JNK signaling involved in the effects of cyclic AMP on IL-1β plus IFNγ-induced inducible nitric oxide synthase expression in hepatocytes

Zhang, Baochun; Perpetua, Michele; Fulmer, Melissa L.; Harbrecht, Brian G.

doi:10.1016/j.cellsig.2004.01.001

Cited by 31 publications

(34 citation statements)

References 45 publications

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“…Pituitary adenylate cyclase-activating polypeptide stimulates p38 in neuronal cells via cAMP/EPAC (32). cAMP activates JNK in certain cell types, and the Ras exchange motif domain of EPAC has been found to be sufficient to stimulate JNK (31,33). The mechanisms whereby cAMP and PKA stimulate the p38 and JNK cascades, however, remain poorly understood.…”

Section: Introductionmentioning

confidence: 99%

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Prostaglandin E2 Induces Breast Cancer–Related Aromatase Promoters via Activation of p38 and c-Jun NH2-Terminal Kinase in Adipose Fibroblasts

et al. 2007

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Aromatase is the key enzyme for estrogen biosynthesis. A distal promoter, PI.4, maintains baseline levels of aromatase in normal breast adipose tissue. In contrast, malignant breast epithelial cells secrete prostaglandin E 2 (PGE 2 ), which stimulates aromatase expression via proximal promoters PI.3/PII in a cyclic AMP (cAMP)-and protein kinase C (PKC)-dependent manner in adjacent breast adipose fibroblasts (BAF), leading to increased local concentrations of estrogen. Although an effective treatment for breast cancer, aromatase inhibitors indiscriminately abolish estrogen synthesis in all tissues, causing major side effects. To identify drug targets to selectively block aromatase and estrogen production in breast cancer, we investigated PGE 2 -stimulated signaling pathways essential for aromatase induction downstream of cAMP and PKC in human BAFs. Here, we show that PGE 2 or its surrogate hormonal mixture dibutyryl cAMP (Bt 2 cAMP) + phorbol diacetate (PDA) stimulated the p38, c-jun NH 2 -terminal kinase (JNK)-1, and extracellular signalregulated kinase (ERK) mitogen-activated protein kinase pathways. Inhibition or small interfering RNA-mediated knockdown of p38 or JNK1, but not ERK, inhibited PGE 2 -or Bt 2 cAMP + PDA-induced aromatase activity and expression via PI.3/PII. Conversely, overexpression of wildtype p38A or JNK1 enhanced PGE 2 -stimulated aromatase expression via PII. PGE 2 or Bt 2 cAMP + PDA stimulated c-Jun and activating transcription factor-2 (ATF2) phosphorylation and binding to the PI.3/PII region. Specific activation of protein kinase A (PKA) or EPAC with cAMP analogues stimulated p38 and JNK1; however, only PKAactivating cAMP analogues induced aromatase expression. The PKC activator PDA effectively stimulated p38 and JNK1 phosphorylation but not aromatase expression. Taken together, PGE 2 activation of p38 and JNK1 via PKA and PKC is necessary for aromatase induction in BAFs, and p38 and JNK1 are potential new drug targets for tissue-specific ablation of aromatase expression in breast cancer. [Cancer Res 2007;67(18):8914-22]

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Section: Introductionmentioning

confidence: 99%

“…EPACs are guanine nucleotide exchange factors for the small G protein Rap1 (26). cAMP-dependent and phorbol ester/ PKC-dependent activations of p38, JNK, and ERK have been reported (18,21,(27)(28)(29)(30)(31). For example, h-adrenergic stimulation of p38 is blocked by a PKA inhibitor in brown adipocytes.…”

Section: Introductionmentioning

confidence: 99%

Prostaglandin E2 Induces Breast Cancer–Related Aromatase Promoters via Activation of p38 and c-Jun NH2-Terminal Kinase in Adipose Fibroblasts

et al. 2007

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“…It is wellestablished that the PKA signalling cascade is of major importance for cellular function and accounts for the intense interest in a specific, high affinity inhibitor. A recent survey of the literature showed that H89 has been used extensively for evaluation of the role of PKA in heart muscle (63,80), osteoblasts (41,61), hepatocytes (23,82), smooth muscle cells (24,70), neuronal tissue (42,44), epithelial cells (11,69), to name but a few. No fewer than 1500 articles have appeared on this subject.…”

Section: Introductionmentioning

confidence: 99%

The Many Faces of H89: A Review

Lochner

Moolman

2006

Cardiovascular Drug Reviews

288

230

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H89 is marketed as a selective and potent inhibitor of protein kinase A (PKA). Since its discovery, it has been used extensively for evaluation of the role of PKA in the heart, osteoblasts, hepatocytes, smooth muscle cells, neuronal tissue, epithelial cells, etc. Despite the frequent use of H89, its mode of specific inhibition of PKA is still not completely understood. It has also been shown that H89 inhibits at least 8 other kinases, while having a relatively large number of PKA-independent effects which may seriously compromise interpretation of data.Thus, while recognizing its kinase inhibiting properties, it is advised that H89 should not be used as the single source of evidence of PKA involvement. H-89 should be used in conjunction with other PKA inhibitors, such as Rp-cAMPS or PKA analogs.

