Tumor Necrosis Factor-α- or Lipopolysaccharide-induced Expression of the Murine P-selectin Gene in Endothelial Cells Involves Novel κB Sites and a Variant Activating Transcription Factor/cAMP Response Element

Glucocorticoid-induced TNFR-related gene (GITR) participates in the immune/inflammatory response. Because GITR expression has been described in cells other than T lymphocytes, we investigated whether it also modulates acute inflammatory response. Using GITR-deficient (GITR−/−) mice, we analyzed the role of GITR in the development of carrageenan-induced lung inflammation (pleurisy) by studying several proinflammatory markers 2–8 h after carrageenan injection. When compared with GITR+/+, GITR−/− mice exhibited decreased production of turbid exudate containing a lower number of leukocytes. This was correlated with the reduction of inflammatory markers (including TNF-α, IL-1β, myeloperoxidase, inducible NO synthase, and cyclooxygenase 2) in the pleural exudate and/or in the lung. Moreover, endothelial cells expressed lower levels of adhesion molecules. In lungs of GITR+/+ mice, GITR ligand expression was not modulated during pleurisy, while that of GITR increased, as a consequence of increased infiltration by GITR-expressing cells and of GITR up-regulation in macrophages and endothelial cells. Finally, cotreatment of GITR+/+ mice with carrageenan and Fc-GITR fusion protein decreased the number of inflammatory cells (pleural macrophages and lung neutrophils) as compared with carrageenan treatment alone, confirming that GITR plays a role in the modulation of pleurisy.

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“…triggered by GITRL-expressing cells, contributing to modulation of endothelial function as demonstrated for other TNFRSF members (53,54).…”

Section: Discussionmentioning

confidence: 92%

Proinflammatory Role of Glucocorticoid-Induced TNF Receptor-Related Gene in Acute Lung Inflammation

Cuzzocrea

Nocentini

Paola

et al. 2006

The Journal of Immunology

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“…14 Because IL-6, MCP-1, and P-selectin gene promoters contain functional NF-kB binding sites essential for their induction in response to inflammatory stimuli, 15,16 we further assessed NF-kB activation using the electrophoretic mobility shift assay. The NF-kB DNA binding activity from nuclear extracts of mouse renal kidney cells infected with lentivirus containing miR-494 was markedly increased compared with the NF-kB DNA binding activity of control cells not expressing miR-494 ( Figure 5D, upper panel, lane 5 versus lane 4).…”

Section: Role Of Mir-494 In I/r-induced Inflammatory Responsesmentioning

confidence: 99%

MicroRNA-494 Reduces ATF3 Expression and Promotes AKI

Lan

Chen

Lai

et al. 2012

Journal of the American Society of Nephrology

121

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MicroRNA-494 mediates apoptosis and necrosis in several types of cells, but its renal target and potential role in AKI are unknown. Here, we found that microRNA-494 binds to the 39UTR of activating transcription factor 3 (ATF3) and decreases its transcription. In mice, overexpression of microRNA-494 significantly attenuated the level of ATF3 and induced inflammatory mediators, such as IL-6, monocyte chemotactic protein-1, and P-selectin, after renal ischemia/reperfusion, exacerbating apoptosis and further decreasing renal function. Activation of NF-kB mediated this proinflammatory response. In this ischemia/reperfusion model, urinary levels of microRNA-494 increased significantly before the rise in serum creatinine. In humans, urinary microRNA-494 levels were 60-fold higher in patients with AKI than normal controls. In conclusion, upregulation of microRNA-494 contributes to inflammatory or adhesion molecule-induced kidney injury after ischemia/reperfusion by inhibiting expression of ATF3. Furthermore, microRNA-494 may be a specific and noninvasive biomarker for AKI.

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“…22 Because the IL-6 and P-selectin gene promoters contain functional NF-B-binding sites essential for their induction in response to inflammatory stimuli, 23,24 we further assessed NF-B activation by electrophoretic mobility shift assay (EMSA). Renal I/R injury caused increased NF-B DNA-binding activity in nuclear extracts from WT kidneys, which was further markedly increased in ATF3-KO kidneys ( Figure 5B, top).…”

Section: Atf3 Is Induced In a Mousementioning

confidence: 99%

ATF3-Mediated Epigenetic Regulation Protects against Acute Kidney Injury

Cheng

Liao

et al. 2010

Journal of the American Society of Nephrology

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A variety of stress stimuli, including ischemia-reperfusion (I/R) injury, induce the transcriptional repressor ATF3 in the kidney. The functional consequences of this upregulation in ATF3 after renal I/R injury are not well understood. Here, we found that ATF3-deficient mice had higher renal I/R-induced mortality, kidney dysfunction, inflammation (number of infiltrating neutrophils, myeloperoxidase activity, and induction of IL-6 and P-selectin), and apoptosis compared with wild-type mice. Furthermore, gene transfer of ATF3 to the kidney rescued the renal I/R-induced injuries in the ATF3-deficient mice. Molecular and biochemical analysis revealed that ATF3 interacted directly with histone deacetylase 1 (HDAC1) and recruited HDAC1 into the ATF/NF-B sites in the IL-6 and IL-12b gene promoters. The ATF3-associated HDAC1 deacetylated histones, which resulted in the condensation of chromatin structure, interference of NF-B binding, and inhibition of inflammatory gene transcription after I/R injury. Taken together, these data demonstrate epigenetic regulation mediated by the stress-inducible gene ATF3 after renal I/R injury and suggest potential targeted approaches for acute kidney injury.

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Tumor Necrosis Factor-α- or Lipopolysaccharide-induced Expression of the Murine P-selectin Gene in Endothelial Cells Involves Novel κB Sites and a Variant Activating Transcription Factor/cAMP Response Element

Cited by 71 publications

References 66 publications

Proinflammatory Role of Glucocorticoid-Induced TNF Receptor-Related Gene in Acute Lung Inflammation

Proinflammatory Role of Glucocorticoid-Induced TNF Receptor-Related Gene in Acute Lung Inflammation

MicroRNA-494 Reduces ATF3 Expression and Promotes AKI

ATF3-Mediated Epigenetic Regulation Protects against Acute Kidney Injury

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