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Role for NK Cells Inflammatory Response Reveals a Critical A A Fatal Cytokine-Induced Systemic Inflammatory Response Reveals a Critical Role for NK Cells This information is current as William E. Carson, Haixin Yu, Julie Dierksheide, Klaus of September 28, 2021. Pfeffer, Page Bouchard, Reed Clark, Joan Durbin, Albert S. Baldwin, Jacques Peschon, Philip R. Johnson, George Ku, Heinz Baumann and Michael A. Caligiuri J Immunol 1999; 162:4943-4951; ; http://www.jimmunol.org/content/162/8/4943 Downloaded from References This article cites 61 articles, 37 of which you can access for free at: http://www.jimmunol.org/content/162/8/4943.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 28, 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 © 1999 by The American Association of Immunologists All rights reserved. Print ISSN: 0022-1767 Online ISSN: 1550-6606. A Fatal Cytokine-Induced Systemic Inflammatory Response Reveals a Critical Role for NK Cells1 William E. Carson,2*† Haixin Yu,† Julie Dierksheide,‡ Klaus Pfeffer,§ Page Bouchard,¶ Reed Clark,| Joan Durbin,| Albert S. Baldwin,** Jacques Peschon,†† Philip R. Johnson,| George Ku,‡‡ Heinz Baumann,§§ and Michael A. Caligiuri†¶¶ The mechanism of cytokine-induced shock remains poorly understood. The combination of IL-2 and IL-12 has synergistic anti- tumor activity in vivo, yet has been associated with significant toxicity. We examined the effects of IL-2 plus IL-12 in a murine model and found that the daily, simultaneous administration of IL-2 and IL-12 resulted in shock and 100% mortality within 4 to 12 days depending on the strain employed. Mice treated with IL-2 plus IL-12 exhibited NK cell apoptosis, pulmonary edema, degenerative lesions of the gastrointestinal tract, and elevated serum levels of proinflammatory cytokines and acute phase reac- Downloaded from tants. The actions of TNF-a, IFN-g, macrophage-inflammatory protein-1a, IL-1, IL-1-converting enzyme, Fas, perforin, inducible nitric oxide synthase, and STAT1 did not contribute to the observed toxicity, nor did B or T cells. However, toxicity and death from treatment with IL-2 plus IL-12 could be completely abrogated by elimination of NK cells. These results suggest that the fatal systemic inflammatory response induced by this cytokine treatment is critically dependent upon NK cells, but does not appear to be mediated by the known effector molecules of this cellular compartment. These data may provide insight into the pathogenesis of cytokine-induced shock in humans. The Journal of Immunology, 1999, 162: 4943–4951. http://www.jimmunol.org/ ctivation of monocytes/macrophages by bacteria, fungi, immunomodulatory effects via activation of the IL-2/15R and the viruses, or their products results in the rapid production IL-12R expressed on NK cells has led to investigations of this A of monokines such as TNF-a, IL-1, IL-12, IL-15, and cytokine combination for the immunotherapy of neoplastic disease IL-18, which in turn induce NK cell production of IFN-g and (11, 12). In the current study, we examined the effects of admin- TNF-a (1–4). IL-12 appears to be pivotal to the NK cell response, istering IL-2 or IL-15 in combination with IL-12 in a murine tox- as there is only modest NK cell cytokine production in the absence icity model. While the dose of the individual cytokines was well of this factor (5, 6). We have demonstrated previously that the tolerated, the administration of IL-2 or IL-15 in combination with combination of IL-15 and IL-12 exerts a profound synergy upon IL-12 induced a lethal systemic inflammatory response that did not by guest on September 28, 2021 resting NK cell production of IFN-g, TNF-a, and MIP-1a3 (6–8). require any of the major proinflammatory factors or signaling path- These proinflammatory cytokines and chemokines play a critical ways felt to be active in the induction of septic shock. However, role in the clearance of obligate intracellular pathogens and, in the lethal toxicity of this cytokine combination therapy was criti- some cases, the promotion of sepsis, shock, and death (9). An cally dependent upon NK cells, but not B or T cells. identical profile of NK cell cytokine and chemokine production can be induced by the combination of IL-2 and IL-12 (5, 6). This Materials and Methods reflects the fact that the heterotrimeric IL-15R and IL-2R share the Reagents IL-2Rb and g signaling subunits and differ only in the specificity of their high affinity a-chains (10). The ability to obtain synergistic