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01.10.2010 | Research | Ausgabe 5/2010 Open Access

Critical Care 5/2010

A novel model of common Toll-like receptor 4- and injury-induced transcriptional themes in human leukocytes

Zeitschrift:
Critical Care > Ausgabe 5/2010
Autoren:
Beatrice Haimovich, Michael T Reddell, Jacqueline E Calvano, Steve E Calvano, Marie A Macor, Susette M Coyle, Stephen F Lowry
Wichtige Hinweise

Electronic supplementary material

The online version of this article (doi:10.​1186/​cc9283) contains supplementary material, which is available to authorized users.

Competing interests

The authors declare that they have no competing interests.

Authors' contributions

BH assisted with the data analysis and prepared the final manuscript. MTR performed all the analysis of gene expression data and pathways. SMC assisted with study design and performance of the clinical studies. JEC performed all microarray studies. MAM recruited all subjects and performed the clinical studies. SEC assisted in study design, while SFL designed the study, oversaw all clinical aspects of the project, assisted with data analysis and prepared the final manuscript.

Abstract

Introduction

An endotoxin challenge, sepsis, and injury/trauma, trigger significant changes in human peripheral blood leukocytes (PBL) gene expression. In this study, we have sought to test the hypothesis that the Toll-like receptor 4 (TLR4) induced transcription patterns elicited in humans exposed to in vivo endotoxin would parallel gene expression patterns observed in trauma patients with initial non-infectious injury. In addition, we sought to identify functional modules that are commonly affected by these two insults of differing magnitude and duration.

Methods

PBL were obtained from seven adult human subject experimental groups. The groups included a group of healthy, hospitalized volunteers (n = 15), that comprised four study groups of subjects challenged with intravenous endotoxin, without or with cortisol, and two serial samplings of trauma patients (n = 5). The PBL were analyzed for gene expression using a 8,793 probe microarray platform (Gene Chip® Focus, Affymetrix). The expression of a subset of genes was determined using qPCR.

Results

We describe sequential selection criteria of gene expression data that identifies 445 genes that are significantly differentially expressed (both P ≤ 0.05 and >1.2 fold-change) in PBL derived from human subjects during the peak of systemic inflammatory responses induced by in vivo endotoxin, as well as in PBL obtained from trauma patients at 1 to 12 days after admission. We identified two functional modules that are commonly represented by this analysis. The first module includes more than 50 suppressed genes that encode ribosomal proteins or translation regulators. The second module includes up-regulated genes encoding key enzymes associated with glycolysis. Finally, we show that several circadian clock genes are also suppressed in PBL of surgical ICU patients.

Conclusions

We identified a group of >400 genes that exhibit similar expression trends in PBL derived from either endotoxin-challenged subjects or trauma patients. The suppressed translational and circadian clock modules, and the upregulated glycolytic module, constitute a robust and long lasting PBL gene expression signature that may provide a tool for monitoring systemic inflammation and injury.
Zusatzmaterial
Additional file 1:Table S1. TLR4 and injury responsive (TIR) genes list. All genes included on this list were significantly differentially expressed (P- value < 0.05 and ≥1.2-fold change) in PBL obtained from healthy subjects at six hours after challenge with in vivo endotoxin, and in trauma patients studied within 1 to 12 days after admission, as compared to baseline healthy subjects (Please see Figure 1 for details). Expression increase relative to baseline is shown in red, and expression decrease is shown in green. (PDF 152 KB)
13054_2010_8776_MOESM1_ESM.PDF
Authors’ original file for figure 1
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Authors’ original file for figure 2
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Authors’ original file for figure 3
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Authors’ original file for figure 4
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