Gene- and exon-expression profiling reveals an extensive LPS-induced response in immune cells in patients with cirrhosis

详细信息    查看全文

• 作者：Sonia Gandoura¹ ; ² ; ^&dagger ; ; Emmanuel Weiss¹ ; ² ; ^&dagger ; ; Pierre-Emmanuel Rautou¹ ; ² ; ³ ; ^&dagger ; ; Magali Fasseu¹ ; ² ; ^&dagger ; ; Thierry Gustot¹ ; Fré ; dé ; ric Lemoine⁴ ; Margarita Hurtado-Nedelec¹ ; ² ; Caroline Hego⁴ ; Nathalie Vadrot¹ ; ² ; Laure Elkrief¹ ; ² ; ³ ; Philippe Letté ; ron¹ ; ² ; Zé ; ra Tellier⁵ ; Marie-Anne Pocidalo¹ ; ² ; Dominique Valla¹ ; ² ; ³ ; Didier Lebrec¹ ; ² ; ³ ; André ; Groyer¹ ; ² ; ^&Dagger ; ; Renato C. Monteiro² ; ⁶ ; ⁷ ; Pierre de la Grange⁴ ; Richard Moreau¹ ; ² ; ³ ; ^{richard.moreau@inserm.fr}
• 关键词：TLR ; Toll-like receptor ; PRR ; pattern recognition receptor ; PAMP ; pathogen-associated molecular pattern ; LPS ; lipopolysaccharide ; NF-¦ÊB ; nuclear factor-¦ÊB ; TNF ; tumor necrosis factor ; IL ; interleukin ; IFN ; interferon ; MHC ; major histocompatibility compl
• 刊名：Journal of Hepatology
• 出版年：2013
• 出版时间：May, 2013
• 年：2013
• 卷：58
• 期：5
• 页码：936-948
• 全文大小：1844 K

文摘

| Figures/TablesFigures/Tables | ReferencesReferences

Background & Aims

Lipopolysaccharide (LPS)-expressing bacteria cause severe inflammation in cirrhotic patients. The global gene response to LPS is unknown in cirrhotic immune cells.

Methods

Gene-expression profiling using Affymetrix Human Exon Array analyzed the expression of 14,851 genes in LPS-stimulated peripheral blood mononuclear cells (PBMCs) from 4 patients with cirrhosis and 4 healthy subjects. We performed validation studies using RT-qPCR in LPS-stimulated PBMCs from 52 patients and 9 healthy subjects and investigated the association of gene induction with mortality in 26 patients.

Results

Gene-expression profiling of LPS-stimulated cirrhotic cells showed 509 upregulated genes and 1588 downregulated genes. In LPS-stimulated ¡°healthy¡± cells, 952 genes were upregulated and 838 genes downregulated. The 741 LPS-regulated genes shared by cirrhotic and ¡°healthy¡± cells were involved in cytokine production/activity and induction of ¡°immune paralysis¡±. Comparison of functions associated with the 1356 genes, specifically regulated by LPS in cirrhotic cells, to functions of the 1049 genes, specifically regulated in ¡°healthy¡± cells, allowed to define a cirrhosis-specific phenotype. Unlike in ¡°healthy¡± cells, LPS failed to induce an interferon-mediated program in cirrhotic cells. In cirrhotic PBMCs, LPS specifically induced certain molecules involved in apoptosis and downregulated molecules involved in endocytic trafficking. RT-qPCR experiments showed that LPS-stimulated cirrhotic PBMCs had an enhanced induction of certain proinflammatory cytokines and chemokines. In the prognosis study, higher ex vivo LPS-induction of the inflammatory genes IL6 and CXCL5 was a significant predictor of mortality.

Conclusions

Our results show that LPS-stimulated cirrhotic PBMCs exhibit an extensive and often unexpected transcriptional response.