Hostname: page-component-cd9895bd7-dk4vv Total loading time: 0 Render date: 2024-12-23T17:02:04.082Z Has data issue: false hasContentIssue false
  • English
  • Français

Fatty acid-mediated inhibition of IL-12 production by murine macrophages is independent of PPARγ

Published online by Cambridge University Press:  09 March 2007

Meijuan Zhang  and
Kevin L. Fritsche
Meijuan Zhang
Affiliation:
Department of Animal Sciences and the Nutritional Sciences Graduate Program, University of Missouri-Columbia, Columbia, MO 65211, USA
Kevin L. Fritsche*
Affiliation:
Department of Animal Sciences and the Nutritional Sciences Graduate Program, University of Missouri-Columbia, Columbia, MO 65211, USA
*
*Corresponding author: Dr Kevin Fritsche, fax +1 573 882 6827, email [email protected]
Rights & Permissions [Opens in a new window]

Abstract

Core share and HTML view are not available for this content. However, as you have access to this content, a full PDF is available via the ‘Save PDF’ action button.

Our laboratory has reported that n-3 PUFA can reduce host resistance to Listeria infection, in part, by impairing in vivo IL-12 biosynthesis. Recently, PUFA were shown to be ligands for PPAR, a novel family of nuclear receptors with three isoforms: PPARα, PPARδ/β and PPARγ. PPARγ is expressed in immune cells, such as T cells and macrophages. Two PPARγ agonists, 15-deoxy-Δ12,14-prostaglandin (PG) J2 and rosiglitazone, have been shown to have immunomodulatory activity in vitro, including inhibiting IL-12 biosynthesis. We hypothesized that n-3 PUFA inhibit IL-12 production through activating PPARγ. We used thioglycolate-elicited mouse peritoneal macrophages to study the effect of various fatty acids and their oxidized metabolites on in vitro IL-12 production. Our present results demonstrate that both n-3 and n-6 PUFA can reduce in vitro IL-12 biosynthesis, though less potently than 15-deoxy-PGJ2 and rosiglitazone. GW9662, a PPARγ antagonist, reversed the inhibitory effect of rosiglitazone, but not that of PUFA. Our present findings suggest that fatty acid-mediated inhibition of IL-12 production is independent of PPARγ.

Keywords

Polyunsaturated fatty acidsPeroxisome proliferator-activated receptor-γInterleukin 12Macrophages
Type
Research Article
Information
British Journal of Nutrition , Volume 91 , Issue 5 , May 2004 , pp. 733 - 739
Copyright
Copyright © The Nutrition Society 2004

