Role of omega-3 fatty acid supplementation in inflammation and malignancy.

Omega-3 fatty acids (FAs), which include eicosapentaenoic acid (EPA) and docosahexaenoic acid, are found in fish oils and have long been investigated as components of therapy for various disease states. Population studies initially revealed the cardioprotective and anti-inflammatory effects of omega-3 FAs and EPA, with subsequent clinical studies supporting the therapeutic role of omega-3 FAs in cardiovascular and chronic inflammatory conditions. Prospective randomized placebo-controlled trials have also demonstrated the utility of omega-3 FA supplementation in malignancy and cancer cachexia. In recent years, in vitro and animal studies have elucidated some of the mechanistic explanations underlying the wide range of biological effects produced by omega-3 FAs and EPA, including their antiproliferative and anticachectic actions in malignancy. In this review, the authors discuss the recent progress made with omega-3 FAs, focusing on the advances in mechanistic understanding and the results of clinical trials.

Fas ligation on macrophages enhances IL-1R1-Toll-like receptor 4 signaling and promotes chronic inflammation.

The nonapoptotic functions of Fas ligation are incompletely characterized. In contrast to expectations, we show here that Fas-deficient mice developed less-severe collagen-induced arthritis than did control mice. Despite having milder arthritis, Fas-deficient mice had more of the critical pro-inflammatory mediator interleukin-1 beta (IL-1 beta) in their joints, suggesting inefficient activation through IL-1 receptor 1 (IL-1R1) when Fas signaling is deficient. In primary human macrophages and macrophages from Fas- or Fas ligand (FasL)-deficient mice, interruption of Fas-FasL signaling suppressed nuclear factor-kappa B activation and cytokine expression induced by IL-1 beta and lipopolysaccharide. This cross-talk was mediated by the Fas-associated death domain through interaction with myeloid differentiation factor 88. These observations document a unique mechanism whereby Fas-FasL interactions enhance activation through the IL-1R1 or Toll-like receptor 4 pathway, which may contribute to the pathogenesis of chronic arthritis.

Serine phosphorylation of STAT3 is essential for Mcl-1 expression and macrophage survival.

The Bcl-2 family member Mcl-1 is essential for macrophage survival. However, the mechanisms that contribute to the expression of Mcl-1 in these cells have not been fully characterized. The present study focused on the role of signal transducer and activator of transcription 3 (STAT3) in regulation of Mcl-1 in macrophages. Sodium salicylate (NaSal) treatment induced apoptotic cell death in primary human macrophages in a dose- and time-dependent fashion. Incubation with NaSal resulted in the loss of mitochondrial transmembrane potential, the release of cytochrome c and second mitochondria-derived activator of caspase/direct IAP binding protein with low pH of isoelectric point (pI) from the mitochondria, and the activation of caspases 9 and 3. Western blot analysis and reverse transcription-polymerase chain reaction demonstrated that NaSal down-regulated the expression of Mcl-1. Electrophoretic mobility shift assay and Western blot analysis for phosphorylated STAT3 demonstrated that STAT3 was constitutively activated in macrophages and that this STAT3 activation was suppressed by NaSal. The activation of STAT3 in macrophages was dependent on Ser727 phosphorylation, in the absence of detectable Tyr705 phosphorylation. Ectopic expression of STAT3 in murine RAW264.7 macrophages rescued the inhibition of Mcl-1 promoter-reporter gene activation and the cell death induced by NaSal treatment, while a dominant-negative STAT3 resulted in cell death. To confirm its role in primary macrophages, STAT3 antisense (AS) oligodeoxynucleotides (ODNs) were employed. STAT3 AS, but not control, ODNs decreased STAT3 and Mcl-1 expression and resulted in macrophage apoptosis. These observations demonstrate that the STAT3-mediated expression of Mcl-1 is essential for the survival of primary human in vitro differentiated macrophages.