Purified, yeast-derived rhuIL-2 (Chiron, Emeryville, CA) or rhuIL-15 (Im- munex, Seattle, WA) was administered at a dose of 3 3 105 U/day via the i.p. route. rIL-12 of murine (mu) origin (Genetics Institute, Cambridge, Departments of *Surgery, ¶¶Medicine, ‡Pathology, and †Medical Microbiology and MA) was administered i.p. at a dose of 1 mg/day. rhuIL-2 and rmuIL-12 Immunology, Arthur G. James Comprehensive Cancer Center, Ohio State University, were administered daily until the death of the animal. rmuIL-10 was sup- Columbus, OH 43210; §Institute for Medicine, Microbiology, and Hygiene, Munich, plied by Schering-Plough (Kenilworth, NJ). Platelet-derived huTGF-b1 \ Germany; ¶Genetics Institute, Andover, MA 01810; Children’s Hospital, Columbus, (which has activity in murine systems) was purchased fromR&DSystems OH 43205; **Lineberger Comprehensive Cancer Center, Curriculum in Genetics and (Minneapolis, MN) and reconstituted according to the manufacturer’s rec- Molecular Biology, Chapel Hill, NC 27514; ††Immunex Research and Development ‡‡ ommendations in 4 mM HCl supplemented with 0.1% BSA (13). Rat IgG1 Corporation, Seattle, WA 98101; Vertex Pharmaceuticals, Cambridge, MA 02139; g and §§Roswell Park Cancer Institute, Buffalo, NY 14263 anti-muIFN- mAb (Endogen, Cambridge, MA), and hamster IgG anti- muIFN-g mAb (Genzyme Diagnostics, Cambridge, MA) were adminis- Received for publication October 13, 1998. Accepted for publication January tered at a dose of 100 mg per mouse via the i.p. route 12 h before cytokine 13, 1999. therapy and then daily thereafter. Control Abs were purchased from Sigma The costs of publication of this article were defrayed in part by the payment of page (St. Louis, MO). A dimeric rhuTNF receptor p80/IgG1 Fc fusion protein charges. This article must therefore be hereby marked advertisement in accordance (TNFR-Fc; Immunex) was used in TNF-a neutralization experiments (100 with 18 U.S.C. Section 1734 solely to indicate this fact. mg/mouse/day i.p. beginning 24 h prior cytokine treatment) (14). Human 1 This work was supported by National Institute of Health Grants CA68326 and IgG was used as a control for the fusion protein (Baxter, Glendale, CA). CA68458, and in part by Grant P30 CA16058. Dexamethasone was purchased from Moore Medical (New Britain, CT). 2 Address correspondence and reprint requests to Dr. William E. Carson III, Arthur G. Depletion of NK cells was accomplished via i.p. administration of an anti- James Comprehensive Cancer Center, Ohio State University, N924 Doan Hall, 410 asialo GM1 Ab (Wako BioProducts, Richmond, VA) every 3 days begin- W. 10th Street, Columbus, OH 43210. E-mail address: [email protected] ning 2 wk before the injection of cytokines (0.2 mg/mouse) (15). NK cell 3 Abbreviations used in this paper: MIP, macrophage-inflammatory protein; hu, hu- numbers postdepletion were evaluated via flow-cytometric analysis of mu- man; I-kB, inhibitor of NF-kB; ICE, IL-1b-converting enzyme; iNOS, inducible ni- rine splenocytes using a phycoerythrin (PE)-labeled pan-NK mAb (clone tric oxide synthase; KC, ??; mu, murine; PE, phycoerythrin; rAd, recombinant DX5; PharMingen, San Diego, CA). Mice were depleted of monocytes/ adenovirus. macrophages via i.v. and i.p. injection of the F4/80 mAb (an IgG2b mAb) Copyright © 1999 by The American Association of Immunologists 0022-1767/99/$02.00 4944 FATAL CYTOKINE-MEDIATED INFLAMMATORY RESPONSE 48 and 24 h before cytokine therapy (16). Macrophage numbers postdeple- tion were evaluated via the enumeration of plastic-adherent cells following a 2-h culture of PBMCs, splenocytes, bone marrow cells, or peritoneal cells in 24-well plastic culture dishes (1 3 106 cells/well in RPMI 1640 sup- plemented with 10% FBS) (7). All cytokine reagents contained less than 0.015 EU/ml endotoxin, as measured by the E-Toxate system (Sigma). Mice Female mice age 4–6 wk were utilized in all experiments. C.B-17 scid/scid (SCID) mice (BALB/c background), splenectomized C.B-17 SCID mice, sham-operated C.B-17 SCID mice, and inbred BALB/c mice were pur- chased from Taconic Farms (Germantown, NY). Perforin-deficient (2/2) mice, CD3e transgenic mice, IFN-g2/2 mice, and Faslpr/lpr mice were pur- chased from The Jackson Laboratory (Bar Harbor, ME) (17–20). TNFR p552/2 mice, TNFR p752/2 mice, and TNFR p552/2/TNFR p752/2 mice were provided by Immunex (21). Type I IL-1R2/2 mice, type I IL-1R2/ 2 2 2 2 2 2 2/TNFR p55 / mice, and type I IL-1R / /TNFR p75 / mice were also provided by Immunex (22).
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