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

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

Peroxisome Proliferator-Activated Receptor γ Is Required for Regulatory CD4+ T Cell-Mediated Protection against Colitis

“…IL-4 was shown to simultaneously increase the expression of PPAR-␥ and 12,15-lipooxygenase, the enzyme involved in the generation of 13-HODE (30). Thus, it has been proposed that IL-4 indirectly down-regulates IL-2 production by T cells through PPAR-␥ (29,30). Overall, these results demonstrate that PPAR-␥ is a negative regulator of adaptive immune responses.…”

“…More specifically, PPAR-␥ activation by rosiglitazone decreased IFN-␥ production by splenocytes in vitro stimulated with PMA and ionomycin (27). Treatment of CD4 ϩ T cells with ciglitazone or 15-deoxy-PGJ2 triggered the physical association between PPAR-␥ and NFATc1, resulting in IL-4 promoter inhibition and decreased IL-4 production (28), and 13-hydroxyoctadecadienoic acid (13-HODE) a putative endogenously generated PPAR-␥ agonist, down-regulated IL-2 production by human peripheral blood T lymphocytes by reducing NFAT and NF-B binding to the IL-2 promoter (29). IL-4 was shown to simultaneously increase the expression of PPAR-␥ and 12,15-lipooxygenase, the enzyme involved in the generation of 13-HODE (30).…”

Étude d'association entre certains gènes candidats et l'asthme dans une cohorte familiale originaire du Saguenay-Lac-Saint-Jean :

“…D'autres études ont également identifié le PPARy comme un facteur hautement exprimé dans les cellules structurales et la sous-muqueuse pendant l'inflammation et le remodelage dans l'asthme (Benayoun et al, 2001). Le PPARy est exprimé dans les macrophages (Huang et al, 1999;Asada et al, 2004), les lymphocytes T activés (Yang et al, 2000;Yang et al, 2002), les cellules épithéliales (Wang et al, 2001) et les cellules du muscle lisse (Patel et al, 2003) dans le tissu pulmonaire humain.…”

“…La sélection du gène PPARG a été motivée sur la base de son expression dans les macrophages et les cellules épithéliales des voies respiratoires (Huang et al, 1999;Wang et al, 2001;Yang et al, 2002) et pour son rôle d'agent anti-inflammatoire dans des maladies à composante inflammatoire (Chinetti et al, 2000). Les résultats des Tableaux Bien que PPARy fut décrit comme un facteur d'importance dans les maladies lipidiques (diabète de type 2, sensibilité à l'insuline) (Deeb et al, 1998;Altshuler et al, 2000) et initialement associé à une augmentation du degré d'obésité (Beamer et al, 1998), de plus en plus de travaux montrent les implications physiologiques du PPARy dans les maladies à composantes inflammatoires, comme la régulation de l'inflammation (Mueller et al, 2003;Trifilieff et al, 2003), l'infiltration des éosinophiles (Woerly et al, 2003) ou le remodelage bronchique (Benayoun et al, 2001).…”

Hepatic stellate cells as a target for TZD: Can we treat liver fibrosis and type II diabetes at the same time?

“…10 The antagonism of transcription factors such as AP-1, STAT, NF-B, and NRF2 with TZD and/or PPAR␥, has been proposed for some of these effects. [4][5][6][7][8] Moreover, 13-hydroxyoctadecadienoic acid (13-HODE) and 15-hydroxyeicosatetraenoic acid (15-HETE) are considered as endogenous PPAR␥ ligands that are generated by 12/15-lipoxygenase and provide negative regulation in macrophages exposed to interleukin 4 (IL-4). 11 This mode of regulation is now extended to human T lymphocytes in which IL-4 -stimulated release of 13-HODE by macrophages is shown to exert a paracrine inhibitory effect on IL-2 expression via a direct negative cross-coupling of the transcription factor, NFAT with activated PPAR␥.…”