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Originally published In Press as doi:10.1074/jbc.M105619200 on November 28, 2001

J. Biol. Chem., Vol. 277, Issue 6, 3973-3978, February 8, 2002
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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*

Xiao Yi YangDagger , Li Hua Wang§, Kelly MihalicDagger , Weihua XiaoDagger , Taosheng ChenDagger , Peng Li, Larry M. Wahl||, and William L. Farrar§**

From the Dagger  Intramural Research Support Program, Science Applications International Corporation, Frederick, the § Cytokine Molecular Mechanisms Section, Laboratory of Molecular Immunoregulation, and the  Laboratory of Medicinal Chemistry, NCI, National Institutes of Health, Frederick, Maryland 21702 and the || Immunopathology Section, NIDR, National Institutes of Health, Bethesda, Maryland 20892

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 kappa B, 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.

* This work was supported by National Institutes of Health NCI Contract NO1-CO-56000.The costs of publication of this article were defrayed in part by the payment of page charges. The article must therefore be hereby marked "advertisement" in accordance with 18 U.S.C. Section 1734 solely to indicate this fact.

** To whom reprint requests should be addressed: Cytokine Molecular Mechanisms Section, Laboratory of Molecular Immunoregulation, NCI, National Institutes of Health, P.O. Box B, Bldg. 560, Rm. 31-76, Frederick, MD 21702. Tel.: 301-846-1503; Fax: 301-846-6019/6187; E-mail: farrar@mail.ncifcrf.gov.

Copyright © 2002 by The American Society for Biochemistry and Molecular Biology, Inc.
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