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STAT4 Signaling and Is Inhibited by IL-4 The Production of IFN-γ by IL-12/IL-18-Activated Macrophages Requires STAT4 Signaling and Is Inhibited by IL-4 This information is current as Heike Schindler, Manfred B. Lutz, Martin Röllinghoff and of September 24, 2021. Christian Bogdan J Immunol 2001; 166:3075-3082; ; doi: 10.4049/jimmunol.166.5.3075 http://www.jimmunol.org/content/166/5/3075 Downloaded from References This article cites 39 articles, 20 of which you can access for free at: http://www.jimmunol.org/content/166/5/3075.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 24, 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 © 2001 by The American Association of Immunologists All rights reserved. Print ISSN: 0022-1767 Online ISSN: 1550-6606. The Production of IFN-␥ by IL-12/IL-18-Activated Macrophages Requires STAT4 Signaling and Is Inhibited by IL-41 Heike Schindler,* Manfred B. Lutz,† Martin Ro¨llinghoff,* and Christian Bogdan2* Macrophages release IFN-␥ on combined stimulation with IL-12 and IL-18, but the signaling requirements of this process and its regulation by other cytokines are unknown. Here, we demonstrate that STAT4 is indispensable for IL-12/IL-18-induced produc- tion of IFN-␥ by mouse peritoneal macrophages. Type 2 NO synthase (NOS2), which we previously found to be a prerequisite for IL-12-induced IFN-␥ production in NK cells, was not required for IFN-␥ production by these macrophages. IL-12 alone already induced the expression of IFN-␥ mRNA, but nuclear translocation of STAT4, the release of IFN-␥ protein, and the subsequent production of NO was strictly dependent on the simultaneous presence of IL-18. NF-␬B, which mediates IL-18 effects in T cells, Downloaded from was only weakly activated by IL-12 and/or IL-18 in macrophages. Known inhibitors of macrophage functions (e.g., IL-4 and TGF-␤) also suppressed macrophage IFN-␥ production and the subsequent production of NOS2-derived NO. The inhibitory effect of IL-4 was paralleled by nuclear translocation of STAT6, which in EMSAs was able to bind to the same DNA oligonucleotide as STAT4. These results further define the production of IFN-␥ by macrophages and point to a diversity in the signals required for IFN-␥ production by various cell types. The Journal of Immunology, 2001, 166: 3075–3082. http://www.jimmunol.org/ he activation of macrophages by IFN-␥, which is typically protein found in the cultures of bone marrow-derived macrophages released by NK cells, CD4ϩ type 1 Th cells, and several approached or even exceeded the amounts that are usually released T other subsets of T cells (e.g., ␥␦ T cells, NKT cells, CD8ϩ by T or NK cells. The activation of macrophages for the secretion T cells), has been a hallmark of the immune responses against of IFN-␥ by IL-12 and IL-18 is of particular interest, because both intracellular pathogens and tumor cells as well as of certain auto- IL-12 and IL-18 are known products of macrophages, which sug- immune reactions. IFN-␥ activates macrophages to produce cyto- gests the possibility of autocrine stimulation. Cytokines that are kines, to express antimicrobial and tumoricidal effector pathways, able to counteract this pathway have not yet been defined. and to act as APCs (1, 2). During more recent years, macrophages In T and NK cells, STAT4 is critical for the production of IFN-␥ themselves were recognized also to be producers of IFN-␥ under in response to IL-12, which was shown by the analysis of STAT4- by guest on September 24, 2021 certain conditions. IFN-␥ mRNA and/or protein was detected in deficient mice (12–14). In addition, NK cells, but not T cells, re- various populations of mononuclear phagocytes, including human quired NO derived from type 2 NO synthase (NOS2)3 for IL-12 alveolar macrophages (3), and resting peritoneal macrophages (4, signaling, i.e., for the activation of Tyk2 kinase, the tyrosine phos- 5), peritoneal exudate macrophages (6–8), bone marrow-derived phorylation of STAT4, and the production of IFN-␥ (15). Re- macrophages (9), splenic macrophages (10), and lung macro- cently, evidence was provided that a STAT4-independent pathway phages from mice (11). Although a possible (minor) contamination of IFN-␥ production exists in CD8ϩ T cells; however, it was only with T, NK, or NKT cells has not always been vigorously ex- observed after cross-linking of the TCR and not after stimulation cluded, most of these studies unequivocally demonstrate the pro- with IL-12/IL-18 (16). A similar