Inflammation modulating effects of prostaglandins and omega-3 fatty acids

Abstract

Omega-(omega6) and omega-3 fatty acids (FA) and their metabolites (eikosanoids, such as prostaglandins, PG) are important modulators of immune and inflammatory responses in various ways. The aim of this thesis was to assess some in vitro and ex vivo effects of these lipids on blood leukocytes.

In the first part of this thesis (studies I and II), we examined the in vitro effects on peripheral blood lymphocytes and monocytes by various PGs. We found that the natural killer (NK) activity of lymphocytes was decreased by PGD2 and PGE2. PGD2 also decreased surface expression of the CD8 antigen (on cytotoxic/suppressor T cells), as well as of Fc receptors for IgG on T cells. In peripheral blood mononuclear cells (PBMC), the proliferative response to phytohemagglutinin (PHA) was reduced in the presence of PGD2, PGA2 and PGE2, in falling order of potency. In lipopolysaccharide (LPS) stimulated purified monocytes we found that, although PGD2 did not influence TNF-alpha release, its metabolites PGJ2, delta12-PGJ2 and 15-deoxy delta12, delta14 -PGJ2 (15d-PGJ2) enhanced the TNF-alpha release. The monocyte NADPH oxidase activity was not affected by PGB2, PGD2 or PGE2.

In the second part of the thesis (III-V), we assessed various ex vivo effects on PBMC of a dietary treatment for 6 months with a DHA enriched fish oil preparation (1.7 g of docosahexaenoic acid (DHA) and 0.6 g of eicosapentaenoic acid (EPA) per day; omega-3 FA group) or an isocaloric placebo oil in patients with Alzheimer disease (AD; the OmegAD trial). The omega-3 FA-treated group displayed significant increases of DHA and EPA plasma levels whereas the placebo group did not. The release of PGF2alpha (a stable metabolite of PGE2) was significantly diminished from LPS (but not from PHA) stimulated PBMC in the omega-3 FAs group, while no change was noted for the placebo group (III). The omega-3 group showed significant decreases of IL-1beta, IL-6, and G-CSF release after LPS stimulation of PBMC (IV). PGF2alpha, IL-1beta and IL-6 changes correlated inversely with changes in DHA and EPA plasma levels. Furthermore, reductions of IL-1beta and IL-6 were significantly correlated with each other, and decreased IL-1beta and IL-6 levels correlated with decreased PGF2alpha levels.

In paper V, we studied gene expressions in the PBMC, using a genome wide technique with approx. 8000 genes. At 6 months, a significant up-regulation of nine, and a down-regulation of 10 genes were noted in the omega-3 group. Many of these genes are involved in inflammation and neurodegeneration, e.g. CD63, RHOB, CASP4, NAIP, VCP and SORL1. The up-regulation of CD63 and SUPT4H1 genes and the down-regulation of RHOB, LOC 399491, ZNF24 and ANAPC5 genes were significant in the omega-3 group compared to placebo group. The downregulated ANAPC5 and RHOB genes correlated to increased DHA and EPA levels.

In conclusion, cyclooxygenase products of arachidonic acid, i.e. prostaglandin of the E and D series, influence various immune and inflammatory responses of lymphocytes and monocytes in vitro in a complex way, depending on the specific eikosanoid, the dose and studied functions. Dietary intake of DHA rich fish oil reduces the release of PGE2, pro- inflammatory cytokines and the myeloid growth factor G-CSF ex vivo in PBMCs. Moreover, the DHA rich fish oil affected several genes, which might be of significance for inflammation or Alzheimer's disease. Although these responses point to a down-regulation of inflammatory reactions, it remains to be seen whether the DHA rich fish oil also affects the inflammatory process in the AD brain.