Both N- and C-terminal Domains of Parathyroid Hormone-related Protein Increase Interleukin-6 by Nuclear Factor-κB Activation in Osteoblastic Cells

Guillén, Carlos; Martı́nez, P; Gortázar, Arancha R.; Martı́nez, Marı́a Eugenia; Esbrit, Pedro

doi:10.1074/jbc.m111013200

Cited by 31 publications

(29 citation statements)

References 57 publications

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“…Several studies have shown that NF-B plays an important role in mediating the suppression of P450 expression by inflammatory agents, such as inflammatory cytokines and LPS (40,41). Moreover, it has been reported that PTH and PTH-rP cause dosage-and time-related increases in NF-B in human and rat osteoblastic cells (42,43). Our results support the hypothesis that PTH may act via NF-B to downregulate P450.…”

Section: Figure 5 Effect Of Pth 10supporting

confidence: 88%

Role of Parathyroid Hormone in the Downregulation of Liver Cytochrome P450 in Chronic Renal Failure

Jl¹,

Naud²,

Chouinard³

et al. 2006

Journal of the American Society of Nephrology

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Chronic renal failure (CRF) is associated with a decrease in drug metabolism secondary to a decrease in liver cytochrome P450 (P450). The predominant theory to explain this decrease is the presence of factors in the blood of uremic patients. This study tested the hypothesis that parathyroid hormone (PTH) could be this factor. The objectives of this study were to determine (1) the role of PTH in the downregulation of hepatocyte P450 induced by rat uremic serum, (2) the role of PTH in the downregulation of liver P450 in rats with CRF, and (3) the effects of PTH on P450 in hepatocytes. For this purpose, (1) hepatocytes were incubated with serum from rat with CRF that was depleted with anti-PTH antibodies or with serum from parathyroidectomized (CRF-PTX) rat with CRF, (2) the effect of PTX on liver P450 was evaluated in rats with CRF, and ( C hronic renal failure (CRF) interferes with the elimination of many drugs because of the reduction in GFR and tubular secretion (1). However, renal failure also diminishes the metabolic clearance of selected drugs secondary to decrease of hepatic and intestinal metabolism of these drugs (2-6). The major determinant for these metabolic changes is a reduction in enzymatic activity.Cytochrome P450 (P450) is the major catalyst of drug biotransformation. Several animal studies have shown that liver and intestinal P450 are reduced in CRF (7-10). These studies demonstrated that CRF is associated with a decrease in the activity as well as in the expression of liver and intestinal P450 isoforms secondary to reduced mRNA levels (9,10). The main hypothesis to explain P450 activity and expression downregulation is the presence in the blood of uremic animals of endogenous inhibitors that modulate the P450. Indeed, we have shown that in normal hepatocytes that were incubated for 24 h with serum from rats with CRF, total P450 level and protein expression of several P450 isoforms decreased by 45% compared with serum from control animals (11). This decrease in protein expression of P450 isoforms was secondary to reduced gene expression (11). Similar results have been shown with serum of patients with severe CRF (12). The next step was to find which factor in the uremic blood downregulates P450 in CRF.CRF is associated with multiple metabolic disturbances. As a consequence, numerous molecules are increased in CRF. However, taking into account the changes that are induced by CRF (metabolic, hormonal, and retention of toxins) and the factors that are known to affect the P450, two main mediators are most likely to be associated with downregulation of P450 in CRF: parathyroid hormone (PTH) and proinflammatory cytokines (6). Although the potency of cytokines to downregulate P450 have been established in inflammatory disease (13), we hypothesized that PTH could be implicated in the downregulation of P450 in CRF for the following reasons: (1) secondary hyperparathyroidism is frequent in CRF (14); (2) PTH is known to downregulate the mRNA of many proteins, particularly in the liver but also in other tiss...

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Section: Figure 5 Effect Of Pth 10supporting

confidence: 88%

Role of Parathyroid Hormone in the Downregulation of Liver Cytochrome P450 in Chronic Renal Failure

Jl¹,

Naud²,

Chouinard³

et al. 2006

Journal of the American Society of Nephrology

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“…In the present study, we demonstrated that NF-κB is a key transcriptional factor in the downregulation of CYPs caused by uremic serum since NF-κB inhibition nearly eliminated the effect of pre-HD serum on CYP expression. These results implicate potential uremic mediators such as PTH and cytokines since these proteins act via NF-κB signaling pathways (13,16). Interestingly, changes in the metabolic clearance of CYP substrates that cannot be explained by transcriptional or translational modifications have also been reported.…”