pathway was also observed in duction of IFN-␥ by monocytes/macrophages. The stimuli that CD4ϩ T cells lacking both STAT4 and STAT6 (14). In dendritic were reported to induce IFN-␥ in monocytes/macrophages include cells isolated from mouse spleens, IL-12 signaling was reported to type I IFNs (7), IFN-␥ itself (4), IL-12 (bioactive p70 homodimer) involve nuclear translocation of NF-␬B rather than activation of (3, 5, 10), LPS (6, 8) (which largely acts via induction of endog- members of the STAT family (17). In contrast, in human blood enous IL-12), Mycobacterium tuberculosis (3), Mycobacterium monocyte-derived dendritic cells stimulation with IL-12 led to ty- bovis bacillus Calmette-Gue´rin plus IL-12 (11), and a combination rosine-phosphorylation of Tyk2 and Jak2 kinase as well as of of IL-12 and IL-18 (9). In the latter case, the levels of IFN-␥ STAT3 and STAT4 (18). In LPS-activated human monocytes, STAT4 protein was shown to be expressed and tyrosine-phospho- rylated on stimulation with IFN-␣ (19). However, whether NF-␬B, *Institute of Clinical Microbiology, Immunology, and Hygiene and †Department of NOS2, and/or the Jak/STAT pathway are actually required for the Dermatology, University of Erlangen, Erlangen, Germany production of IFN-␥ by dendritic cells or macrophages is unknown Received for publication September 9, 2000. Accepted for publication December 20, to date. In the present study, we show that STAT4 is essential for 2000. the production of IFN-␥ by inflammatory macrophages in response The costs of publication of this article were defrayed in part by the payment of page to IL-12/IL-18, whereas NOS2-derived NO is dispensable. We charges. This article must therefore be hereby marked advertisement in accordance ␤ with 18 U.S.C. Section 1734 solely to indicate this fact. also demonstrate that IL-4, IL-10, IL-13, and TGF- 1 inhibit IL- ␥ 1 This work was supported by grants from the Deutsche Forschungsgemeinschaft 12/IL-18-induced IFN- production in macrophages. The effect of (Sonderforschungsbereich 263) to C.B. (Project A5) and M.B.L. (Project C13). IL-4 appears to be mediated by the activation of STAT6, which in 2 Address correspondence and reprints requests to Dr. Christian Bogdan, Institut fu¨r Klinische Mikrobiologie, Immunologie und Hygiene, Universita¨t Erlangen-Nu¨rnberg, Wasserturmstrasse 3, D-91054 Erlangen, Germany. E-mail address: christian. 3 Abbreviations used in this paper: NOS2 (iNOS), type 2 (or inducible) NO synthase; [email protected] rm, recombinant murine. Copyright © 2001 by The American Association of Immunologists 0022-1767/01/$02.00 3076 MACROPHAGE, IFN-␥, AND STAT4 EMSA was able to bind to the same DNA oligonucleotide as IL- RNA preparation, cDNA synthesis, and RT-PCR 12/IL-18-induced STAT4. Total RNA was isolated from macrophage monolayers by the guanidinium isothiocyanate method, reverse transcribed (1 ␮g), and analyzed by qual- itative or quantitative (competitive) RT-PCR as published (22). The Materials and Methods competitor plasmids for the different genes were as follows: 1) piNOSL1 Mice (HincII 162 bp) for NOS2 (22); 2) pMCQ for ␤-actin and IFN-␥ (24); and 3) pIL-12R␤1 and pIL-12R␤2 for IL-12 receptor ␤1 and IL-12 receptor ␤2, Female CD1 mice (20–24 g; 8–12 wk old) and C57BL/6 mice (16–18 g; respectively (15). The primer sequences for NOS2, IFN-␥, ␤-actin, and 6–8 wk old) were purchased from Charles River Breeding Laboratories IL-12 receptor ␤1 and ␤2 were as published previously (15, 25). The se- (Sulzfeld, Germany). Breeding pairs of (129/SvEv ϫ C57BL/6) mice with Ϫ Ϫ ϩ ϩ quences of the IL-18 receptor upstream and downstream primer used for a disrupted NOS2 gene (NOS2 / ) (20) and wild-type controls (NOS2 / ) qualitative PCR analysis were 5Ј-CGT GAC AAG CAG AGA TGT TG-3Ј were originally provided by C. F. Nathan (New York, NY) and J. S. ϩ ϩ Ϫ Ϫ and 5Ј-ATG TTG TCG TCT CCT TCC TG-3Ј, respectively. The annealing Mudgett (Merck, Rahway, NJ). The NOS2 / and NOS2 / mice used temperatures were 57°C (IL-18R), 58°C (NOS2, IL-12R␤1, and IL- here were obtained from homozygous intercrosses in the F8 to F9 genera- ␤ ␤ ␥ tion (129/SvEv ϫ C57BL/6). C57BL/6 mice deficient for the IFN-␥ gene 12R 2), or 60°C ( -actin and IFN- ). The number of PCR cycles was 35. (IFN-␥Ϫ/Ϫ) were provided by M. Kopf (Basel Institute for Immunology, Basel, Switzerland). Breeding pairs of FVB/NJ mice deficient for the STAT4 gene (STAT4Ϫ/Ϫ) and the respective wild-type controls Oligonucleotide probes (STAT4ϩ/ϩ; Ref.
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