PUFA are potent immunosuppresive agents

haidut

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Just a quick post for all those PUFA/fish-oil lovers who keep sending me hate-mail about the "incredibly beneficial" omega-3, and even omega-6 (e.g. some athletes/bodybuilders tout arachidonic acid as a natural "anabolic agent"). As the study below discusses, all PUFA, but especially omega-3, are about as potent as glucocorticoids in inducing T-cell death. Modern medicine has already recognized that anything that suppresses T-cell formation likely increases cancer risk, and some of the most promising cancer therapies to get recently approved are precisely T-cell activity boosters (e.g. Opdivo). Hopefully, the study below will give all PUFA fans a pause and reconsideration before they continue consuming this carcinogenic, immunosuppressive poison.

Polyunsaturated fatty acids, membrane organization, T cells, and antigen presentation

'"...Although the studies are not conclusive and there are conflicting reports (17), the n−3 PUFAs decrease specific disease symptoms and the need for antiinflammatory drugs for patients with chronic inflammatory diseases (6, 18). n−3 Fatty acids may be immunosuppressive agents for a variety of inflammatory ailments, including Crohn disease, atherosclerosis, colitis, graft-versus-host disease, rheumatoid arthritis, psoriasis, multiple sclerosis, asthma, and systemic lupus erythematosus (19–28). "

"...A series of studies from Kleinfeld’s laboratory (55) showed that unsaturated free fatty acids (FFAs) could inhibit specific aspects of cytotoxic T cell function by perturbing membranes. Initially, it was shown that short-term exposure of murine allogeneic effector T cells to low levels of unsaturated FFAs (<10 μmol/L), including PUFAs, inhibited lysis of target APCs. The change in lysis of target cells was a direct consequence of the FFA added to the CTLs, because lysis could be inhibited by extracting the unsaturated FFA with bovine serum albumin before CTL-target conjugation (55). Specific aspects of T cell function inhibited by unsaturated lipids included the initial rise in intracellular [Ca2+] on conjugate formation, protein phosphorylation events, and subsequent CTL esterase release. On the other hand, release of inositol phosphates and binding to target cells were unaffected (55–59). Because the inhibition in CTL calcium release linearly correlated with the decrease in membrane acyl chain order induced by the presence of increasing unsaturation in the plasma membrane (56), it was hypothesized that modulation of membrane structure affected T cell Ca2+ signaling. Information on the effects of PUFAs on the T cell calcium response has continued to grow (60, 61). For example, Stulnig et al (61) showed that administration of PUFAs reduced the calcium response dose dependently in vitro on stimulation of Jurkat T lymphocytes. Although no change was observed with the saturated palmitic acid, maximal effects were observed with GLA and DGLA and modest effects with EPA and AA."

"...Some of the in vivo or ex vivo data on PUFAs and T cell function are consistent with findings from cell culture. For example, healthy persons infused with lipids to elevate serum PUFAs had a reduced calcium response of their CD4+ and CD8+ T cells (61). Also, feeding mice n−3 PUFAs, predominately DHA, lowered the proliferative response of splenic T lymphocytes on in vitro stimulation through CD28 and the TCR/CD3 complex (74)...Inner leaflet lipids (eg, PEs and PSs) isolated from mice fed diets rich in fish oils were enriched with PUFAs to a greater extent than were outer leaflet lipids (77, 78). Surprisingly, it was also observed that the sphingomyelin content of DRM fractions was significantly (≈30%) lower in fish oil–fed mice than in control corn oil–fed animals (77, 78). In the same study, recruitment of PKCθ into rafts of T cells from mice fed diets supplemented with fish oils or purified DHA was inhibited relative to cells isolated from mice fed corn oil. In addition, receptor-induced activation of the transcription factors AP-1 and nuclear transcription factor κB was lowered and, consequently, IL-2 production and T cell proliferation were inhibited in cells isolated from fish oil–fed mice (78). Fish oil–fed mice also show elevated concentrations of Fas colocalization with raft molecules in naive T cells (78). In light of data that showed that n−3 PUFAs enhanced activation induced cell death in T cells (79), it was speculated that Fas relocalization by PUFAs may be yet another mechanism by which n−3 PUFAs inhibit T cell activity (78, 80)."

