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Cells IL-10 in Bone Marrow-Derived IFN-γ Negatively Regulates CpG-Induced IL-10 in Bone Marrow-Derived Dendritic Cells This information is current as Rafael R. Flores, Kelly A. Diggs, Lauren M. Tait and of September 23, 2021. Penelope A. Morel J Immunol 2007; 178:211-218; ; doi: 10.4049/jimmunol.178.1.211 http://www.jimmunol.org/content/178/1/211 Downloaded from References This article cites 57 articles, 26 of which you can access for free at: http://www.jimmunol.org/content/178/1/211.full#ref-list-1 http://www.jimmunol.org/ Why The JI? Submit online. • Rapid Reviews! 30 days* from submission to initial decision • No Triage! Every submission reviewed by practicing scientists • Fast Publication! 4 weeks from acceptance to publication by guest on September 23, 2021 *average Subscription Information about subscribing to The Journal of Immunology is online at: http://jimmunol.org/subscription Permissions Submit copyright permission requests at: http://www.aai.org/About/Publications/JI/copyright.html Email Alerts Receive free email-alerts when new articles cite this article. Sign up at: http://jimmunol.org/alerts The Journal of Immunology is published twice each month by The American Association of Immunologists, Inc., 1451 Rockville Pike, Suite 650, Rockville, MD 20852 Copyright © 2007 by The American Association of Immunologists All rights reserved. Print ISSN: 0022-1767 Online ISSN: 1550-6606. The Journal of Immunology IFN-␥ Negatively Regulates CpG-Induced IL-10 in Bone Marrow-Derived Dendritic Cells1 Rafael R. Flores, Kelly A. Diggs, Lauren M. Tait, and Penelope A. Morel2 Dendritic cells (DCs) are important players in the regulation of Th1- and Th2-dominated immune responses. In these studies we showed that IFN-␥, the key mediator of Th1 immunity, actively suppressed the production of IL-10 in murine DCs when activated with LPS or CpG. Our analysis revealed that both LPS and CpG induced IL-10 and IL-12 production but that the presence of IFN-␥, in a dose-dependent manner, suppressed the production of IL-10 while enhancing that of IL-12. The observed inhibition of IL-10 production was independent of IL-12. Experiments performed with STAT-1 knockout mice demonstrated that the primary production of IL-12 induced by CpG was STAT-1 dependent, whereas the production of IL-10 was not. This finding was confirmed by the observation that CpG-induced IL-12 production could be inhibited by anti-IFN-␤ Abs, whereas CpG-induced ␥ IL-10 production could not be inhibited. These data also demonstrated that the inhibitory effect of IFN- on IL-10 expression was Downloaded from STAT-1 dependent and transcriptionally regulated. Thus, DCs respond to CpG by producing proinflammatory and anti- inflammatory cytokines such as IL-12 and IL-10, respectively, and IFN-␥ acts to not only enhance IL-12 but also to inhibit IL-10 production. The current data demonstrate a novel pathway for IFN-␥-mediated immunoregulation and suggest that IFN-␥- dependent suppression of IL-10 production by DCs may be involved in the antagonism between Th1 and Th2 patterns of immune reactivity. The Journal of Immunology, 2007, 178: 211–218. http://www.jimmunol.org/ endritic cells (DCs)3 are APCs that provide a link be- The innate response by DCs is mediated by receptors that rec- tween the innate and adaptive immune systems. Imma- ognize conserved molecular structures on pathogens known as D ture DCs reside in peripheral tissue and sample the en- pathogen-associated molecular patterns. The recognition of these vironment for pathogens. The uptake of pathogens and the patterns is performed by pattern recognition receptors that include secretion of inflammatory cytokines induce DC maturation and lectins (DC-SIGN, DEC-205, and the mannose receptor) (11, 12) migration to draining lymph nodes, where DCs encounter Ag-spe- and TLRs of which there are 11 human and 10 murine (13). TLR2, cific T cells (1). During this encounter, DCs present Ag, in the TLR4, and TLR6 form multisubunit complexes and preferentially form of MHC-peptide complexes, and also provide costimulatory respond to bacterial structures. Other TLRs such as TLR3, TLR7, signals that induce T cell activation. and TLR9 respond to and detect intracellular pathogens. TLR9 is by guest on September 23, 2021 Cytokines secreted by DCs have a profound impact on subse- found in endosomal vesicles within the cell, and recent studies quent Th cell differentiation (2, 3). IL-12 and/or IL-18 contribute have shown that activated TLR9 signals from these vesicles (14, significantly to the development of Th1 cells, whereas IL-6 and 15). TLR9 binds unmethylated DNA structures containing a C-G IL-10 stimulate the development of Th2 or Tr1 cells (2–5). In dinucleotide motif, known as CpG. Activation of TLR9 induces addition, the CD40-CD40L interaction plays an important role in DC