References

Adorini, L, Aloisi, F, Galbiati, F, et al. (1997) Targeting IL-12, the key cytokine driving th1-mediated autoimmune diseases. Chem Immunol 68, 175–197.Google ScholarPubMed
Alleva, DG, Johnson, EB, Lio, FM et al. (2002) Regulation of murine macrophage proinflammatory and anti-inflammatory cytokines by ligands for peroxisome proliferator-activated receptor-gamma: Counter-regulatory activity by IFN-gamma. J Leukoc Biol 71, 677–685.CrossRefGoogle ScholarPubMed
Blok, WL, Deslypere, JP, Demacker, PN et al. (1997) Pro- and anti-inflammatory cytokines in healthy volunteers fed various doses of fish oil for 1 year. Eur J Clin Invest 27, 1003–1008.CrossRefGoogle ScholarPubMed
Calder, PC (1996) Effects of fatty acids and dietary lipids on cells of the immune system. Proc Nutr Soc 55, 127–150.CrossRefGoogle ScholarPubMed
Calder, PC (1997) n -3 Polyunsaturated fatty acids and cytokine production in health and disease. Ann Nutr Metab 41, 203–234.CrossRefGoogle ScholarPubMed
Calder, PC (1998) Dietary fatty acids and lymphocyte functions. Proc Nutr Soc 57, 487–502.CrossRefGoogle ScholarPubMed
Chawla, A, Repa, JJ, Evans, RM & Mangelsdorf, DJ (2001) Nuclear receptors and lipid physiology: Opening the X-files. Science 294, 1866–1870.Google Scholar
Chen, C-W, Chang, Y-H, Tsi, C-J & Lin, W-W (2003) Inhibition of IFN-γ-mediated inducible nitric oxide synthase induction by the peroxisome proliferator-activated receptor γ agonist, 15-deoxy-Δ 12,14 -prostaglandin J 2, involves inhibition of upstream janus kinase/STAT1 signaling pathway. J Immunol 171, 979–988.CrossRefGoogle ScholarPubMed
Chung, SW, Kang, BY, Kim, SH et al. (2000) Oxidized low density lipoprotein inhibits interleukin-12 production in lipopolysaccharide-activated mouse macrophages via direct interactions between peroxisome proliferator-activated receptor-gamma and nuclear factor-kappa b. J Biol Chem 275, 32681–32687.CrossRefGoogle ScholarPubMed
D'Andrea, A, Rengaraju, M, Valiante, NM et al. (1992) Production of natural killer cell stimulatory factor (NKSF/IL-12) by peripheral blood mononuclear cells. J Exp Med 176, 1387–1398.Google Scholar
de Urquiza, AM, Liu, S, Sjoberg, M et al. (2000) Docosahexaenoic acid, a ligand for the retinoid X receptor in mouse brain. Science 290, 2140–2144.CrossRefGoogle ScholarPubMed
Ehrt, S, Schnappinger, D, Bekiranov, S et al. (2001) Reprogramming of the macrophage transcriptome in response to interferon-gamma and mycobacterium tuberculosis: Signaling roles of nitric oxide synthase-2 and phagocyte oxidase. J Exp Med 194, 1123–1140.Google Scholar
Endres, S (1996) n -3 Polyunsaturated fatty acids and human cytokine synthesis. Lipids 31, SupplS239–S242.Google Scholar
Feng, C, Keisler, DH & Fritsche, KL (1999) Dietary omega-3 polyunsaturated fatty acids reduce IFN-gamma receptor expression in mice. J Interferon Cytokine Res 19, 41–48.CrossRefGoogle ScholarPubMed
Fitzpatrick, FA & Wynalda, MA (1983) Albumin-catalyzed metabolism of prostaglandin D2. Identification of products formed in vitro. J Biol Chem 258, 11713–11718.Google Scholar
Flesch, I, Hess, JH, Huang, S et al. (1995) Early interleukin-12 production by macrophages in response to mycobacterial infection depends on interferon-γ and tumor necrosis factor α. J Exp Med 181, 1615–1621.CrossRefGoogle ScholarPubMed
Fritsche, KL, Anderson, M & Feng, C (2000) Consumption of eicosapentaenoic acid and docosahexaenoic acid impair murine interleukin-12 and interferon-gamma production in vivo. J Infect Dis 182, Suppl 1S54–S61.Google Scholar
Fritsche, KL, Byrge, M & Feng, C (1999) Dietary omega-3 polyunsaturated fatty acids from fish oil reduce interleukin-12 and interferon-gamma production in mice. Immunol Lett 65, 167–173.CrossRefGoogle ScholarPubMed
Gelman, L, Fruchart, JC & Auwerx, J (1999) An update on the mechanisms of action of the peroxisome proliferator-activated receptors (PPARs) and their roles in inflammation and cancer. Cell Mol Life Sci 55, 932–943.CrossRefGoogle ScholarPubMed
Grimble, RF & Tappia, PS (1998) Modulation of pro-inflammatory cytokine biology by unsaturated fatty acids. Z Ernahrungswiss 37, 57–65.Google ScholarPubMed
Harbige, LS (1998) Dietary n -6 and n -3 fatty acids in immunity and autoimmune disease. Proc Nutr Soc 57, 555–562.CrossRefGoogle Scholar
Hinz, B, Brune, K & Pahl, A (2003) 15-deoxy-delta(12,14)-prostaglandin J2 inhibits the expression of proinflammatory genes in human blood monocytes via a PPAR-gamma-independent mechanism. Biochem Biophys Res Commun 302, 415–420.CrossRefGoogle Scholar
Hsieh, C, Macatonia, SE, Tripp, CS et al. (1993) Development of Th1 CD4 + T cells through IL-12 produced by listeria-induced macrophages. Science 260, 547–549.CrossRefGoogle ScholarPubMed