"...

  1. 1) PUFA incorporation disrupts sphingomyelin-cholesterol microdomain formation and alters signal transduction. A perturbation in the stability of liquid ordered microdomains by PUFAs changes the distribution of proteins between domains as readout by localization to either DRMs or DSMs (assuming that detergent extraction is some crude representation of differing membrane heterogeneities). The physical disruption would be driven by the low affinity of cholesterol for PUFA acyl chains. Disruption of liquid ordered domains by PUFAs may also explain the reduction in sphingomyelin concentrations in DRM fractions in ex vivo studies (77). Indeed, raft disruption by cholesterol depletion has been shown to effect cellular signaling (141).
  2. 2) DRMs may not accurately depict the differing types of lipid microdomains that may sequester into these fractions. It has become increasingly clear from cell studies that raft microdomains may exist as nanoclusters <5 nm, with a few glycosylphosphatidylinositol-anchored proteins in each cluster (142). It has been suggested that there is tremendous heterogeneity in DRM microdomains (51) and it is reasonable to speculate that PUFA microdomains may exist on a nanometer scale (143). Therefore, PUFA-rich microdomains may show up in DRM fractions but may still segregate from liquid ordered domains based on steric incompatibility between cholesterol and PUFAs. These interactions may trigger protein displacement and loss of function.
  3. 3) On dietary intake, most PUFAs are esterified to phospholipids in the sn-2 position, with saturated acyl chains in the sn-1 position. Therefore, the sn-1 chains may participate in microdomain formation with cholesterol and exclude PUFAs, as suggested by the work of Huster et al (1998). However, during detergent extraction, the high affinity between the sn-1 chain and cholesterol may result in PUFA enrichment in the DRM fraction. Even though biochemical analysis of DRMs shows substantial amounts of PUFAs, they are not directly involved in the formation of liquid ordered domains.
  4. 4) PUFA incorporation into cells drives cholesterol from the outer to the inner leaflet (144, 145). The efflux of cholesterol may drive changes in outer and inner leaflet microdomain formation. The signaling complexes of the inner leaflet may respond to a reduction in cholesterol concentrations and alter T cell signaling. Our laboratory has shown that cholesterol depletion can result in a reorganization of the actin cytoskeleton (106). Perhaps PUFA-induced changes in cholesterol also alter the organization of the cytoskeleton, which could modify cellular signaling."
"...As the data grow on how select PUFAs may modulate inflammatory and autoimmune diseases, there is a growing need for elucidating the underlying molecular mechanisms. An understanding of the effect of PUFAs at the level of T cell membrane organization is only starting to emerge, whereas relatively little is known about membrane modulation of APCs. The data from cellular and animal studies tell us that PUFAs induce changes in localization of proteins from DRM to DSM fractions, which has measurable consequences for T cell signaling and proliferation. However, the mechanisms by which PUFAs induce changes in protein localization are not known, and it is here that model membrane experiments suggest testable hypotheses. We know that PUFA-containing phospholipids impart unique structural effects on bilayers, but what is required is better knowledge of how these effects translate into functional consequences at the cellular level. Further investigation at the interface between model bilayers and cellular systems may answer some questions regarding PUFA-raft interactions. How PUFAs modulate MHC conformation, vertical orientation, lateral organization, and trafficking—on the basis of literature reports and some data from our own laboratory—also requires extensive investigation at all levels, from synthetic bilayers to animal experiments. Because dietary intake of PUFAs will result in a distribution to virtually every cell of the body, the changes described above for APCs are also applicable to T cells. PUFA modification of cellular membranes may be an important target for immunosuppression."
 
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