subunits / Q000037:antagonists & inhibitors / Q000096:biosynthesis; D015375:Receptors, Interleukin-2 / Q000037:antagonists & inhibitors / Q000096:biosynthesis; D015398:Signal Transduction / Q000187:drug effects* / Q000276:immunology*; D013601:T-Lymphocytes / Q000187:drug effects* / Q000201:enzymology* / Q000378:metabolism
D000276:Adjuvants, Immunologic; D005231:Fatty Acids, Unsaturated; D007166:Immunosuppressive Agents; D018793:Interleukin-13; D007376:Interleukin-2; D016328:NF-kappa B; D021122:Protein Subunits; D015375:Receptors, Interleukin-2; D048031:JNK Mitogen-Activated Protein Kinases; D020928:Mitogen-Activated Protein Kinases