Abstract
Lipoxins are eicosanoid mediators that show potent inhibitory effects on the acute inflammatory process. We show here that the induction of lipoxin A4 (LXA4) accompanied the in vivo suppression of interleukin 12 (IL-12) responsiveness of murine splenic dendritic cells (DCs) after microbial stimulation with an extract of Toxoplasma gondii. This paralysis of DC function could not be triggered in mice that were deficient in a key lipoxygenase involved in LXA4 biosynthesis. In addition, DCs pre-treated with LXA4 became refractory to microbial stimulation for IL-12 production in vitro and mice injected with a stable LXA4 analog showed reduced splenic DC mobilization and IL-12 responses in vivo. Together, these findings indicate that the induction of lipoxins in response to microbial stimulation can provide a potent mechanism for regulating DC function during the innate response to pathogens.
This is a preview of subscription content, access via your institution
Access options
Subscribe to this journal
Receive 12 print issues and online access
$209.00 per year
only $17.42 per issue
Rent or buy this article
Prices vary by article type
from$1.95
to$39.95
Prices may be subject to local taxes which are calculated during checkout
Similar content being viewed by others
References
Trinchieri, G. Interleukin-12: a cytokine at the interface of inflammation and immunity. Adv. Immunol. 70, 83–243 (1998).
Yap, G., Pesin, M. & Sher, A. Cutting edge: IL-12 is required for the maintenance of IFN-γ production in T cells mediating chronic resistance to the intracellular pathogen, Toxoplasma gondii. J. Immunol. 165, 628–631 (2000).
Gazzinelli, R. T. et al. In the absence of endogenous IL-10, mice acutely infected with Toxoplasma gondii succumb to a lethal immune response dependent on CD4+ T cells and accompanied by overproduction of IL-12, IFN-γ and TNF-α. J. Immunol. 157, 798–805 (1996).
Shevach, E. M., Chang, J. T. & Segal, B. M. The critical role of IL-12 and the IL-12R β 2 subunit in the generation of pathogenic autoreactive Th1 cells. Springer Semin. Immunopathol. 21, 249–262 (1999).
Braun, M. C. & Kelsall, B. L. Regulation of interleukin-12 production by G-protein-coupled receptors. Microbes Infect. 3, 99–107 (2001).
Kelsall, B. L. & Karp, C. L. Introduction: the power of negative signaling. Microbes Infect. 3, 97–98 (2001).
Moser, M. & Murphy, K. M. Dendritic cell regulation of TH1-TH2 development. Nature Immunol. 1, 199–205 (2000).
Reis e Sousa, C. et al. In vivo microbial stimulation induces rapid CD40 ligand-independent production of interleukin 12 by dendritic cells and their redistribution to T cell areas. J. Exp. Med. 186, 1819–1829 (1997).
Reis e Sousa, C. et al. Paralysis of dendritic cell IL-12 production by microbial products prevents infection-induced immunopathology. Immunity 11, 637–647 (1999).
Aliberti, J. et al. CCR5 provides a signal for microbial induced production of IL-12 by CD8 α+ dendritic cells. Nature Immunol. 1, 83–87 (2000).
Sallusto, F. et al. Rapid and coordinated switch in chemokine receptor expression during dendritic cell maturation. Eur. J. Immunol. 28, 2760–2769 (1998).
Shen, W. et al. Activation of the chemotactic peptide receptor FPRL1 in monocytes phosphorylates the chemokine receptor CCR5 and attenuates cell responses to selected chemokines. Biochem. Biophys. Res. Commun. 272, 276–283 (2000).
Deng, X. et al. A synthetic peptide derived from human immunodeficiency virus type 1 gp120 downregulates the expression and function of chemokine receptors CCR5 and CXCR4 in monocytes by activating the 7-transmembrane G-protein-coupled receptor FPRL1/LXA4R. Blood 94, 1165–1173 (1999).