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“…Hepatocytes were plated in 6-well plates and transfected using LipofectAMINE as previously described (44). For experiments investigating p38, recombinant adenovirus expressing the dominant negative p38␣ MAPK or adenovirus expressing GFP were used.…”

Section: Reagentsmentioning

confidence: 99%

“…The role of other counterregulatory mediators produced in shock and sepsis on iNOS regulation remain incompletely studied (8). Glucagon and cAMP regulate hepatocyte iNOS expression through intracellular signaling pathways involving JNK and NF-B (15,20,44). Our laboratory and others have demonstrated that cAMP activates protein kinase B/Akt in hepatocytes (9,27,43,45).…”

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confidence: 99%

Insulin inhibits hepatocyte iNOS expression induced by cytokines by an Akt-dependent mechanism

Nweze

Smith

Zhang

2012

American Journal of Physiology-Gastrointestinal and Liver Physi

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Harbrecht BG, Nweze I, Smith JW, Zhang B. Insulin inhibits hepatocyte iNOS expression induced by cytokines by an Akt-dependent mechanism. Am J Physiol Gastrointest Liver Physiol 302: G116-G122, 2012. First published October 28, 2011 doi:10.1152/ajpgi.00114.2011.-Hepatocyte inducible nitric oxide synthese (iNOS) expression is a tightly controlled pathway that mediates hepatic inflammation and hepatocyte injury in a variety of disease states. We have shown that cyclic adenosine monophosphate (cAMP) regulates cytokine-induced hepatocyte iNOS expression through mechanisms that involve protein kinase B/Akt. We hypothesized that insulin, which activates Akt signaling in hepatocytes, as well as signaling through p38 and MAPK p42/p44, would regulate iNOS expression during inflammation. In primary rat hepatocytes, insulin inhibited cytokine-stimulated nitrite accumulation and iNOS expression in a dose-dependent manner. Inhibition of MAPK p42/p44 with PD98059 had no effect on iNOS activation, whereas SB203580 to block p38 reversed insulin's inhibitory effect. However, insulin did not increase p38 activation and inhibition of p38 signaling with a dominant negative p38 plasmid had no effect on cytokine-or insulin-mediated effects on iNOS. We found that SB203580 blocked insulin-induced Akt activation. Inhibition of Akt signaling with LY294002 or a dominant negative Akt plasmid increased cytokine-stimulated nitrite production and iNOS protein expression and blocked the inhibitory effects of insulin. NF-B induces iNOS expression and can be regulated by Akt, but insulin had no effect on cytokine-mediated IB␣ levels or NF-B p65 translocation. Our data demonstrate that insulin inhibits cytokine-stimulated hepatocyte iNOS expression and does so through effects on Aktmediated signaling. nitric oxide; nitric oxide synthase; sepsis; inflammation; liver HEPATIC DYSFUNCTION WAS IDENTIFIED decades ago as a component of the multiple organ failure syndrome (10). Liver dysfunction can be manifested in a variety of ways and is associated with increased morbidity and mortality in critically ill patients (13,18,25). Nitric oxide synthesis is an important pathway in the host's response to inflammation and mediates hepatic dysfunction and hepatic injury in models of shock and organ failure (19,28). Proinflammatory cytokines stimulate hepatic nitric oxide production, and we have shown that glucagon and cyclic AMP inhibit hepatocyte inducible nitric oxide synthase (iNOS) expression (14 -16). The role of other counterregulatory mediators produced in shock and sepsis on iNOS regulation remain incompletely studied (8). Glucagon and cAMP regulate hepatocyte iNOS expression through intracellular signaling pathways involving 20,44). Our laboratory and others have demonstrated that cAMP activates protein kinase B/Akt in hepatocytes (9,27,43,45). Akt-mediated signaling changes have profound effects on hepatocyte function and physiology (9, 27, 43), and we have shown that the cAMP-induced changes in iNOS expression are mediated in part through Akt-induce...

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JNK signaling involved in the effects of cyclic AMP on IL-1β plus IFNγ-induced inducible nitric oxide synthase expression in hepatocytes

Cited by 31 publications

References 45 publications

Prostaglandin E2 Induces Breast Cancer–Related Aromatase Promoters via Activation of p38 and c-Jun NH2-Terminal Kinase in Adipose Fibroblasts

Prostaglandin E2 Induces Breast Cancer–Related Aromatase Promoters via Activation of p38 and c-Jun NH2-Terminal Kinase in Adipose Fibroblasts

The Many Faces of H89: A Review

Insulin inhibits hepatocyte iNOS expression induced by cytokines by an Akt-dependent mechanism

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