scholarly journals Functional Analysis of KSRP Interaction with the AU-Rich Element of Interleukin-8 and Identification of Inflammatory mRNA Targets

2007 ◽  
Vol 27 (23) ◽  
pp. 8388-8400 ◽  
Author(s):  
Reinhard Winzen ◽  
Basant Kumar Thakur ◽  
Oliver Dittrich-Breiholz ◽  
Meera Shah ◽  
Natalie Redich ◽  
...  
Keyword(s):  
Gene Expression ◽  
Map Kinase ◽  
P38 Map Kinase ◽  
Interleukin 8 ◽  
Limiting Factor ◽  
Inflammatory Gene Expression ◽  
Rapid Degradation ◽  
Inflammatory Gene ◽  
Mrna Targets ◽  
Reporter Mrna

ABSTRACT mRNA stability is a major determinant of inflammatory gene expression. Rapid degradation of interleukin-8 (IL-8) mRNA is imposed by a bipartite AU-rich element (ARE) in the 3′ untranslated region (R. Winzen et al., Mol. Cell. Biol. 24:4835-4847, 2004). Small interfering RNA-mediated knockdown of the ARE-binding protein KSRP resulted in stabilization of IL-8 mRNA or of a β-globin reporter mRNA containing the IL-8 ARE. Rapid deadenylation was impaired, indicating a crucial role for KSRP in this step of mRNA degradation. The two IL-8 ARE domains both contribute to interaction with KSRP, corresponding to the importance of both domains for rapid degradation. Exposure to the inflammatory cytokine IL-1 has been shown to stabilize IL-8 mRNA through p38 mitogen-activated protein (MAP) kinase and MK2. IL-1 treatment impaired the interaction of KSRP with the IL-8 ARE in a manner dependent on p38 MAP kinase but apparently independent of MK2. Instead, evidence that TTP, a target of MK2, can also destabilize the IL-8 ARE reporter mRNA is presented. In a comprehensive approach to identify mRNAs controlled by KSRP, two criteria were evaluated by microarray analysis of (i) association of mRNAs with KSRP in pulldown assays and (ii) increased amounts in KSRP knockdown cells. According to both criteria, a group of 100 mRNAs is controlled by KSRP, many of which are unstable and encode proteins involved in inflammation. These results indicate that KSRP functions as a limiting factor in inflammatory gene expression.

Activation of Nrf2/ARE pathway protects endothelial cells from oxidant injury and inhibits inflammatory gene expression

2006 ◽  
Vol 290 (5) ◽  
pp. H1862-H1870 ◽  
Author(s):  
Xi-Lin Chen ◽  
Geraldine Dodd ◽  
Suzanne Thomas ◽  
Xiaolan Zhang ◽  
Martin A. Wasserman ◽  
...  
Keyword(s):  
Gene Expression ◽  
Endothelial Cells ◽  
Map Kinase ◽  
P38 Map Kinase ◽  
Control Element ◽  
Related Factor ◽  
Dependent Manner ◽  
Inflammatory Gene Expression ◽  
Inflammatory Gene ◽  
Tnf Α

The antioxidant response element (ARE) is a transcriptional control element that mediates expression of a set of antioxidant proteins. NF-E2-related factor 2 (Nrf2) is a transcription factor that activates ARE-containing genes. In endothelial cells, the ARE-mediated genes are upregulated by atheroprotective laminar flow through a Nrf2-dependent mechanism. We tested the hypothesis that activation of ARE-regulated genes via adenovirus-mediated expression of Nrf2 may suppress redox-sensitive inflammatory gene expression. Expression of Nrf2 in human aortic endothelial cells (HAECs) resulted in a marked increase in ARE-driven transcriptional activity and protected HAECs from H2O2-mediated cytotoxicity. Nrf2 suppressed TNF-α-induced monocyte chemoattractant protein (MCP)-1 and VCAM-1 mRNA and protein expression in a dose-dependent manner and inhibited TNF-α-induced monocytic U937 cell adhesion to HAECs. Nrf2 also inhibited IL-1β-induced MCP-1 gene expression in human mesangial cells. Expression of Nrf2 inhibited TNF-α-induced activation of p38 MAP kinase. Furthermore, expression of a constitutively active form of MKK6 (an upstream kinase for p38 MAP kinase) partially reversed Nrf2-mediated inhibition of VCAM-1 expression, suggesting that p38 MAP kinase, at least in part, mediates Nrf2's anti-inflammatory action. In contrast, Nrf2 did not inhibit TNF-α-induced NF-κB activation. These data identify the Nrf2/ARE pathway as an endogenous atheroprotective system for antioxidant protection and suppression of redox-sensitive inflammatory genes, suggesting that targeting the Nrf2/ARE pathway may represent a novel therapeutic approach for the treatment of inflammatory diseases such as atherosclerosis.

