Interleukin (IL)-4 Indirectly Suppresses IL-2 Production by Human T Lymphocytes via Peroxisome Proliferator-activated Receptor γ Activated by Macrophage-derived 12/15-Lipoxygenase Ligands

• Published in: The Journal of biological chemistry 2002-02, Vol.277 (6), p.3973-3978
• Main Authors: Yang, Xiao Yi, Wang, Li Hua, Mihalic, Kelly, Xiao, Weihua, Chen, Taosheng, Li, Peng, Wahl, Larry M., Farrar, William L.
• Format: Article
• Language: English
• Subjects: 12/15-lipoxygenase; 13-hydroxyoctadecadienoic acid; Arachidonate 12-Lipoxygenase - metabolism; Arachidonate 15-Lipoxygenase - metabolism; Base Sequence; DNA - metabolism; DNA Probes; DNA-Binding Proteins - genetics; Humans; Interleukin-2 - biosynthesis; Interleukin-4 - physiology; Ligands; lipoxygenase; Macrophages - enzymology; NF-kappa B - genetics; NFAT protein; NFATC Transcription Factors; Nuclear Proteins; peroxisome proliferator-activated receptor-g; Protein Binding; Receptors, Cytoplasmic and Nuclear - agonists; Receptors, Cytoplasmic and Nuclear - physiology; T-Lymphocytes - metabolism; Transcription Factors - agonists; Transcription Factors - genetics; Transcription Factors - physiology; Transcriptional Activation
• ISSN: 0021-9258; 1083-351X
• DOI: 10.1074/jbc.M105619200

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 γ (PPARγ) ligands by inducing macrophage 12/15-lipoxygenase (12/15-LO). We have shown previously that the activated PPARγ 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 PPARγ 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 PPARγ-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 κB, 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 PPARγ. These data provide a mechanism whereby IL-4 may indirectly affect Thp function via PPARγ activated by macrophage products of the 12/15-LO pathway.