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505.Full.Pdf Pseudomonas aeruginosa Delays Kupffer Cell Death via Stabilization of the X-Chromosome-Linked Inhibitor of Apoptosis Protein This information is current as of September 26, 2021. Alix Ashare, Martha M. Monick, Amanda B. Nymon, John M. Morrison, Matthew Noble, Linda S. Powers, Timur O. Yarovinsky, Timothy L. Yahr and Gary W. Hunninghake J Immunol 2007; 179:505-513; ; doi: 10.4049/jimmunol.179.1.505 Downloaded from http://www.jimmunol.org/content/179/1/505 References This article cites 44 articles, 21 of which you can access for free at: http://www.jimmunol.org/ http://www.jimmunol.org/content/179/1/505.full#ref-list-1 Why The JI? Submit online. • Rapid Reviews! 30 days* from submission to initial decision • No Triage! Every submission reviewed by practicing scientists by guest on September 26, 2021 • Fast Publication! 4 weeks from acceptance to publication *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 Pseudomonas aeruginosa Delays Kupffer Cell Death via Stabilization of the X-Chromosome-Linked Inhibitor of Apoptosis Protein1 Alix Ashare,2* Martha M. Monick,* Amanda B. Nymon,* John M. Morrison,* Matthew Noble,* Linda S. Powers,* Timur O. Yarovinsky,* Timothy L. Yahr,† and Gary W. Hunninghake*‡ Kupffer cells are important for bacterial clearance and cytokine production during infection. We have previously shown that severe infection with Pseudomonas aeruginosa ultimately results in loss of Kupffer cells and hepatic bacterial clearance. This was associated with prolonged hepatic inflammation. However, there is a period of time during which there is both preserved hepatic bacterial clearance and increased circulating TNF-␣. We hypothesized that early during infection, Kupffer cells are protected against TNF-␣-induced cell death via activation of survival pathways. KC13-2 cells (a clonal Kupffer cell line) were Downloaded from treated with P. aeruginosa (strain PA103), TNF-␣, or both. At early time points, TNF-␣ induced caspase-mediated cell death, but PA103 did not. When we combined the two exposures, PA103 protected KC13-2 cells from TNF-␣-induced cell death. PA103, in the setting of TNF exposure, stabilized the X-chromosome-linked inhibitor of apoptosis protein (XIAP). Stabili- zation of XIAP can occur via PI3K and Akt. We found that PA103 activated Akt and that pretreatment with the PI3K inhibitor, LY294002, prevented PA103-induced protection against TNF-␣-induced cell death. The effects of LY294002 in- cluded decreased levels of XIAP and increased amounts of cleaved caspase-3. Overexpression of Akt mimicked the effects of http://www.jimmunol.org/ PA103 by protecting cells from TNF-␣-induced cell death and XIAP cleavage. Transfection with a stable, nondegradable XIAP mutant also protected cells against TNF-␣-induced cell death. These studies demonstrate that P. aeruginosa delays TNF-␣-induced Kupffer cell death via stabilization of XIAP. The Journal of Immunology, 2007, 179: 505–513. he hepatic reticuloendothelial system (RES)3 plays an im- actively phagocytose and kill bacteria but do not produce a large portant role in removing bacteria and endotoxin from the inflammatory response. T blood stream. Kupffer cells, the resident macrophages of We have previously shown that hepatic bacterial clearance by the hepatic RES, provide a crucial means of defense against mi- Kupffer cells is decreased during severe bacteremia with Pseudo- by guest on September 26, 2021 croorganisms. Although they were once thought to be uniform, monas aeruginosa (3). This loss of hepatic bacterial clearance Kupffer cells are now known to be a heterogeneous group of mac- could be exacerbated by Kupffer cell ablation with gadolinium rophages. They are 2-fold more abundant in the periportal region, chloride and prevented by pretreatment with the nonspecific where blood enters the liver (1). Periportal Kupffer cells are larger caspase inhibitor, N-benzyloxycarbonyl-Val-Ala-Asp-fluorometh- and have greater phagocytic function but appear to be less in- ylketone. A notable difference between mild bacteremia (where volved in inflammatory reactions. The smaller centrilobular hepatic bacterial clearance was preserved) and severe bacteremia Kupffer cells appear to be more important in generating inflam- was that severe bacteremia was associated with a prolonged in- matory responses. Recently, a clonal cell line of murine periportal crease in hepatic TNF-␣, suggesting that hepatic inflammation Kupffer cells (KC13-2 cells) has been generated (2). These cells may be involved in the eventual loss of bacterial clearance. Inter- estingly, there was a period of time during severe P. aeruginosa bacteremia during which hepatic bacterial clearance persisted *Division of Pulmonary, Critical Care, and Occupational Medicine, and †Department despite significant inflammation. This lead to the hypothesis of of Microbiology, University of Iowa Roy J. and Lucille A. Carver College of Med- these studies that early in infection, P. aeruginosa protects icine and ‡Veterans Administration Medical Center, Iowa City, IA 52242 Kupffer cells from TNF-␣-induced cell death via activation of Received for publication February 5, 2007. Accepted for publication April 14, 2007. survival pathways. The costs of publication of this article were defrayed in part by the payment of page P. aeruginosa has previously been shown to prevent apoptosis charges. This article must therefore be hereby marked advertisement in accordance in corneal epithelial cells by activation of the epidermal growth with 18 U.S.C. Section 1734 solely to indicate this fact. factor (EGF) receptor (4). More recently, Pseudomonas syringae, 1 This work was supported by a Veterans Affairs Merit Review Grant, by National a plant pathogen, has been shown to prevent apoptosis by trans- Institutes of Health Grants HL-60316, HL-077431, and HL079901-01A1 (to G.W.H.); K12 RR017700 and K08 DK073519-01A1 (to A.A.); and RR00059 from location of an ubiquitin ligase protein (5). Our data demonstrate the General Clinical Research Centers Program, National Center for Research Re- that P. aeruginosa promotes KC13-2 cell survival in the setting of sources, National Institutes of Health. inflammation via stabilization of the X-chromosome-linked inhib- 2 Address correspondence and reprint requests to Dr. Alix Ashare, Division of Pul- monary, Critical Care and Occupational Medicine, University of Iowa, 200 Hawkins itor of apoptosis protein (XIAP). Drive, C33GH, Iowa City, IA 52242. E-mail address: [email protected] The inhibitor of apoptosis protein (IAP) are a family of eight 3 Abbreviations used in this paper: RES, reticuloendothelial system; EGF, epidermal proteins that block the activity of caspases-3, -7, and -9 (6–8). growth factor; IAP, inhibitor of apoptosis protein; XIAP, X-chromosome-linked IAP; XIAP is the most potent IAP, blocking caspase activity with nano- Z-DEVD-FMK, Z-D(OMe)-E(OMe)-V-D(OMe)-FMK; T3S, type III secretions. molar affinity (7). TNF-␣ induces cleavage of XIAP to an inactive Copyright © 2007 by The American Association of Immunologists, Inc. 0022-1767/07/$2.00 fragment (9). Recently, XIAP was found to be phosphorylated by www.jimmunol.org 506 KUPFFER CELLS AND XIAP FIGURE 1. PA103 protects Kupffer cells from early TNF-␣-induced cell death. A, ATP viability assay was per- formed after incubation of KC13-2 cells with PA103, TNF-␣, or both (left). PA103 was protective against TNF-␣- ␣-p Ͻ 0.05, TNF ,ء .induced cell death alone compared with TNF-␣ with PA103. Values reflect mean Ϯ SE of three separate experiments. Staining KC13-2 cells with ethidium homo- dimers after incubation with PA103, TNF-␣, or both confirms the protective effect of PA103 (right). The number of cells positive for ethidium per 100 cells counted is expressed as percent of cell death. B, ATP viability assay compar- ing PA103 ExsA⍀, TNF-␣, or both shows protection by PA103 ExsA⍀. Downloaded from p Ͻ 0.05, TNF-␣ alone compared ,ء with TNF-␣ with PA103 ExsA⍀. Values reflect mean Ϯ SE of three separate experiments. C, ATP viabil- ity assay comparing LPS (600 ng/ml), TNF-␣, or both shows no protection against TNF-␣-induced cell death by http://www.jimmunol.org/ LPS (left). Values reflect mean Ϯ SE of three separate experiments. ATP viability assay comparing TNF-␣, smooth PAO, rough PAO, or smooth or rough PAO in combination with TNF-␣ shows improved survival in cells treated with rough PAO and TNF-␣ or smooth PAO and TNF-␣ Ͻ ء ␣ compared with TNF- alone. , p by guest on September 26, 2021 0.05) (right). Values reflect mean Ϯ SE of three separate experiments. Akt, a kinase downstream of PI3K, rendering it resistant to formed according to the manufacturer’s instructions. The caspase-3 inhib- cleavage (10). We demonstrate that inhibition of PI3K blocked itor, Z-D(OMe)-E(OMe)-V-D(OMe)-FMK (Z-DEVD-FMK) was obtained the protective effect of P. aeruginosa on KC13-2 cell death. from R&D Systems. A stock solution of 2 mM concentration in DMSO was diluted in PBS before use in cell culture. The final concentration in cell Conversely, overexpression of Akt protected cells against TNF- culture was 20 ␮M. ␣-induced cell death. Finally, transfection with a mutant XIAP that is resistant to cleavage resulted in protection of KC13-2 cells against TNF-␣. These data illustrate that P. aeruginosa Cell culture protects Kupffer cells against caspase-mediated cell death early KC13-2 cells were a gift from Professor R. Landman (University Hospital, via stabilization of XIAP. Furthermore, there may be a window Basel, Basel, Switzerland; see Ref.
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