Up-regulation of IL-1 receptor through PI3K/Akt is essential for the induction of iNOS gene expression in hepatocytes

Teshima, Shigeru; Nakanishi, Hideki; Nishizawa, Mikio; Kitagawa, K.; Kaibori, Masaki; Yamada, Masakazu; Habara, Kozo; Kwon, A‐Hon; Kamiyama, Yasuo; Ito, Seiji; Okumura, Tadayoshi

doi:10.1016/j.jhep.2003.12.018

Cited by 63 publications

(48 citation statements)

References 48 publications

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“…Therefore, PI3K/Akt pathway regulation of gene transcription in A549 cells was not through NF-B or p65 transcriptional activity. In agreement with these findings, several studies have also shown that inhibition of the PI3K/Akt pathway did not prevent TNF-␣-or interleukin-1-induced NF-B activation and IB␣ degradation in hepatocytes and A549 and human umbilical vein endothelial cells (25,32,41). Therefore, the PI3K/Akt pathway seems not to induce NF-B activation in every cell type (42).…”

Section: Discussionsupporting

confidence: 64%

Akt Phosphorylation of p300 at Ser-1834 Is Essential for Its Histone Acetyltransferase and Transcriptional Activity

Huang

Chen

2005

Molecular and Cellular Biology

250

243

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The PI3K/Akt pathway plays a critical role in the regulation of gene expression induced by numerous stimuli. p300, a transcriptional coactivator, acts in concert with transcription factors to facilitate gene expression. Here, we show that Akt is activated and translocated to the nucleus in response to tumor necrosis factor alpha. Nuclear Akt associates with p300 and phosphorylates its Ser-1834 both in vivo and in vitro. The phosphorylation induces recruitment of p300 to the ICAM-1 promoter, leading to the acetylation of histones in chromatin and association with the basal transcriptional machinery RNA polymerase II. These two events facilitate ICAM-1 gene expression and are abolished by the p300 S1834A mutant, inhibitors of PI3K/Akt, or small interfering RNA of Akt. Histone acetylation is attributed to the Akt-enhanced intrinsic histone acetyltransferase (HAT) activity of p300 and its association with another

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Section: Discussionsupporting

confidence: 64%

Akt Phosphorylation of p300 at Ser-1834 Is Essential for Its Histone Acetyltransferase and Transcriptional Activity

Huang

Chen

2005

Molecular and Cellular Biology

250

243

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“…Recently, we found that IL-1␤ stimulates the upregulation of IL-1R1 through PI3-kinase/Akt in addition to the activation of NF-B in hepatocytes, which is required to induce the expression of iNOS gene (42). In the present study, EGF and IL-1␤ induced the activations of Akt and NF-B, respectively, in IEC-6 cells, leading to the induction of iNOS expression.…”

Section: Effect Of Egf and Il-1␤ On The Activation Of Akt (Protein Kisupporting

confidence: 64%

“…Several reports indicate that phosphatidylinositol 3-kinase (PI3-kinase) plays an important role in the regulation of iNOS induction in glial cells (28), macrophages (8), and hepatocytes (42). TyrA25 and LY-294002 significantly blocked the increases of NO production stimulated by IL-1␤ plus EGF, with the maximal effects at 100 and 10 M, respectively (Fig.…”

Section: Effects Of Tyra25 (Egf Receptor Kinase Inhibitor) and Ly-294mentioning

confidence: 92%

Epidermal growth factor and interleukin-1β synergistically stimulate the production of nitric oxide in rat intestinal epithelial cells

Kitagawa¹,

Hamada²,

Kato³

et al. 2004

American Journal of Physiology-Gastrointestinal and Liver Physi

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growth factor (EGF) is one of the trophic factors for intestinal adaptation after small bowel transplantation (SBT). A recent report indicates that nitric oxide (NO) has cytoprotective effects on bacterial translocation (BT) after SBT. We hypothesized that EGF stimulates the expression of the inducible NO synthase (iNOS) gene in the graft after SBT, followed by increased production of NO, resulting in the decrease of BT. Intestinal epithelial cells (IEC)-6 were treated with EGF and/or IL-1␤ in the presence and absence of phosphatidylinositol 3-kinase (PI3-kinase) and EGF receptor kinase inhibitors (LY-294002 and tyrphostin A25). The induction of NO production and iNOS and its signal molecules, including the inhibitory protein of NF-B (IB), NF-B, and Akt, were analyzed. IL-1␤ stimulated the degradation of IB and the activation of NF-B but had no effect on iNOS induction. EGF, which had no effect on the NF-B activation and iNOS induction, stimulated the upregulation of type 1 IL-1 receptor (IL-1R1) through PI3-kinase/Akt. Simultaneous addition of EGF and IL-1␤ stimulated synergistically the induction of iNOS, leading to the increased production of NO. Our results indicate that EGF and IL-1␤ stimulate two essential signals for iNOS induction in IEC-6 cells: the upregulation of IL-1R1 through PI3-kinase/Akt and the activation of NF-B through IB kinase, respectively. Simultaneous addition of EGF and IL-1␤ can enhance the production of NO, which may contribute to the cytoprotective effect of EGF against intestinal injury. inducible nitric oxide synthase; nuclear factor-B; phosphatidylinositol 3-kinase; Akt; type 1 interleukin-1 receptor.

