Summary The production of inflammatory mediators, relevant to (auto)immune diseases and chronic inflammatory conditions, can be modulated by dietary intake of n‐3 and n‐6 long chain polyunsaturated fatty acids (PUFAs). It was suggested that these effects are related to the formation of different series of eicosanoids, in particular prostaglandin‐E (PGE). In this study we investigated whether prostaglandin subtypes metabolized from arachidonic acid (PGE2), dihomo‐γ‐linolenic acid (PGE1) or eicosapentaenoic acid (PGE3) have different effects on T‐cell proliferation and cytokine production in vitro. Freshly isolated human peripheral blood mononuclear cells (PBMC) were stimulated with concanavalin A (ConA) or lipopolysaccharide (LPS) in the presence or absence of exogenous PGE1, PGE2 or PGE3. We found that tumour necrosis factor‐α (TNF‐α), interferon‐γ (IFN‐γ) and to a lesser extent interleukin (IL)‐10 production was inhibited by all PGE‐subtypes in ConA‐stimulated PBMC concomitant with unaffected IL‐2 levels. The modulated cytokine production of ConA stimulated cells was independent of T‐cell proliferation. PGE2 and PGE1 moderately stimulated proliferation, while PGE3 inhibited the proliferative response to some extent. In LPS‐stimulated PBMC, TNF‐α production was inhibited by all PGE‐subtypes, whereas IL‐6 remained unaffected and IL‐10 production was increased. Time course experiments on the effects of PGE‐subtypes on cytokine production after ConA or LPS stimulation showed these effects to be time dependent, but indifferent of the prostaglandin subtype added. Overall, the modulatory effects of PGE on cytokine production were irrespective of the subtype. This may implicate that the immunomodulatory effects of PUFAs, with respect to cytokine production, are not caused by a shift in the subtype of PGE.
Previous mouse studies have shown that IL-4 increases the expression of ICOS on activated Th cells, resulting in enhanced ICOS expression on Th2 cells. In this study, we show that ICOS expression on human Th cells is not increased by IL-4, but by IL-12 and by IL-23 instead. Consequently, ICOS expression during IL-12-driven Th1 cell polarization was transiently increased compared with the levels on Th0 cells and IL-4-driven Th2 cells. Addition of IL-12 and/or IL-23 during restimulation increased ICOS expression to the same extent on pre-established Th1, Th2, and Th0 cells, indicating that ICOS levels are not stably imposed by prior polarization. In contrast to the findings in the mouse, IL-4 significantly suppressed the ICOS-enhancing effects of IL-12 and IL-23. The functional consequence of variable ICOS levels was shown in coculture experiments with cells expressing the ICOS-ligand B7-related protein 1 (either transfected Chinese hamster ovary cells or autologous dendritic cells). Ligation of ICOS on 2-day-preactivated effector cells increased their cytokine production to an extent proportional to their ICOS expression levels. As the ICOS-enhancing potentials of IL-12 and IL-23 were maintained for several days after stimulation, both on Th1 and Th2 cells, we propose the concept that local regulation of ICOS expression on activated Th cells by IL-12 and/or IL-23 may provide a powerful means to amplify effector T cell responses in peripheral tissues, independently of the polarized state of the Th cells.
The CD28 homologue inducible costimulator (ICOS) has been demonstrated to regulate a number of T cell-dependent immune responses in vivo. However, the expression and functional importance of ICOS during APC-Th cell interaction in the human is not fully understood. Here, we demonstrate that ICOS-mediated signaling plays an important role in the production of selective cytokines during both primary and subsequent Th cell responses upon allospecific or superantigen activation. In contrast, ICOS does not play a role in the differentiation of naive cells into Th1 or Th2 effector cells, nor does it determine the type of effector function of memory cells upon subsequent allogeneic challenge. In addition, our data demonstrate that ICOS provides a novel and unique role in regulating DC-mediated Th2, but not Th1 cell clonal expansion. These data suggest that ICOS-mediated signaling plays a discrete role in the regulation of human T helper cell responses.
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