The online version of this article (doi:10.1186/cc9283) contains supplementary material, which is available to authorized users.
The authors declare that they have no competing interests.
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.
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.
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.
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.
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.
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 113054_2010_8776_MOESM2_ESM.pdf
Authors’ original file for figure 213054_2010_8776_MOESM3_ESM.pdf
Authors’ original file for figure 313054_2010_8776_MOESM4_ESM.pdf
Authors’ original file for figure 413054_2010_8776_MOESM5_ESM.pdf
Calvano SE, Xiao W, Richards DR, Felciano RM, Baker HV, Cho RJ, Chen RO, Brownstein BH, Cobb JP, Tschoeke SK, Miller-Graziano C, Moldawer LL, Mindrinos MN, Davis RW, Tompkins RG, Lowry SF, Large Scale Collab Res Program IA: A network-based analysis of systemic inflammation in humans. Nature 2005, 437: 1032-1037. Epub 2005 Aug 1031 10.1038/nature03985 CrossRefPubMed
Talwar S, Munson PJ, Barb J, Fiuza C, Cintron AP, Logun C, Tropea M, Khan S, Reda D, Shelhamer JH, Danner RL, Suffredini AF: Gene expression profiles of peripheral blood leukocytes after endotoxin challenge in humans. Physiol Genomics 2006, 25: 203-215. 10.1152/physiolgenomics.00192.2005 CrossRefPubMed
Jan BU, Coyle SM, Macor MA, Reddell M, Calvano SE, Lowry SF: Relationship of basal heart rate variability to in vivo cytokine responses after endotoxin exposure. Shock 33: 363-368. 10.1097/SHK.0b013e3181b66bf4
Park JS, Gamboni-Robertson F, He Q, Svetkauskaite D, Kim JY, Strassheim D, Sohn JW, Yamada S, Maruyama I, Banerjee A, Ishizaka A, Abraham E: High mobility group box 1 protein interacts with multiple Toll-like receptors. Am J Physiol Cell Physiol 2006, 290: C917-924. 10.1152/ajpcell.00401.2005 CrossRefPubMed
Imai Y, Kuba K, Neely GG, Yaghubian-Malhami R, Perkmann T, van Loo G, Ermolaeva M, Veldhuizen R, Leung YH, Wang H, Liu H, Sun Y, Pasparakis M, Kopf M, Mech C, Bavari S, Peiris JS, Slutsky AS, Akira S, Hultqvist M, Holmdahl R, Nicholls J, Jiang C, Binder CJ, Penninger JM: Identification of oxidative stress and Toll-like receptor 4 signaling as a key pathway of acute lung injury. Cell 2008, 133: 235-249. 10.1016/j.cell.2008.02.043 CrossRefPubMed
Gill R, Tsung A, Billiar T: Linking oxidative stress to inflammation: Toll-like receptors. Free Radic Biol Med 48: 1121-1132. 10.1016/j.freeradbiomed.2010.01.006
Spek CA, Verbon A, Aberson H, Pribble JP, McElgunn CJ, Turner T, Axtelle T, Schouten J, Van Der Poll T, Reitsma PH: Treatment with an anti-CD14 monoclonal antibody delays and inhibits lipopolysaccharide-induced gene expression in humans in vivo . J Clin Immunol 2003, 23: 132-140. 10.1023/A:1022528912387 CrossRefPubMed
Wiersinga WJ, Dessing MC, Kager PA, Cheng AC, Limmathurotsakul D, Day NP, Dondorp AM, van der Poll T, Peacock SJ: High-throughput mRNA profiling characterizes the expression of inflammatory molecules in sepsis caused by Burkholderia pseudomallei. Infect Immun 2007, 75: 3074-3079. 10.1128/IAI.01733-06 PubMedCentralCrossRefPubMed