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“…Recently, a putative mechanism through which IL-1␤ is able to stimulate iNOS expression in hepatocytes has been proposed. 28 The effect of BV therapy downregulating IL-1␤ expression can be another mechanism that explains the profound iNOS decrease in BV-treated OLTs. There are at least two reasons why the cytokines may be suppressed.…”

Section: Discussionmentioning

confidence: 99%

Biliverdin Therapy Protects Rat Livers From Ischemia and Reperfusion Injury

et al. 2004

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Heme oxygenase (HO-1) provides a cellular defense mechanism during oxidative stress and catalyzes the rate-limiting step in heme metabolism that produces biliverdin (BV). The role of BV and its potential use in preventing ischemia/reperfusion injury (IRI) had never been studied. This study was designed to explore putative cytoprotective functions of BV during hepatic IRI in rat liver models of ex vivo perfusion and orthotopic liver transplantation (OLT) after prolonged periods of cold ischemia. In an ex vivo hepatic IRI model, adjunctive BV improved portal venous blood flow, increased bile production, and decreased hepatocellular damage. These findings were correlated with amelioration of histological features of IRI, as assessed by Suzuki's criteria. Following cold ischemia and syngeneic OLT, BV therapy extended animal survival from 50% in untreated controls to 90% to 100%. This effect correlated with improved liver function and preserved hepatic architecture. Additionally, BV adjuvant after OLT decreased endothelial expression of cellular adhesion molecules (P-selectin and intracellular adhesion molecule 1), and decreased the extent of infiltration by neutrophils and inflammatory macrophages. BV also inhibited expression of inducible nitric oxide synthase and proinflammatory cytokines (interleukin 1␤, tumor necrosis factor ␣, and interleukin 6) in OLTs. Finally, BV therapy promoted an increased expression of antiapoptotic molecules independently of HO-1 expression, consistent with BV being an important mediator through which HO-1 prevents cell death. In conclusion, this study documents and dissects potent cytoprotective effects of BV in well-established rat models of hepatic IRI. Our results provide the rationale for a novel therapeutic approach using BV to maximize the function and thus the availability of donor organs. (HEPATOLOGY 2004;40:1333-1341 I schemia and reperfusion injury (IRI), an antigen-independent component of the insult to the liver during "harvesting," represents an important problem affecting liver transplantation. IRI causes up to 10% of early liver failures and can lead to a higher incidence of acute and chronic rejection. 1 Moreover, with the increasing donor shortage, more functionally "suboptimal" or "marginal" livers are being used. Such livers are more susceptible to the damage caused by IRI compared with normal livers. 2 Indeed, minimizing the adverse effects of IRI could significantly increase the number of patients that successfully undergo liver transplantation.Liver IRI is mediated by several processes that lead to hepatocellular damage, which is triggered when the liver is transiently deprived of oxygen during the organ procurement for transplantation, and later reoxygenated during reperfusion. The structural changes promoted by cold ischemia and reperfusion become more prominent with increased storage time. 3 The sinusoidal endothelial cells are very sensitive to IRI, thus affecting the delicate balance that maintains homeostasis in the microcirculation with

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Up-regulation of IL-1 receptor through PI3K/Akt is essential for the induction of iNOS gene expression in hepatocytes

Cited by 63 publications

References 48 publications

Akt Phosphorylation of p300 at Ser-1834 Is Essential for Its Histone Acetyltransferase and Transcriptional Activity

Akt Phosphorylation of p300 at Ser-1834 Is Essential for Its Histone Acetyltransferase and Transcriptional Activity

Epidermal growth factor and interleukin-1β synergistically stimulate the production of nitric oxide in rat intestinal epithelial cells

Biliverdin Therapy Protects Rat Livers From Ischemia and Reperfusion Injury

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