Dysregulation of inflammatory gene expression in lesional and nonlesional skin of patients with pyoderma gangrenosum

2017 ◽  
Vol 178 (1) ◽  
Author(s):  
A.G. Ortega‐Loayza ◽  
W.H. Nugent ◽  
O.M. Lucero ◽  
S.L. Washington ◽  
J.R. Nunley ◽  
...  
Keyword(s):  
Gene Expression ◽  
Pyoderma Gangrenosum ◽  
Inflammatory Gene Expression ◽  
Inflammatory Gene

TNF-α and serum induce SKALP/elafin gene expression in human keratinocytes by a p38 MAP kinase-dependent pathway

2000 ◽  
Vol 292 (4) ◽  
pp. 180-187 ◽  
Author(s):  
R. Pfundt ◽  
M. Wingens ◽  
M. Bergers ◽  
M. Zweers ◽  
M. Frenken ◽  
...  
Keyword(s):  
Gene Expression ◽  
Map Kinase ◽  
Human Keratinocytes ◽  
P38 Map Kinase ◽  
Tnf Α ◽  
Dependent Pathway

scholarly journals Gene Expression Profile in Delay Graft Function: Inflammatory Markers Are Associated with Recipient and Donor Risk Factors

2014 ◽  
Vol 2014 ◽  
pp. 1-9 ◽  
Author(s):  
Diego Guerrieri ◽  
Luis Re ◽  
Jorgelina Petroni ◽  
Nella Ambrosi ◽  
Roxana E. Pilotti ◽  
...  
Keyword(s):  
Gene Expression ◽  
Risk Factors ◽  
Kidney Transplantation ◽  
Inflammatory Markers ◽  
Graft Function ◽  
Deceased Donor ◽  
Specific Pattern ◽  
Inflammatory Gene Expression ◽  
Inflammatory Gene ◽  
Recipient Age

Background.Delayed graft function (DGF) remains an important problem after kidney transplantation and reduced long-term graft survival of the transplanted organ. The aim of the present study was to determine if the development of DGF was associated with a specific pattern of inflammatory gene expression in expanded criteria of deceased donor kidney transplantation. Also, we explored the presence of correlations between DGF risk factors and the profile that was found.Methods.Seven days after kidney transplant, a cDNA microarray was performed on biopsies of graft from patients with and without DGF. Data was confirmed by real-time PCR. Correlations were performed between inflammatory gene expression and clinical risk factors.Results.From a total of 84 genes analyzed, 58 genes were upregulated while only 1 gene was downregulated in patients with DGF compared with no DGF (P=0.01). The most relevant genes fold changes observed was IFNA1, IL-10, IL-1F7, IL-1R1, HMOX-1, and TGF-β. The results were confirmed for IFNA1, IL-1R1, HMOX-1 and TGF-β. A correlation was observed between TGF-β, donor age, and preablation creatinine, but not body mass index (BMI). Also, TGF-βshowed an association with recipient age, while IFNA1 correlated with recipient BMI. Furthermore, TGF-β, IFNA1 and HMOX-1 correlated with several posttransplant kidney function markers, such as diuresis, ultrasound Doppler, and glycemia.Conclusions.Overall, the present study shows that DGF is associated with inflammatory markers, which are correlated with donor and recipient DGF risk factors.

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