maturation, characterized by increases in the expression of stimulating IL-12 production (6), which is augmented in the pres- costimulatory markers and MHC class II molecules (16), as well as ence of IFN-␥ (7, 8). Recent work by Mailliard et al. (9, 10) has the secretion of cytokines such as TNF-␣, IL-1, IL-6, IL-10, IL-12, ϩ shown that IFN-␥, produced by activated NK cells or CD8 T or IFN-␣␤, IP-10, and RANTES, depending on which DC subset cells, can skew the development of DCs toward a type I phenotype, is activated (17). characterized by their ability to secrete high levels of IL-12p70 Due to its ability to stimulate DC activation, CpG has been following CD40 ligation and to stimulate Th1 differentiation. considered for use as an adjuvant in immunotherapy for various conditions such as allergies, infections, or tumors (18, 19). In a murine model of atopic asthma, mice sensitized with methacho- Department of Immunology and Department of Medicine, University of Pittsburgh, line, along with CpG, had reduced eosinophilic infiltration of the Pittsburgh, PA 15261 lung, decreased serum levels of IgE, and decreased airway hyper- Received for publication November 23, 2005. Accepted for publication October 18, 2006. reactivity (20). Atopic mice treated with CpG experienced an in- crease in IL-12 and IFN-␥ detected in the bronchoalveolar lavage The costs of publication of this article were defrayed in part by the payment of page charges. This article must therefore be hereby marked advertisement in accordance fluid. Similar effects of CpG have been shown in infectious models with 18 U.S.C. Section 1734 solely to indicate this fact. such as Leishmania major (19, 21). In another study, mice injected 1 This work was supported by National Institutes of Health Grant CA73743 (to with a tumor cell line were treated with CpG resulting in the in- P.A.M.) and Department of Defense Training Grant DAMD17-99-1-9352 (to R.R.F.). filtration of the tumor by DCs expressing/producing high levels of K.A.D. and L.M.T. were supported by a National Science Foundation Research Ex- periences for Undergraduates Award 0243735. costimulatory molecules and IL-12. This stimulated a Th1 re- 2 Address correspondence and reprint requests to Dr. Penelope A. Morel, Department sponse complete with tumor-specific cytolytic activity (22–24). of Immunology, University of Pittsburgh, Biomedical Science Tower E-1048, 200 These results have led to the use of CpG in a phase I clinical trial Lothrop Street, Pittsburgh, PA 15261. E-mail address: [email protected] testing a cancer vaccine (25). 3 Abbreviations used in this paper: DC, dendritic cell; BMDC, bone marrow-derived In the present study, we analyzed the impact of IFN-␥, a key DC; KO, knockout; WT, wild type; IRF, IFN regulatory factor. mediator of Th1-dominated immunity, upon the ability of different Copyright © 2006 by The American Association of Immunologists, Inc. 0022-1767/06/$2.00 TLR ligands to induce the production of DC cytokines, IL-12 and www.jimmunol.org 212 IFN-␥ REGULATES IL-10 PRODUCTION Downloaded from http://www.jimmunol.org/ FIGURE 1. IFN-␥ enhances IL-12 but suppresses the production of IL-10 in CpG activated BMDCs. Bone marrow cells grown in GM-CSF alone and ␣ then matured in the presence of TNF- (10 ng/ml) and PGE2 (TP DCs) and GM4 DCs were generated as described in Materials and Methods from BALB/c mice. A, TP DCs and GM4 DCs were stimulated with LPS (100 ␮g/ml) with or without IFN-␥ (10 ng/ml) or CpG 1668 phosphothiolated (10 ␮g/ml) with or without IFN-␥ for 24 h. The supernatants were collected and the presence of IL-10 and IL-12p70 was detected using a cytokine-specific ELISA. The results shown represent the mean Ϯ SE of three to six independent experiments. B, GM4 DCs were treated with CpG with or without IFN-␥ as in A. DCs were stained with FITC-labeled Abs specific for CD80, CD86, MHC class II, and CD11c and PE-labeled Abs specific for CD11c and CD40. The histograms depict the expression of the indicated marker on CD11cϩ DC. Unstimulated DCs (thin line histogram), CpG-stimulated DCs (thick line histogram), and CpG plus IFN-␥-stimulated DCs (dashed histogram) are represented. The results shown are representative of three experiments. C, GM4 DCs were generated from 129/J mice and stimulated with LPS (100 ␮g/ml) with or without IFN-␥ (10 ng/ml), CpG 1668 (10 ␮g/ml) with or without IFN-␥,or peptidoglycan (PG, 10 ␮g/ml) with or without IFN-␥ for 24 h. The supernatants were collected and the presence of IL-10 and IL-12p70 was detected using by guest on September 23, 2021 a cytokine-specific ELISA. The results shown represent the mean Ϯ SE of three to six independent experiments. IL-10, which drive the differentiation of the Th1 and Th2/Th3, harvested using an anti-CD11c microbead MACS column (Miltenyi Bio- tec) according to the manufacturer’s instructions.
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