Abstract
The respective development of either T helper type 1 (Th1) or Th2 cells is believed to be mediated by the effects of cytokines acting directly on Th precursors (Thp). We have generated evidence for an indirect monocyte-dependent immunoregulatory pathway. Recently, interleukin (IL) 4 has been shown to produce "new" potential peroxisome proliferator-activated receptor gamma (PPARgamma) ligands by inducing macrophage 12/15-lipoxygenase (12/15-LO). We have shown previously that the activated PPARgamma is a profound inhibitor of IL-2 transcription in human T lymphocytes. It is hypothetically possible that IL-4 might indirectly affect IL-2 production by Thp cells via macrophage-derived PPARgamma ligands. Using human monocytes and T lymphocytes from same donors, we have found that monocyte 12/15-LO products mediate the indirect inhibitory effect of IL-4 on anti-CD3- or phytohemagglutinin/phorbol 12-myristate 13-acetate-stimulated IL-2 production by T lymphocytes. We further analyzed which major 12/15-LO metabolites contributed to the above inhibition. 13-Hydroxyoctadecadienoic acid (13-HODE), a 12/15-LO product, markedly blocked IL-2 production by human blood T lymphocytes, but not Jurkat T cells. Moreover, the IL-4-conditioned macrophage medium contained a sufficient amount of 13-HODE and anti-13-HODE antibody indeed neutralized the inhibitory effects of the IL-4-conditional medium on T-cell IL-2 production. Using human T lymphocytes and the PPARgamma-transfected Jurkat T cells, we demonstrated the specific inhibition by 13-HODE of the transcription factors NFAT (nuclear factor of activated T cells) and nuclear factor kappaB, the IL-2 promoter reporter, and IL-2 production. However, 15-hydroxytetraenoic acid had little inhibitory effect. The potency of such inhibitory effects correlates well with the capability of the above metabolic lipids to activate PPARgamma. These data provide a mechanism whereby IL-4 may indirectly affect Thp function via PPARgamma activated by macrophage products of the 12/15-LO pathway.
Highlights
The respective development of either T helper type 1 (Th1) or Th2 cells is believed to be mediated by the effects of cytokines acting directly on Th precursors (Thp)
IL-4 Indirectly Inhibits Anti-CD3- or PHA/PMA-stimulated IL-2 Production by T Lymphocytes via Monocyte 12/15-LO Products—To examine the possibility and physiological relevance of the regulation of the soluble mediators released by IL-4-treated monocyte/macrophages on T lymphocyte activation, we first tested the effect of products from IL-4-treated macrophages on IL-2 production by fresh human T lymphocytes
Western blot analysis showed the expression of 12/15-LO by IL-4-induced monocytes, but not by blood primary T lymphocytes or Jurkat T cells (Fig. 1b), which was consistent with the previous reports that IL-4 induces 12/15-LO expression on human monocyte [27], but not human lymphocytes [28]
Summary
T helper; IL, interleukin; ELISA, enzyme-linked immunosorbent assay; EMSA, electrophoretic mobility shift assay; 15-HETE, 15-hydroxytetraenoic acid; 13-HODE, 13-hydroxy octadecadienoic acid; LO, lipoxygenase; NFAT, nuclear factor of activated T cells; NF-B, nuclear factor B; PHA, phytohemagglutinin; PMA, phorbol 12-myristate 13-acetate; PPAR, peroxisome proliferatoractivated receptor. This represented a novel mechanism and function of the PPAR␥ nuclear receptor in T cell biology [16]. It is well known that IL-4 exerts immunomodulatory effects on monocytes and T cells. These observations led us to hypothesize that IL-4 might indirectly affect the production of IL-2 by Thp helper cells by inducing the production of these potential PPAR␥ ligands by macrophage 12/15-lipoxygenase, which in turn interfere with the subsequent development of T helper cells
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