Regulation of interleukin-2 signaling by fatty acids in human lymphocytes

Renata Gorjão¹^,*, Sandro Massao Hirabara^*^,, Thaís Martins de Lima^*, Maria Fernanda Cury-Boaventura^*^, and Rui Curi^*

^* Department of Physiology and Biophysics, Institute of Biomedical Sciences, University of São Paulo, São Paulo, Brazil
Program of Post-Graduation Studies in Physical Education, Center of Biological Sciences and Health, Cruzeiro do Sul University, São Paulo, Brazil

Published, JLR Papers in Press, June 25, 2007.

^¹ To whom correspondence should be addressed. e-mail: renatag{at}icb.usp.br

Docosahexaenoic (DHA; C22:6 n-3), eicosapentaenoic (EPA; C20:5n-3), palmitic (PA; C16:0), and stearic (SA; C18:0) acids decreaselymphocyte proliferation in concentrations of >50 µM,as observed in our previous study. However, oleic acid (OA;C18:1 n-9) and linoleic acid (LA; C18:2 n-6) increase lymphocyteproliferation at 25 µM. In this study, the effect of theseFAs on the interleukin-2 (IL-2) signaling pathway in human lymphocyteswas investigated. Cells were isolated from heparinized venousblood of healthy human donors by density-gradient sedimentation.Cells were stimulated with 5 µg/ml concanavalin A andtreated with FAs in the absence or presence of IL-2 for 1 hour.CD25- ${alpha}$ externalization was analyzed by flow cytometry, and Januskinase 1 (JAK1), JAK3, signal transducer and activator of transcription(STAT) 5, extracellular signal-regulated kinases (ERKs) 1 and2, Akt, and protein kinase C (PKC)- ${zeta}$ phosphorylation were analyzedby Western blotting. The expression of CD25- ${alpha}$ at the cell surfacewas 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 notcause any effect. OA and LA increased ERK1/2 phosphorylation,whereas the other FAs caused a marked decrease. PKC- ${zeta}$ phosphorylationwas decreased by OA and LA and was not altered by the remainingFAs. In conclusion, the inhibitory effect of PA, SA, DHA, andEPA on lymphocyte proliferation observed in our previous studywas attributable to a decrease in JAK/STAT, ERK, and Akt pathwaysactivated by IL-2. Probably, OA and LA stimulated lymphocyteproliferation by increasing ERK1/2 phosphorylation through PKC- ${zeta}$ activation. The inhibition of JAK1, JAK3, STAT5, ERK1/2, andAkt phosphorylation caused by DHA, SA, and PA is associatedwith an alteration of CD25 expression at the cell surface.

Supplementary key words oleic acid • linoleic acid • palmitic acid • stearic acid • eicosapentaenoic acid • docosahexaenoic acid • Janus kinase-signal transducer and activator of transcription • mitogen-activated protein kinase • protein kinase B

Abbreviations: ConA, concanavalin A; DHA, docosahexaenoic acid; EPA, eicosapentaenoic acid; ERK, extracellular signal-regulated kinase; IL-2, interleukin-2; IL-2R, interleukin-2 receptor; JAK, Janus kinase; LA, linoleic acid; MAPK, mitogen-activated protein kinase; NF- ${kappa}$ B, nuclear factor ${kappa}$ B; OA, oleic acid; PA, palmitic acid; PI3K, phosphatidylinositol 3-kinase; PKC, protein kinase C; PMA, phorbol myristate acetate; SA, stearic acid; STAT, signal transducer and activator of transcription

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