Introduction

Long chain n-3 polyunsaturated fatty acids (PUFA) derived from marine sources, namely eicosapentaenoic acid (EPA; 20:5Δ5,8,11,14,17) and docosahexaenoic acid (DHA; 22:6Δ4,7,10,13,16,19), have been shown to exhibit beneficial anti-inflammatory effects in multiple inflammatory disease states (Chapkin et al., 2007; Sijben & Calder, 2007). Within the typical American diet, the daily consumption of n-3 PUFA is between 0.7 and 1.6 g, which is equivalent to approximately 0.2–0.7% of total calories (Conquer & Holub, 1998; Kris-Etherton et al., 2000). Of this, the amount of fish-derived long chain n-3 PUFA (i.e., EPA and DHA) is reported to be less than 0.1–0.2 g per day with the majority being comprised of alpha-linolenic acid (ALA), the plant based form of n-3 PUFA (Kim et al., 2010b). In human clinical trials, n-3 PUFA intake levels, mainly in the form of EPA and DHA, are consumed at 1–9 g/day, which corresponds to 0.45–4.0% of calories (Kelley et al., 1998, 1999; Rees et al., 2006; Thies et al., 2001). This physiological range is comparable to levels consumed in traditional Japanese diets (containing 1–2% of daily energy as long chain n-3 PUFA) or by the Greenland Inuit, consuming 2.7–6.3% of daily energy (6–14 g/day) (Damsgaard et al., 2008; Feskens & Kromhout, 1993; Nagata et al., 2002; Okuyama et al., 1996).

Research conducted to elucidate the beneficial effects of n-3 PUFA on both physiological and pathophysiological processes highlights the attempt to determine if this bioactive food component is beneficial with respect to both preventing disease onset and/or improving the clinical outcomes in already established pathologies. Our objective in this chapter is to highlight some of the recent findings pertaining to the impact of n-3 PUFA consumption on prevalent human diseases, which include an inflammatory dimension, and thus, are most likely to be impacted by an anti-inflammatory food component. Since this is an expansive topic that is both an active and prolific area of research, where appropriate, the reader is referred to more specific comprehensive review papers for further details. Additionally, in making comments on the outcomes from clinical trials, we preferentially selected meta-analyses, thereby systematically providing the findings from multiple studies to allow for the opportunity to make more conclusive comments on what is currently known.

Putative Mechanisms of n-3 PUFA Action

Following n-3 PUFA consumption, tissue enrichment readily occurs, and this is particularly apparent in diverse immunological cell populations wherein n-3 PUFA are incorporated into both plasma and intracellular membranes as summarized in detail elsewhere (Calder, 2007). Generally, increasing the dietary intake of n-3 PUFA from fish oil results in increased proportions of the respective n-3 PUFA (DHA and EPA) into cells and, typically, this occurs at the expense of n-6 PUFAs, especially linoleic and arachidonic acid, therefore the cellular level is readily influenced by diet (Calder, 2007; Chapkin et al., 2007;). Further, time-course studies indicate that the incorporation of EPA and DHA into human immune cells reaches its peak within 4 weeks post initiation of dietary intake in a dose-response manner, as reviewed elsewhere (Calder, 2007). The sub-cellular incorporation of n-3 PUFA is localized primarily within the membrane phospholipids at the sn-2 position (Anderson & Sperling, 1971; Stillwell & Wassall, 2003). In this connection, dietary n-3 PUFA have been shown to specifically alter plasma membrane micro-organization (lipid rafts) at the immunological synapse between T cells and antigen-presenting cells ultimately suppressing signal transduction and nuclear translocation/activation of transcription factors (Fan et al., 2004; Kim et al., 2008, 2010; Yog et al., 2010). Interestingly, DHA and EPA enrichment has been shown to occur in both membrane lipid raft and non-raft membrane fractions isolated from CD4+ T cells (Switzer et al., 2004). Therefore, the presence of long chain n-3 PUFA in the membrane imparts unique physiochemical properties to cellular membranes, and DHA-induced alterations in membrane structure and function have been proposed to underlie the beneficial effects of n-3 PUFA (Chapkin et al., 2007; Ma et al., 2004, 2004b; Seo et al., 2006; Stillwell & Wassall, 2003).

Generally, n-3 PUFA (DHA and EPA) exert anti-inflammatory and immune suppressive functions, which may explain the beneficial role of this bioactive food component in human clinical trials and supplementation studies. The mechanisms through which n-3 PUFA exert these effects are broadly based and represent an active and ongoing research front. Appropriately crafted studies in animal and cell culture models relevant to human disease states have provided insight into the multiple mechanisms through which n-3 PUFA appear to play a beneficial role in either preventing the onset or slowing the progression of many human pathologies. Interestingly, n-3 PUFA appear to mediate effects at multiple stages of cellular complexity and organization affecting signaling pathways generated at the level of tissue, the cell membrane, or the intracellular second messengers and transcription factors, thereby ultimately impacting gene expression (Fig. 2.1). Thus, the pleiotropic effects of n-3 PUFA on physiological processes demonstrate that this biologically relevant bioactive food component exerts a more diverse and potent effect compared to other nutraceuticals.

Putative mechanisms of action elicited by n-3 PUFA impact diverse physiological processes including cell membrane structure/function, eicosanoid signaling, nuclear receptor activation, and whole-body glucose and lipid metabolism, thereby providing significant protection against a variety of apparently unrelated human diseases (Chapkin et al., 2007; Hu et al., 2003; Jump et al., 2005; Lupton & Chapkin, 2003; Stulnig, 2003).

Immunmodulatory effects are elicited by n-3 PUFA through multiple mechanisms, including diminishing T-cell proliferative capacity in response to mitogenic and antigenic stimulation (Anderson & Fritsche, 2004; Arrington et al., 2001, 2001b; Zhang et al., 2005, 2006). These suppressive effects have also been observed in the dendritic cell, endothelial cell, macrophage, and neutrophil components of the inflammatory response (Bagga et al., 2003; Hughes & Pinder, 2000; Massaro et al., 2008; Novak et al., 2003; Prescott, 1984; Zeyda et al., 2005). Additionally, dietary n-3 PUFA modulate components of intracellular signaling pathways regulating T-cell activation are summarized in detail elsewhere (Chapkin et al., 2009). Alterations in T-cell function by n-3 PUFA could reflect direct effects on the ability of target T-cell populations to respond to activating stimuli and/or indirect effects on the activity of accessory cells (non-T-cell populations), which promote T-cell activation or a combination of these two distinct mechanisms (Chapkin et al., 2009).

It is well documented that EPA and DHA (n-3 PUFA) supplant n-6 PUFA, principally linoleic acid and arachidonic acid (the major eicosanoid precursor), and can therefore dramatically alter both the spectrum and biological properties impacted by cyclooxygenase (COX) and lipoxygenase (LOX) derived metabolites (Chapkin et al., 2007; Smith, 2005). Arachidonic acid (n-6 PUFA) derived metabolites such as COX-derived prostaglandin (PG)-E2 and LOX-derived leukotriene (LT)-B4 are largely pro-inflammatory...