Molecular mechanisms of immunosuppressive effects of dietary n-3 pufa, curcumin and limonin on murine cd4+ t cells

dc.contributorChapkin, Robert S.
dc.contributorMcMurray, David N.
dc.creatorKim, Wooki
dc.description.abstractThe molecular mechanisms of putative anti-inflammatory nutrients, i.e., fish oil, curcumin and limonin, were investgated with respect to CD4+ T cell function. Initially, using a DO11.10 mouse model which exhibits a transgenic T cell receptor specific to OVA 323-339 peptide, we demonstrated that dietary fish oil suppresses antigen-specific Th1 clonal expansion in vivo. Following immunization, the accumulation of adoptively transferred transgenic cells in wild type recipient mouse lymph nodes was suppressed. In addition, cell division analysis by carboxyfluorescein succinimidyl ester (CFSE) revealed that both total cell number in lymph nodes as well as cell division were decreased by fish oil. Since n-3 polyunsaturated fatty acids (PUFA), active long chain fatty acids in fish oil, elicit favorable effects on a variety of cell types, e.g., anti-tumor effect on colonocytes, amelioration of coronary heart disease and anti-inflammatory effects involving T cells, B cells, dendritic cells and macrophages, we postulated that a fundamental mechanism of action may explain the multiple effects observed. In a series of experiments described herein, we demonstrated that n-3 PUFA alters the formation/location of membrane subdomains, referenced to as lipid rafts. Specifically, lipid raft formation at the immunological synapse (IS) in CD4+ T cells was suppressed following membrane enrichment with n-3 PUFA. The alteration of lipid rafts down-regulated the localization of select signaling proteins, including F-actin, PKC? and PLC?-1, and phosphorylation of PLC?-1 at the IS. Consequently, CD4+ T cell proliferation was suppressed as assessed by CFSE analysis and radioactive thymidine incorporation. Phytochemicals have been used for chemopreventive and chemotherapeutic purposes. We examined the putative anti-inflammatory effects of curcumin (1%) and limonin (0.02%) with respect to CD4+ T cell function. Dietary curcumin and limonin suppressed NF-?B activation in CD4+ T cells. In addition, CD4+ T cell proliferation was modulated by 2% curcumin. We further investigated the combined therapeutic potential of phytochemicals and fish oil, containing n-3 PUFA. Interestingly, fish oil and limonin together significantly (P<0.05) suppressed T cell proliferation, whereas feeding either fish oil or limonin alone showed little effect. In summary, our data indicated that dietary fish oil alters proximal signaling of T cells by perturbing lipid raft formation. Curcumin and limoin are capable of suppressing NF-?B in T cells, thereby exhibiting a synergistic effect when combined with fish oil. Further studies are required to elucidate the relationship of dietary dose of active compoments with respect to mechanism of actions.
dc.subjectn-3 PUFA
dc.subjectT cell
dc.subjectlipid rafts
dc.titleMolecular mechanisms of immunosuppressive effects of dietary n-3 pufa, curcumin and limonin on murine cd4+ t cells