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.

Publisher: Elsevier Inc. on behalf of American Society for Biochemistry and Molecular Biology Country of Publication: United States NLM ID: 2985121R Publication Model: Print-Electronic Cited Medium: Print ISSN: 0021-9258 (Print) Linking ISSN: 00219258 NLM ISO Abbreviation: J Biol Chem Subsets: MEDLINE

Publication: 2021- : [New York, NY] : Elsevier Inc. on behalf of American Society for Biochemistry and Molecular Biology
Original Publication: Baltimore, MD : American Society for Biochemistry and Molecular Biology

Nuclear Proteins*; Arachidonate 12-Lipoxygenase/*metabolism ; Arachidonate 15-Lipoxygenase/*metabolism ; Interleukin-2/*biosynthesis ; Interleukin-4/*physiology ; Macrophages/*enzymology ; Receptors, Cytoplasmic and Nuclear/*physiology ; T-Lymphocytes/*metabolism ; Transcription Factors/*physiology; Base Sequence ; DNA/metabolism ; DNA Probes ; DNA-Binding Proteins/genetics ; Humans ; Ligands ; NF-kappa B/genetics ; NFATC Transcription Factors ; Protein Binding ; Receptors, Cytoplasmic and Nuclear/agonists ; Transcription Factors/agonists ; Transcription Factors/genetics ; Transcriptional Activation

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.

N01-CO-56000 United States CO NCI NIH HHS

0 (DNA Probes)
0 (DNA-Binding Proteins)
0 (Interleukin-2)
0 (Ligands)
0 (NF-kappa B)
0 (NFATC Transcription Factors)
0 (Nuclear Proteins)
0 (Receptors, Cytoplasmic and Nuclear)
0 (Transcription Factors)
207137-56-2 (Interleukin-4)
9007-49-2 (DNA)
EC 1.13.11.31 (Arachidonate 12-Lipoxygenase)
EC 1.13.11.33 (Arachidonate 15-Lipoxygenase)

Date Created: 20011201 Date Completed: 20020305 Latest Revision: 20210209

20240104

10.1074/jbc.M105619200

11726648