Chiang, N., Fierro, I. M., Gronert, K. & Serhan, C. N. Activation of lipoxin A4 receptors by aspirin-triggered lipoxins and select peptides evokes ligand-specific responses in inflammation. J. Exp. Med. 191, 1197–1208 (2000).
Serhan, C. N., Takano, T., Chiang, N., Gronert, K. & Clish, C. B. Formation of endogenous “antiinflammatory” lipid mediators by transcellular biosynthesis. Lipoxins and aspirin-triggered lipoxins inhibit neutrophil recruitment and vascular permeability. Am. J. Respir. Crit. Care Med. 161, 95–101 (2000).
Funk, C. D., Chen, X. S., Kurre, U. & Griffis, G. Leukotriene-deficient mice generated by targeted disruption of the 5-lipoxygenase gene. Adv. Prostaglandin Thromboxane Leukotriene Res. 23, 145–150 (1995).
Sodin-Semrl, S., Taddeo, B., Tseng, D., Varga, J. & Fiore, S. Lipoxin A4 inhibits IL-1 β-induced IL-6, IL-8, and matrix metalloproteinase-3 production in human synovial fibroblasts and enhances synthesis of tissue inhibitors of metalloproteinases. J. Immunol. 164, 2660–2666 (2000).
Ramstedt, U. et al. Lipoxin A-induced inhibition of human natural killer cell cytotoxicity: studies on stereospecificity of inhibition and mode of action. J. Immunol. 138, 266–270 (1987).
Hachicha, M., Pouliot, M., Petasis, N. A. & Serhan, C. N. Lipoxin LXA4 and aspirin-triggered 15-epi-LXA4 inhibit tumor necrosis factor 1α-initiated neutrophil responses and trafficking: regulators of a cytokine-chemokine axis. J. Exp. Med. 189, 1923–1930 (1999).
Maddox, J. F. et al. Lipoxin B4 regulates human monocyte/neutrophil adherence and motility: design of stable lipoxin B4 analogs with increased biologic activity. FASEB J. 12, 487–494 (1998).
Le, Y. et al. Desensitization of chemokine receptor CCR5 in dendritic cells at the early stage of differentiation by activation of formyl peptide receptors. Clin. Immunol. 99, 365–372 (2001).
Robbiani, D. F. et al. The leukotriene C4 transporter MRP1 regulates CCL19 (MIP-3β, ELC)-dependent mobilization of dendritic cells to lymph nodes. Cell 103, 757–768 (2000).
Braun, M. C., Wang, J. M., Lahey, E., Rabin, R. L. & Kelsall, B. L. Activation of the formyl peptide receptor by the HIV-derived peptide T-20 suppresses interleukin-12 p70 production by human monocytes. Blood 97, 3531–3536 (2001).
Spanbroek, R. et al. 5-lipoxygenase expression in dendritic cells generated from CD34+ hematopoietic progenitors and in lymphoid organs. Blood 96, 3857–3865 (2000).
Spanbroek, R. et al. IL-4 determines eicosanoid formation in dendritic cells by down-regulation of 5-lipoxygenase and up-regulation of 15-lipoxygenase 1 expression. Proc. Natl. Acad. Sci. USA 98, 5152–5157 (2001).
Schade, U. F., Engel, R. & Jakobs, D. The role of lipoxygenases in endotoxin-induced cytokine production. Prog. Clin. Biol. Res. 367, 73–82 (1991).
Surette, M. E., Palmantier, R., Gosselin, J. & Borgeat, P. Lipopolysaccharides prime whole human blood and isolated neutrophils for the increased synthesis of 5-lipoxygenase products by enhancing arachidonic acid availability: involvement of the CD14 antigen. J. Exp. Med. 178, 1347–1355 (1993).
Calorini, L., Mannini, A., Bianchini, F., Mugnai, G. & Ruggieri, S. The change in leukotrienes and lipoxins in activated mouse peritoneal macrophages. Biochim. Biophys. Acta 1484, 87–92 (2000).
