期刊
BIOCHEMICAL JOURNAL
卷 443, 期 -, 页码 27-37出版社
PORTLAND PRESS LTD
DOI: 10.1042/BJ20111589
关键词
actin remodelling; immunological synapse; n-3 polyunsaturated fatty acid; PtdIns(4,5)P-2; T-cell activation; Wiskott-Aldrich syndrome protein
资金
- National Institutes of Health [DK07107, CA59034, CA107668]
- U.S. Department of Agriculture CSREES (Cooperative State Research, Education, and Extension Service) [2008-34402-17121]
- National Science and Engineering Research Council (NSERC) of Canada
n - 3 PUFA (polyunsaturated fatty acids), i.e. DHA (docosahexaenoic acid), found in fish oil, exhibit anti-inflammatory properties; however, the molecular mechanisms remain unclear. Since PldIns(4,5)P-2 resides in raft domains and DHA can alter the size of rafts, we hypothesized that PtdIns(4,5)P-2 and downstream actin remodelling are perturbed by the incorporation of a - 3 PUFA into membranes, resulting in suppressed T-cell activation. CD4(+) T-cells isolated from Fat-l transgenic mice (membranes enriched in n - 3 :PUFA) exhibited a 50 % decrease in PtdIns(4,5)P-2. Upon activation by plate-bound anti-CD3/anti-CD28 or PMA/ionomycin, Fat-l CD4(+) T-cells failed to metabolize PtdIns(4,5)P-2. Furthermore, actin remodelling failed to initiate in Fat-l CD4(+) T-cells upon stimulation; however, the defect was reversed by incubation with exogenous PtdIns(4,5)P-2. When Fat-l CD4(+) T-cells were stimulated with anti-CD3/anti-CD28-coated beads, WASP (Wiskott-Aldrich syndrome protein) failed to translocate to the immunological synapse. The suppressive phenotype, consisting of defects in PtdIns(4,5)P-2 metabolism and actin remodelling, were recapitulated in CD4(+) T-cells isolated from mice fed on a 4% DHA triacylglycerol-enriched diet. Collectively, these data demonstrate that n - 3 PUFA, such as DHA, alter PtdIns(4,5)P-2 in CD4(+) T-cells, thereby suppressing the recruitment of WASP to the immunological synapse, and impairing actin remodelling in CD4(+) T-cells.
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