Huang, JT, Welch, JS, Ricote, M et al. (1999) Interleukin-4-dependent production of PPAR-gamma ligands in macrophages by 12/15-lipoxygenase. Nature 400, 378–382.Google Scholar
Jiang, C, Ting, AT & Seed, B (1998) PPAR-gamma agonists inhibit production of monocyte inflammatory cytokines. Nature 391, 82–86.CrossRefGoogle ScholarPubMed
Kliewer, SA, Forman, BM, Blumberg, B et al. (1994) Differential expression and activation of a family of murine peroxisome proliferator-activated receptors. Proc Natl Acad Sci USA 91, 7355–7359.Google Scholar
Kliewer, SA, Sundseth, SS, Jones, SA et al. (1997) Fatty acids and eicosanoids regulate gene expression through direct interactions with peroxisome proliferator-activated receptors alpha and gamma. Proc Natl Acad Sci USA 94, 4318–4323.Google Scholar
Krey, G, Braissant, O, L'Horset, F et al. (1997) Fatty acids, eicosanoids, and hypolipidemic agents identified as ligands of peroxisome proliferator-activated receptors by coactivator-dependent receptor ligand assay. Mol Endocrinol 11, 779–791.Google Scholar
Lee, CH, Chawla, A, Urbiztondo, N et al. (2003 a) Transcriptional repression of atherogenic inflammation: Modulation by PPAR delta. Science 302, 453–457.Google Scholar
Lee, JY, Plakidas, A, Lee, WH et al. (2003 b) Differential modulation of toll-like receptors by fatty acids: Preferential inhibition by n-3 polyunsaturated fatty acids. J Lipid Res 44, 479–486.CrossRefGoogle ScholarPubMed
Meydani, SN (1996) Effect of (n-3) polyunsaturated fatty acids on cytokine production and their biologic function. Nutrition 12, S8–S14.Google ScholarPubMed
Nagy, L, Tontonoz, P, Alvarez, JG, Chen, H & Evans, RM (1998) Oxidized LDL regulates macrophage gene expression through ligand activation of PPAR gamma. Cell 93, 229–240.Google Scholar
Petrova, TV, Akama, KT, Van Eldik, LJ (1999) Cyclopentenone prostaglandins suppress activation of microglia: Down-regulation of inducible nitric-oxide synthase by 15-deoxy-delta 12,14-prostaglandin J 2. Proc Natl Acad Sci USA 96, 4668–4673.CrossRefGoogle Scholar
Podlaski, FJ, Nanduri, VB, Hulmes, JD et al. (1992) Molecular characterization of interleukin 12. Arch Biochem Biophys 294, 230–237.CrossRefGoogle ScholarPubMed
Ramana, CV, Gil, MP, Schreiber, RD & Stark, GR (2002) STAT1-dependent and -independent pathways in IFN-gamma-dependent signaling. Trends Immunol 23, 96–101.CrossRefGoogle ScholarPubMed
Ricote, M, Li, AC, Willson, TM, Kelly, CJ & Glass, CK (1998) The peroxisome proliferator-activated receptor-gamma is a negative regulator of macrophage activation. Nature 391, 79–82.Google Scholar
Shibata, T, Kondo, M & Osawa, T (2002) 15-deoxy-delta 12,14-prostaglandin J 2. A prostaglandin D 2 metabolite generated during inflammatory processes. J Biol Chem 277, 10459–10466.Google Scholar
Takeda, K, Kaisho, T & Akira, S (2003) Toll-like receptors. Annu Rev Immunol 21, 335–376.Google Scholar
Thieringer, R, Fenyk-Melody, JE & Le Grand, CB (2000) Activation of peroxisome proliferator-activated receptor gamma does not inhibit IL-6 or THF-alpha responses of macrophages to lipopolysaccharide in vitro or in vivo. J Immunol 164, 1046–1054.Google Scholar
Trinchieri, G (1995) Interleukin-12: A proinflammatory cytokine with immunoregulatory functions that bridge innate resistance and antigen-specific adaptive immunity. Annu Rev Immunol 13, 251–276.Google Scholar
van der Pouw Kraan, TCTM, Boeije, LCM, Smeenk, RJT, Wijdenes, J & Aarden, LA (1995) Prostaglandin-E 2 is a potent inhibitor of human interleukin 12 production. J Exp Med 181, 775–779.Google Scholar
Wallace, FA, Miles, EA & Evans, C (2001) Dietary fatty acids influence the production of Th1- but not Th2-type cytokines. J Leukoc Biol 69, 449–457.Google Scholar
Welch, JS, Ricote, M, Akiyama, TE, Gonzalez, FJ & Glass, CK (2003) PPARgamma and PPARdelta negatively regulate specific subsets of lipopolysaccharide and IFN-gamma target genes in macrophages. Proc Natl Acad Sci USA 100, 6712–6717.CrossRefGoogle ScholarPubMed
Willson, TM, Brown, PJ, Sternbach, DD & Henke, BR (2000) The PPARs: From orphan receptors to drug discovery. J Med Chem 43, 527–550.Google Scholar
Wright, HM, Clish, CB & Mikami, T (2000) A synthetic antagonist for the peroxisome proliferator-activated receptor gamma inhibits adipocyte differentiation. J Biol Chem 275, 1873–1877.CrossRefGoogle ScholarPubMed
Wu, D & Meydani, SN (1998) n -3 Polyunsaturated fatty acids and immune function. Proc Nutr Soc 57, 503–509.CrossRefGoogle ScholarPubMed
Xu, HE, Lambert, MH & Montana, VG (1999) Molecular recognition of fatty acids by peroxisome proliferator-activated receptors. Mol Cell 3, 397–403.CrossRefGoogle ScholarPubMed