Knight, J., Lloyd-Evans, P., Rowley, A. F. & Barrow, S. E. Effect of lipoxins and other eicosanoids on phagocytosis and intracellular calcium mobilisation in rainbow trout (Oncorhynchus mykiss) leukocytes. J. Leukoc. Biol. 54, 518–522 (1993).
Grunvald, E. et al. Biochemical characterization and protein kinase C dependency of monokine-inducing activities of Toxoplasma gondii. Infect. Immun. 64, 2010–2018 (1996).
Serhan, C. N. et al. Design of lipoxin A4 stable analogs that block transmigration and adhesion of human neutrophils. Biochemistry 34, 14609–14615 (1995).
Clish, C. B., Levy, B. D., Chiang, N., Tai, H. H. & Serhan, C. N. Oxidoreductases in lipoxin A4 metabolic inactivation: a novel role for 15-oxoprostaglandin 13-reductase/leukotriene B4 12-hydroxydehydrogenase in inflammation. J. Biol. Chem. 275, 25372–25380 (2000).
Acknowledgements
We thank P. Murphy and B. Kelsall for their comments on this manuscript as well as C. Clish, S. Huong, J. Brannon and G. Mirick for their invaluable assistance with the eicosanoid analysis. Supported in part by National Institutes of Health grants GM-38765 and PO1-DE13499 (to C. N. S.).
Author information
Authors and Affiliations
Corresponding author
Supplementary information
Web Figure 1.
MS-MS of endogenous LTB4 generated in vivo after STAg injection. A representative MS-MS from individual murine spleens (n=8) collected 6 h after STAg injection. The diagnostic ions and relative intensity matched those obtained with the authentic eicosanoids indicated for the LC-MS acquisition conditions. (GIF 17 kb)
Web Figure 2.
MS-MS of endogenous 15(S)-HETE generated in vivo after STAg injection. A representative MS-MS from individual murine spleens (n=8) collected 6 h after STAg injection. The diagnostic ions and relative intensity matched those obtained with the authentic eicosanoids indicated for the LC-MS acquisition conditions. (GIF 16 kb)
Web Figure 3.
MS-MS of endogenous 12(S)-HETE generated in vivo after STAg injection. A representative MS-MS from individual murine spleens (n=8) collected 6 h after STAg injection. The diagnostic ions and relative intensity matched those obtained with the authentic eicosanoids indicated for the LC-MS acquisition conditions. (GIF 21 kb)
Web Figure 4.
MS-MS of endogenous 5(S)-HETE generated in vivo after STAg injection. A representative MS-MS from individual murine spleens (n=8) collected 6 h after STAg injection. The diagnostic ions and relative intensity matched those obtained with the authentic eicosanoids indicated for the LC-MS acquisition conditions. (GIF 15 kb)
Rights and permissions
About this article
Cite this article
Aliberti, J., Hieny, S., Reis e Sousa, C. et al. Lipoxin-mediated inhibition of IL-12 production by DCs: a mechanism for regulation of microbial immunity. Nat Immunol 3, 76–82 (2002). https://doi.org/10.1038/ni745
Received:
Accepted:
Published:
Issue Date:
DOI: https://doi.org/10.1038/ni745
This article is cited by
-
Specialized pro-resolving lipid mediators in endodontics: a narrative review
BMC Oral Health (2021)
-
Resolution of neuroinflammation: mechanisms and potential therapeutic option
Seminars in Immunopathology (2019)
-
Specialized pro-resolving mediators: endogenous regulators of infection and inflammation
Nature Reviews Immunology (2016)
-
RETRACTED ARTICLE: Biological Mechanisms Relating Periodontitis and Diabetes
Current Oral Health Reports (2016)
-
Radiation-driven lipid accumulation and dendritic cell dysfunction in cancer
Scientific Reports (2015)