The Immunomodulatory Effects of Novel β-Oxa, β-Thia, and γ-Thia Polyunsaturated Fatty Acids on Human T Lymphocyte Proliferation, Cytokine Production, and Activation of Protein Kinase C and MAPKs

Abstract

We have recently demonstrated that a novel n-3 long chain polyunsaturated fatty acid (PUFA) (β-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 β-oxa, β-thia, and γ-thia compounds. All three types displayed anti-inflammatory activity. Each of the unsaturated β-oxa fatty acids showed similar inhibition of PHA-PMA-induced T cell proliferation with a parallel inhibition of TNF-β production. However, β-oxa 25:6n-3 and β-oxa 21:4n-3 displayed lower inhibitory action on IFN-γ production. Surprisingly, β-oxa 23:4n-6 and β-oxa 21:3n-6 had marginal effect on IL-2 production. Thus, structural variation can generate selectivity for different immunological parameters. The β-thia compounds 23:4n-6, 21:3n-6, and 21:3n-3 were highly effective in inhibiting all immunological responses. Of the two γ-thia PUFA tested, γ-thia 24:4n-6 was a strong inhibitor of all responses apart from IL-2, but γ-thia 22:3n-6 had very little inhibitory effect. Two of the most active compounds, β-thia 23:4n-6 and β-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.

Conjugated Linoleic Acid Suppresses NF-κB Activation and IL-12 Production in Dendritic Cells through ERK-Mediated IL-10 Induction

“…Although c9, t11-CLA enhances production of PGE 2 in DC, it is not involved in IL-12 suppression, as inhibition of PGE 2 using specific inhibitors did not restore IL-12 production in LPS-stimulated DC (C. E. Loscher, K. H. Mills, and H. M. Roche, unpublished observation). This is consistent with other studies, which have demonstrated that the inhibitory effects of PUFA are not dependent on production of PGE 2 (25,32); however, the involvement of other prostaglandins has not yet been investigated.…”

Antioxidants and antioxidant enzymes status of rats fed on n-3 PUFA rich Garden cress (Lepidium Sativum L) seed oil and its blended oils

“…In order to increase n-3 PUFA levels in diet, linseed oil and fish oil are supplemented in milk based formulations (Ramaprasad et al 2004) and blending of α-linolenic acid (ALA 18:3) rich oils with edible vegetable oils are being attempted (Umesha and Naidu 2012). However, n-3 PUFAs are highly unsaturated, susceptible to autoxidation under aerobic conditions (Fritsche and Johnston 1988), cause an increase in oxidative stress through ROS production (Costabile et al 2005) and also ameliorate antioxidant defense system (Venkatraman and Pinnavaia 1998).…”

Dietary fatty acids modulate antigen presentation to hepatic NKT cells in nonalcoholic fatty liver disease

“…Potter ( 1 ). Polyunsaturated fatty acids (PUFA) can modulate cytokine production, lymphocyte proliferation, and apoptosis ( 2,3 ). Saturated fatty acids (SFA) affect MHC I-mediated antigen presentation, impair immune response, and increase host susceptibility to infection speed sorter (Becton Dickenson).…”