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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^*,

^* Division of Pulmonary, Critical Care, and Occupational Medicine, and Department of Microbiology, University of Iowa Roy J. and Lucille A. Carver College of Medicine and Veterans Administration Medical Center, Iowa City, IA 52242

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 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). Stabilization 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 included decreased levels of XIAP and increased amounts of cleaved caspase-3. Overexpression of Akt mimicked the effects of 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 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 with 18 U.S.C. Section 1734 solely to indicate this fact.

¹ This work was supported by a Veterans Affairs Merit Review Grant, by National 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 the General Clinical Research Centers Program, National Center for Research Resources, National Institutes of Health.

² Address correspondence and reprint requests to Dr. Alix Ashare, Division of Pulmonary, Critical Care and Occupational Medicine, University of Iowa, 200 Hawkins Drive, C33GH, Iowa City, IA 52242. E-mail address: alix-ashare{at}uiowa.edu

³ Abbreviations used in this paper: RES, reticuloendothelial system; EGF, epidermal growth factor; IAP, inhibitor of apoptosis protein; XIAP, X-chromosome-linked IAP; Z-DEVD-FMK, Z-D(OMe)-E(OMe)-V-D(OMe)-FMK; T3S, type III secretions.

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