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Objectives: This study investigated the effect of dietary CLA supplementation (3g/day; 50:50 mix of the two major isomers) on the immune system and plasma lipids and glucose of healthy human (male and female) volunteers. Design: Double-blind, randomized, reference-controlled study. Subject and intervention: A total of 28 healthy male and female participants aged 25-50 y received either high oleic sunflower oil (reference) or 50% CLA 9-11 and 50% CLA 10-12 CLA isomers (50:50 CLA-triglyceride form). The treatments were given as supplements in soft-gel capsules providing a total 3 g (6 Â 500 mg capsules) per day in treatment groups for 12 weeks. A 12-week washout period followed the intervention period. Results: Levels of plasma IgA and IgM were increased (Po0.05 and 0.01 respectively), while plasma IgE levels were decreased (Po0.05). CLA supplementation also decreased the levels of the proinflammatory cytokines, TNF-a and IL-1b (Po0.05), but increased the levels of the anti-inflammatory cytokine, IL-10 (Po0.05). Another aspect of immune function, delayed type hypersensitivity (DTH) response, was decreased during and after CLA supplementation (Po0.05). However, plasma glucose, lipids, lymphocyte phenotypic results were not affected significantly by CLA. Conclusion: This is the first study to show that CLA, a fatty acid naturally found in dairy and meat products, can beneficially affect immune function in healthy human volunteers. Sponsorship: This study was supported by Loders-Croklaan, The Netherlands and SEERAD (Scottish Executive Environmental Rural and Agriculture Department).

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SUMMARYSynthesis of interferon (IFN)-g by natural killer (NK) cells is an important pro-in¯ammatory event with interleukin (IL)-12 and IL-18 playing major inductive roles. However, other temporal events are likely to regulate such processes and as prostaglandin E 2 (PGE 2 ) is ubiquitous during in¯ammation this study tested the hypothesis that PGE 2 was capable of directly modulating cytokine-induced NK cell IFN-g synthesis in the absence of other immune cells. Using homogenous NK cell lines to establish direct effects, PGE 2 (0Á1±1 mM) was found to suppress NK cell IFN-g synthesis and antagonized the potent synergistic IFN-g-inducing effects of IL-12 and IL-18. The actions of PGE 2 were mimicked by synthetic PGE 2 analogues including misoprostol and butaprost. The selective EP 2 receptor agonist butaprost, but not the EP 1 /EP 3 agonist sulprostone, suppressed IFN-g synthesis and exclusively competed with PGE 2 for receptor binding on NK cells. Further analysis showed that PGE 2 did not modulate IL-12 receptor mRNA expression and the effects of PGE 2 could be mimicked by the phosphodiesterase inhibitor 3-iosobutyl-1-methylxanthine. The absence of demonstrable receptor modulation coupled with the observed suppression of IFN-g synthesis by both EP 2 receptor-selective agonists and IBMX suggest that PGE 2 acts directly on NK cells via EP 2 receptors with its downstream effects on cAMP metabolism. This conclusion is further supported by ®ndings that PGE 2 and its analogues consistently elevated levels of cAMP in NK cells. The ability of PGE 2 to antagonize the potent inductive signal provided by the combination of IL-12 and IL-18 supports the concept that PGE 2 may play an important role in limiting innate in¯ammatory processes in vivo through direct suppression of NK cell IFN-g synthesis.

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The effect of human recombinant lipocortin-1 (hrLC-1) on the pyrogenic actions of the synthetic polyribonucleotide polyinosinic: polycytidylic acid (poly I: C) has been studied in conscious rabbits. Poly I: C (2.5 pg kg-) given i.v. produced a biphasic fever with a first peak after 90-105 min and a second peak between 225-240 min. hrLC-1 (50ougkg-) given i.v. simultaneously with the poly I: C produced a significant reduction in the febrile response but without complete suppression. The thermal response index over 5 h (TRI5) was 4.69 + 0.51 for poly I: C given with saline and the TRI5 for poly I: C given with hrLC-1 was 2.66 + 0.45 (values are for n = 5 + s.e.mean, P < 0.05). hrLC-1 administered alone had no effect on body temperature and its antipyretic activity was lost on heating. In a separate series of experiments 1 h pretreatment with dexamethasone (1 mgkg -) given i.v. reduced the pyrogenic response (TRI5) to poly I: C (2.5 ug kg-1) from 4.87 + 0.54 without dexamethasone to 2.00 + 0.25 (n = 5, P < 0.05) and dexamethasone given alone had no effect on body temperature. These data demonstrate that LC-1 possesses antipyretic actions and raises the possibility that the antipyretic actions of dexamethasone are mediated through the induction of LC-1.