Down-Regulation of the Acute-Phase Response in Patients with Pancreatic Cancer Cachexia Receiving Oral Eicosapentaenoic Acid is Mediated via Suppression of Interleukin-6

Abstract

1. Weight loss in pancreatic cancer is associated with persistent elevation of the acute-phase protein response. The effect of oral administration of eicosapentaenoic acid on the regulation of the acute-phase response in weight-losing patients with pancreatic cancer was investigated in vitro and in vivo. 2. Oral supplementation with eicosapentaenoic acid, in patients with cancer cachexia, resulted in a significant reduction in the serum concentration of the acute-phase protein C-reactive protein (11.0 +/- 4.8 mg/l before eicosapentaenoic acid compared with 0.8 +/- 0.8 mg/l after 4 weeks of eicosapentaenoic acid, P < 0.05), but no significant reduction in the serum concentration of the hepatocyte-stimulating cytokine interleukin-6. Production of interleukin-6 by peripheral blood mononuclear cells isolated from patients was significantly reduced after supplementation with eicosapentaenoic acid (interleukin-6 production by peripheral blood mononuclear cells exposed to 10 micrograms of lipopolysaccharide/ml: 10.2 +/- 2.1 ng/ml before supplementation with eicosapentaenoic acid compared with 3.5 +/- 1.7 ng/ml after supplementation, P < 0.05) and supernatants from these cells had reduced potential to stimulate C-reactive protein production by isolated human hepatocytes (hepatocyte C-reactive protein production in response to supernatants from peripheral blood mononuclear cell cultures exposed to 10 micrograms of lipopolysaccharide/ml: 150.4 +/- 18.6 ng/ml before eicosapentaenoic acid versus 118 +/- 14.9 ng/ml after 4 weeks of eicosapentaenoic acid, P < 0.05). The potential of lipopolysaccharide-stimulated peripheral blood mononuclear cell supernatants to stimulate C-reactive protein production by hepatocytes could be attenuated by neutralizing anti-interleukin-6 antibody in control subjects and in patients before, but not after, treatment with eicosapentaenoic acid. 3. In conclusion, eicosapentaenoic acid can down-regulate the acute-phase response in patients with pancreatic cancer cachexia and this process is likely to involve suppression of interleukin-6 production.

Plasma and neutrophil fatty acid composition in advanced cancer patients and response to fish oil supplementation

“…The efficacy of fatty acid incorporation during our short-term fish oil supplementation may be compared with related studies. Other authors employing fish oil capsules (Barber et al, 1998;Gogos et al, 1998) or fish oilenriched enteral formula (Barber, 2001) to deliver similar amounts of fish oil to those reported here, report comparable elevations of per cent n-3 fatty acids in plasma PL of advanced cancer patients using longer intervention periods (Wigmore et al, 1997;Barber et al, 1999). In the present study, the ratio of 20 : 3 n-9 to 20 : 4 n-6 in plasma PL was reduced following the fish oil treatment and may suggest an improvement in essential fatty acid status.…”

“…Firstly, patients with advanced cancer had very low levels of plasma PL. Other studies on lipid supplementation reported the fraction of n-3 fatty acids in plasma PL, but not the plasma PL levels (Wigmore et al, 1996(Wigmore et al, , 1997Barber et al, 1999), so this abnormality was previously undetected. The cause(s) or the point in time that low levels of plasma PL evolved has not been identified, therefore it would seem important to follow this variable in newly diagnosed patients over the disease trajectory in further studies.…”

“…Dietary supplementation with the n-3 polyunsaturated fatty acids (PUFA), eicosapentanoic acid (EPA) and docosahexanoic acid (DHA) as either fish oil capsules or a fish oil-supplemented enteral formula has been reported to attenuate weight loss, increase appetite, improve quality of life and prolong survival in weight losing cancer patients (Wigmore et al, 1996(Wigmore et al, , 1997(Wigmore et al, , 2000Barber et al, 1999). Beneficial effects of n-3 fatty acid supplementation imply the presence of an imbalance between essential n-6 and n-3 fatty acids or a deficiency of n-3 fatty acids.…”

n-3 Polyunsaturated fatty acids decrease mucosal/epidermal reactions and enhance antitumour effect of ionising radiation with inhibition of tumour angiogenesis

“…Studies of weight-losing pancreatic cancer patients receiving high-purity EPA have demonstrated suppression of PBMC IL-6 production (Wigmore et al, 1997). Serhan et al (2000) have reported that n-3 PUFA exerts antimicroinflammatory lipid signals via COX-2, which might be involved in its radioprotective action.…”

Fish oil feeding enhances lymphocyte proliferation but impairs virus-specific T lymphocyte cytotoxicity in mice following challenge with influenza virus

“…Dietary long chain (n-3) polyunsaturated fatty acids derived from ®sh oil have been shown to have bene®cial effects on in¯ammatory and autoimmune disorders [1±4], and cancer [5], suggesting that ®sh oil has anti-in¯ammatory and immunomodulatory activities. For instance, ®sh oil has been reported to reduce the production of mediators such as eicosanoids and cytokines which contribute to in¯ammation and pathological changes in atherosclerosis, autoimmunity and infectious disease [6,7].…”