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-Oxa, -Thia, and 
-Thia Polyunsaturated Fatty Acids on Human T Lymphocyte Proliferation, Cytokine Production, and Activation of Protein Kinase C and MAPKs1
,
,
* Department of Immunopathology, Women’s and Children’s Hospital, North Adelaide, South Australia; Departments of
Pediatrics and
Physiology, University of Adelaide, Adelaide, Australia;
School of Pharmacy and Medical Sciences, University of South Australia, Adelaide, Australia; and
¶ Research School of Chemistry, Australian National University, Canberra, Australia
We have recently demonstrated that a novel n-3 long chain polyunsaturated fatty acid (PUFA) (
-oxa 21:3n-3) was a more potent and more selective anti-inflammatory agent than n-3 PUFA. To gain further insights into this technology, we synthesized other novel PUFA consisting of -oxa, -thia, and 
-thia compounds. All three types displayed anti-inflammatory activity. Each of the unsaturated -oxa fatty acids showed similar inhibition of PHA-PMA-induced T cell proliferation with a parallel inhibition of TNF- production. However, -oxa 25:6n-3 and -oxa 21:4n-3 displayed lower inhibitory action on IFN- production. Surprisingly, -oxa 23:4n-6 and -oxa 21:3n-6 had marginal effect on IL-2 production. Thus, structural variation can generate selectivity for different immunological parameters. The -thia compounds 23:4n-6, 21:3n-6, and 21:3n-3 were highly effective in inhibiting all immunological responses. Of the two -thia PUFA tested, -thia 24:4n-6 was a strong inhibitor of all responses apart from IL-2, but -thia 22:3n-6 had very little inhibitory effect. Two of the most active compounds, -thia 23:4n-6 and -thia 21:3n-6, were studied in more detail and shown to have an IC50 of 1–2 µM under optimal conditions. Thus, these PUFA retain the immunosuppressive properties of the n-3 PUFAs, 20:5n-3 and 22:6n-3, but not the neutrophil-stimulating properties. Their action on T lymphocytes is independent of cyclooxygenase or lipoxygenase activity, and they act at a postreceptor-binding level by inhibiting the activation of protein kinase C and ERK1/ERK2 kinases.
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