Pseudomonas aeruginosa delays Kupffer cell death via stabilization of the X-chromosome-linked inhibitor of apoptosis protein

Alix Ashare; Martha M Monick; Amanda B Nymon; John M Morrison; Matthew Noble; Linda S Powers; Timur O Yarovinsky; Timothy L Yahr; Gary W Hunninghake

doi:10.4049/jimmunol.179.1.505

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Pseudomonas aeruginosa delays Kupffer cell death via stabilization of the X-chromosome-linked inhibitor of apoptosis protein

Journal article

Peer reviewed

Pseudomonas aeruginosa delays Kupffer cell death via stabilization of the X-chromosome-linked inhibitor of apoptosis protein

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

The Journal of immunology (1950), Vol.179(1), pp.505-513

07/01/2007

DOI: 10.4049/jimmunol.179.1.505

PMID: 17579071

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Abstract

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-alpha. We hypothesized that early during infection, Kupffer cells are protected against TNF-alpha-induced cell death via activation of survival pathways. KC13-2 cells (a clonal Kupffer cell line) were treated with P. aeruginosa (strain PA103), TNF-alpha, or both. At early time points, TNF-alpha induced caspase-mediated cell death, but PA103 did not. When we combined the two exposures, PA103 protected KC13-2 cells from TNF-alpha-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-alpha-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-alpha-induced cell death and XIAP cleavage. Transfection with a stable, nondegradable XIAP mutant also protected cells against TNF-alpha-induced cell death. These studies demonstrate that P. aeruginosa delays TNF-alpha-induced Kupffer cell death via stabilization of XIAP.

Humans

Liver - microbiology

Apoptosis - genetics

Phosphatidylinositol 3-Kinases - antagonists & inhibitors

Proto-Oncogene Proteins c-akt - genetics

Bacteremia - microbiology

Transfection

Pseudomonas aeruginosa - pathogenicity

Clone Cells

Kupffer Cells - metabolism

Cell Survival - physiology

X-Linked Inhibitor of Apoptosis Protein - biosynthesis

Cell Line

Kupffer Cells - cytology

Kupffer Cells - microbiology

Caspase Inhibitors

Kupffer Cells - enzymology

X-Linked Inhibitor of Apoptosis Protein - genetics

Proto-Oncogene Proteins c-akt - biosynthesis

Bacteremia - metabolism

Tumor Necrosis Factor-alpha - physiology

X-Linked Inhibitor of Apoptosis Protein - metabolism

Cell Line, Tumor

Amino Acid Substitution - genetics

Liver - cytology

Apoptosis - physiology

Bacteremia - pathology

Details

Title: Subtitle: Pseudomonas aeruginosa delays Kupffer cell death via stabilization of the X-chromosome-linked inhibitor of apoptosis protein
Creators: Alix Ashare - Division of Pulmonary, Critical Care, and Occupational Medicine, Roy J. and Lucille A. Carver College of Medicine, University of Iowa, 200 Hawkins Drive, Iowa City, IA 52242, USA. alix-ashare@uiowa.edu
Martha M Monick
Amanda B Nymon
John M Morrison
Matthew Noble
Linda S Powers
Timur O Yarovinsky
Timothy L Yahr
Gary W Hunninghake
Resource Type: Journal article
Publication Details: The Journal of immunology (1950), Vol.179(1), pp.505-513
DOI: 10.4049/jimmunol.179.1.505
PMID: 17579071
NLM abbreviation: J Immunol
ISSN: 0022-1767
eISSN: 1550-6606
Publisher: United States
Grant note: K08 DK073519 / NIDDK NIH HHS HL 079901-01A1 / NHLBI NIH HHS HL 077431 / NHLBI NIH HHS K12 RR 017700 / NCRR NIH HHS K08 DK 073519-01A1 / NIDDK NIH HHS HL 60316 / NHLBI NIH HHS RR 00059 / NCRR NIH HHS
Language: English
Date published: 07/01/2007
Academic Unit: Microbiology and Immunology; Internal Medicine
Record Identifier: 9984001113202771

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