Regulation of interleukin-2 signaling by fatty acids in human lymphocytes.
Docosahexaenoic (DHA; C22:6 n-3), eicosapentaenoic (EPA; C20:5 n-3), palmitic (PA; C16:0), and stearic (SA; C18:0) acids decrease lymphocyte proliferation in concentrations of >50 muM, as observed in our previous study. However, oleic acid (OA; C18:1 n-9) and linoleic acid (LA; C18:2 n-6) increase lymphocyte proliferation at 25 muM. In this study, the effect of these FAs on the interleukin-2 (IL-2) signaling pathway in human lymphocytes was investigated. Cells were isolated from heparinized venous blood of healthy human donors by density-gradient sedimentation. Cells were stimulated with 5 mug/ml concanavalin A and treated with FAs in the absence or presence of IL-2 for 1 hour. CD25-alpha externalization was analyzed by flow cytometry, and Janus kinase 1 (JAK1), JAK3, signal transducer and activator of transcription (STAT) 5, extracellular signal-regulated kinases (ERKs) 1 and 2, Akt, and protein kinase C (PKC)-zeta phosphorylation were analyzed by Western blotting. The expression of CD25-alpha at the cell surface was increased by DHA, SA, and PA but was unaffected by EPA, OA, and LA. PA, SA, DHA, and EPA decreased JAK1, JAK3, STAT5, and Akt phosphorylation induced by IL-2, but OA and LA did not cause any effect. OA and LA increased ERK1/2 phosphorylation, whereas the other FAs caused a marked decrease. PKC-zeta phosphorylation was decreased by OA and LA and was not altered by the remaining FAs. In conclusion, the inhibitory effect of PA, SA, DHA, and EPA on lymphocyte proliferation observed in our previous study was attributable to a decrease in JAK/STAT, ERK, and Akt pathways activated by IL-2. Probably, OA and LA stimulated lymphocyte proliferation by increasing ERK1/2 phosphorylation through PKC-zeta activation. The inhibition of JAK1, JAK3, STAT5, ERK1/2, and Akt phosphorylation caused by DHA, SA, and PA is associated with an alteration of CD25 expression at the cell surface.
Gorjão
Renata
R
Department of Physiology and Biophysics, Institute of Biomedical Sciences, University of São Paulo, São Paulo, Brazil. renatag@icb.usp.br
Hirabara
Sandro Massao
SM
de Lima
Thaís Martins
TM
Cury-Boaventura
Maria Fernanda
MF
Curi
Rui
R
D004281:Docosahexaenoic Acids / Q000494:pharmacology; D015118:Eicosapentaenoic Acid / Q000494:pharmacology; D005227:Fatty Acids / Q000494:pharmacology*; D006801:Humans; D007376:Interleukin-2 / Q000502:physiology*; D053645:Interleukin-2 Receptor alpha Subunit / Q000096:biosynthesis*; D053613:Janus Kinase 1 / Q000378:metabolism; D053616:Janus Kinase 3; D019787:Linoleic Acid / Q000494:pharmacology; D008213:Lymphocyte Activation / Q000187:drug effects*; D008214:Lymphocytes / Q000187:drug effects / Q000502:physiology*; D019950:Mitogen-Activated Protein Kinase 1 / Q000378:metabolism; D048052:Mitogen-Activated Protein Kinase 3 / Q000378:metabolism; D019301:Oleic Acid / Q000494:pharmacology; D019308:Palmitic Acid / Q000494:pharmacology; D011493:Protein Kinase C / Q000378:metabolism; D051057:Proto-Oncogene Proteins c-akt / Q000378:metabolism; D050799:STAT5 Transcription Factor / Q000378:metabolism; D015398:Signal Transduction / Q000187:drug effects*; D013229:Stearic Acids / Q000494:pharmacology; D000099221:Protein Kinase C zeta
D004281:Docosahexaenoic Acids; D015118:Eicosapentaenoic Acid; D005227:Fatty Acids; D007376:Interleukin-2; D053645:Interleukin-2 Receptor alpha Subunit; D053613:Janus Kinase 1; D053616:Janus Kinase 3; D019787:Linoleic Acid; D019950:Mitogen-Activated Protein Kinase 1; D048052:Mitogen-Activated Protein Kinase 3; D019301:Oleic Acid; D019308:Palmitic Acid; D011493:Protein Kinase C; D051057:Proto-Oncogene Proteins c-akt; D050799:STAT5 Transcription Factor; D013229:Stearic Acids; D000099221:Protein Kinase C zeta; C031183:stearic acid; C507933:JAK3 protein, human