Kelly JL, O'Sullivan C, O'Riordain M, O'Riordain D, Lyons A, Doherty J, Mannick JA, Rodrick ML: Is circulating endotoxin the trigger for the systemic inflammatory response syndrome seen after injury? Ann Surg 1997, 225: 530-541. discussion 541-533 10.1097/00000658-199705000-00010 PubMedCentralCrossRefPubMed
Marshall JC, Foster D, Vincent JL, Cook DJ, Cohen J, Dellinger RP, Opal S, Abraham E, Brett SJ, Smith T, Mehta S, Derzko A, Romaschin A: Diagnostic and prognostic implications of endotoxemia in critical illness: results of the MEDIC study. J Infect Dis 2004, 190: 527-534. 10.1086/422254 CrossRefPubMed
Zeller KI, Zhao X, Lee CW, Chiu KP, Yao F, Yustein JT, Ooi HS, Orlov YL, Shahab A, Yong HC, Fu Y, Weng Z, Kuznetsov VA, Sung WK, Ruan Y, Dang CV, Wei CL: Global mapping of c-Myc binding sites and target gene networks in human B cells. Proc Natl Acad Sci USA 2006, 103: 17834-17839. 10.1073/pnas.0604129103 PubMedCentralCrossRefPubMed
TIDBase, a web-based public resource supported by the type 1 diabetes (TID) research community[ http://www.t1dbase.org]
Chesney J, Mitchell R, Benigni F, Bacher M, Spiegel L, Al-Abed Y, Han JH, Metz C, Bucala R: An inducible gene product for 6-phosphofructo-2-kinase with an AU-rich instability element: role in tumor cell glycolysis and the Warburg effect. Proc Natl Acad Sci USA 1999, 96: 3047-3052. 10.1073/pnas.96.6.3047 PubMedCentralCrossRefPubMed
McFate T, Mohyeldin A, Lu H, Thakar J, Henriques J, Halim ND, Wu H, Schell MJ, Tsang TM, Teahan O, Zhou S, Califano JA, Jeoung NH, Harris RA, Verma A: Pyruvate dehydrogenase complex activity controls metabolic and malignant phenotype in cancer cells. J Biol Chem 2008, 283: 22700-22708. 10.1074/jbc.M801765200 PubMedCentralCrossRefPubMed
Meszaros K, Lang CH, Bagby GJ, Spitzer JJ: Contribution of different organs to increased glucose consumption after endotoxin administration. J Biol Chem 1987, 262: 10965-10970. PubMed
Takimoto M, Hamada A, Tomoda A, Ohdo S, Ohmura T, Sakato H, Kawatani J, Jodoi T, Nakagawa H, Terazono H, Koyanagi S, Higuchi S, Kimura M, Tukikawa H, Irie S, Saito H, Miike T: Daily expression of clock genes in whole blood cells in healthy subjects and a patient with circadian rhythm sleep disorder. Am J Physiol Regul Integr Comp Physiol 2005, 289: R1273-1279. CrossRefPubMed
Ramilo O, Allman W, Chung W, Mejias A, Ardura M, Glaser C, Wittkowski KM, Piqueras B, Banchereau J, Palucka AK, Chaussabel D: Gene expression patterns in blood leukocytes discriminate patients with acute infections. Blood 2007, 109: 2066-2077. 10.1182/blood-2006-02-002477 PubMedCentralCrossRefPubMed
Feezor RJ, Oberholzer C, Baker HV, Novick D, Rubinstein M, Moldawer LL, Pribble J, Souza S, Dinarello CA, Ertel W, Oberholzer A: Molecular characterization of the acute inflammatory response to infections with gram-negative versus gram-positive bacteria. Infect Immun 2003, 71: 5803-5813. 10.1128/IAI.71.10.5803-5813.2003 PubMedCentralCrossRefPubMed
- A novel model of common Toll-like receptor 4- and injury-induced transcriptional themes in human leukocytes
Michael T Reddell
Jacqueline E Calvano
Steve E Calvano
Marie A Macor
Susette M Coyle
Stephen F Lowry
- BioMed Central
Neu im Fachgebiet AINS
Meistgelesene Bücher aus dem Fachgebiet AINS
Mail Icon II