Section: Discussionmentioning

confidence: 72%

Effect of Hemodialysis on Hepatic Cytochrome P450 Functional Expression

Nolin

Naud

et al. 2008

J Pharmacol Sci

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Abstract. Cytochrome P450 (CYP) functional expression is reduced in uremia and normalized after restoration of kidney function via transplantation. The aim of this study was to evaluate the effect of conventional hemodialysis on the functional expression of CYP1A, 2C, and 3A. We also investigated the role of nuclear factor-κB (NF-κB) in CYP regulation during uremia. Primary cultures of normal rat hepatocytes were incubated with serum obtained from end-stage renal disease patients pre-and post-hemodialysis and healthy control subjects, in the presence and absence of the NF-κB inhibitor andrographolide. Uremic pre-hemodialysis serum caused significant reductions (P<0.01) in CYP1A (44%), 2C (27%), and 3A (35%) protein expression compared to control serum, while dialyzed serum (i.e., obtained immediately post-hemodialysis) had no effect. CYP1A2, 2C11, and 3A2 mRNA expression, as well as CYP3A activity, were similarly impacted by uremic serum and were improved to >80% of control values after hemodialysis. NF-κB inhibition nearly eliminated the effect of uremic serum on CYP functional expression. This is the first study to demonstrate that conventional hemodialysis acutely improves altered CYP functional expression observed in rat hepatocytes incubated with uremic human serum.

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“…MDA-MB-231 cells were also assayed for NF-nB-mediated PTHrP mRNA expression. PTHrP is a causal factor in tumor-mediated osteolysis whose fragments activate NF-nB signaling in osteoblasts (35,36). Real-time RT-PCR did not show a statistically significant difference in PTHrP mRNA expression between wild-type MDA-MB-231 and MDA.mInB cells (data not shown).…”

Section: Resultsmentioning

confidence: 90%

“…Augmented PTHrP expression can increase bone resorption by stimulating osteoblast RANKL mRNA expression, which in turn fosters bone-resorbing activity by the increased number of osteoclasts made available by IL-6 (43). PTHrP fragments also activate NF-nB transcription in osteoblasts, leading to IL-6 gene induction and suggestive of an autocrine/ paracrine role for PTHrP in NF-nB-mediated osteolytic tumor burden (36,44).…”

Section: Discussionmentioning

confidence: 99%

Nuclear Factor-κB–Dependent Mechanisms in Breast Cancer Cells Regulate Tumor Burden and Osteolysis in Bone

et al. 2005

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A central mediator of a wide host of target genes, the nuclear factor-KB (NF-KB) family of transcription factors, has emerged as a molecular target in cancer and diseases associated with bone destruction. To evaluate how NF-KB signaling in tumor cells regulates processes associated with osteolytic bone tumor burden, we stably infected the boneseeking MDA-MB-231 breast cancer cell line with a dominant-negative mutant IKB that prevents phosphorylation of IKBa and associated nuclear translocation of NF-KB. Blockade of NF-KB signaling in MDA-MB-231 cells by the mutant IKB decreased in vitro cell proliferation, expression of the proinflammatory, bone-resorbing cytokine interleukin-6, and in vitro bone resorption by tumor/osteoclast cocultures while reciprocally up-regulating production of the proapoptotic enzyme caspase-3. Suppression of NF-KB transcription in these breast cancer cells also reduced incidence of in vivo tumor-mediated osteolysis after intratibial injection of tumor cells in female athymic nude mice. Immunohistochemistry showed that the cancerous lesions formed in bone by MDA-MB-231 cells express both interleukin-6 and the p65 subunit of NF-KB at the bone-tumor interface. NF-KB signaling in breast cancer cells therefore promotes bone tumor burden and tumor-mediated osteolysis through combined control of tumor proliferation, cell survival, and bone resorption. These findings imply that NF-KB and its associated genes may be relevant therapeutic targets in osteolytic tumor burden. (Cancer Res 2005; 65(8): 3209-17)

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Both N- and C-terminal Domains of Parathyroid Hormone-related Protein Increase Interleukin-6 by Nuclear Factor-κB Activation in Osteoblastic Cells

Cited by 31 publications

References 57 publications

Role of Parathyroid Hormone in the Downregulation of Liver Cytochrome P450 in Chronic Renal Failure

Role of Parathyroid Hormone in the Downregulation of Liver Cytochrome P450 in Chronic Renal Failure

Effect of Hemodialysis on Hepatic Cytochrome P450 Functional Expression

Nuclear Factor-κB–Dependent Mechanisms in Breast Cancer Cells Regulate Tumor Burden and Osteolysis in Bone

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