title: Interleukin (IL)-4 indirectly suppresses IL-2 production by human T lymphocytes via peroxisome proliferator-activated receptor gamma activated by macrophage-derived 12/15-lipoxygenase ligands.
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.
authors.affiliation: Intramural Research Support Program, Science Applications International Corporation, Frederick, MD 21702, USA.
authors.forename: Xiao Yi
authors.initials: XY
authors.lastname: Yang
authors.forename: Li Hua
authors.initials: LH
authors.lastname: Wang
authors.forename: Kelly
authors.initials: K
authors.lastname: Mihalic
authors.forename: Weihua
authors.initials: W
authors.lastname: Xiao
authors.forename: Taosheng
authors.initials: T
authors.lastname: Chen
authors.forename: Peng
authors.initials: P
authors.lastname: Li
authors.forename: Larry M
authors.initials: LM
authors.lastname: Wahl
authors.forename: William L
authors.initials: WL
authors.lastname: Farrar
mesh_terms: D001092:Arachidonate 12-Lipoxygenase / Q000378:metabolism*; D001093:Arachidonate 15-Lipoxygenase / Q000378:metabolism*; D001483:Base Sequence; D004247:DNA / Q000378:metabolism; D015342:DNA Probes; D004268:DNA-Binding Proteins / Q000235:genetics; D006801:Humans; D007376:Interleukin-2 / Q000096:biosynthesis*; D015847:Interleukin-4 / Q000502:physiology*; D008024:Ligands; D008264:Macrophages / Q000201:enzymology*; D016328:NF-kappa B / Q000235:genetics; D050778:NFATC Transcription Factors; D009687:Nuclear Proteins; D011485:Protein Binding; D018160:Receptors, Cytoplasmic and Nuclear / Q000819:agonists / Q000502:physiology*; D013601:T-Lymphocytes / Q000378:metabolism*; D014157:Transcription Factors / Q000819:agonists / Q000235:genetics / Q000502:physiology*; D015533:Transcriptional Activation
chemical_list: D015342:DNA Probes; D004268:DNA-Binding Proteins; D007376:Interleukin-2; D008024:Ligands; D016328:NF-kappa B; D050778:NFATC Transcription Factors; D009687:Nuclear Proteins; D018160:Receptors, Cytoplasmic and Nuclear; D014157:Transcription Factors; D015847:Interleukin-4; D004247:DNA; D001092:Arachidonate 12-Lipoxygenase; D001093:Arachidonate 15-Lipoxygenase