Endotoxin attenuates growth hormone-induced hepatic insulin-like growth factor I expression by inhibiting JAK2/STAT5 signal transduction and STAT5b DNA binding

Chen, Yu; Sun, Difei; Krishnamurthy, Vidya M. Raj; Rabkin, Ralph

doi:10.1152/ajpendo.00581.2006

Cited by 40 publications

(51 citation statements)

References 44 publications

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“…Hence, upregulation of SOCS protein expression may provide a potential explanation for the impaired JAK2/STAT5 signaling in NCG-SGA rats. Interestingly, an acquired defect in JAK2/STAT signaling with exaggerated increase in SOCS expression has also been described recently in septic or uremic rats with evidence of GH resistance [24,25]. …”

Section: Discussionmentioning

confidence: 91%

Impaired Growth Hormone Receptor Signaling during Non-Catch-Up Growth in Rats Born Small for Gestational Age

Huang

Du²,

Zhuang³

et al. 2010

Horm Res Paediatr

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Background/Aims: Non-catch-up growth (NCG) in children born small for gestational age (SGA) is associated with growth hormone (GH) resistance, although the mechanisms of this association are unknown. Janus kinase/signal transducer and activator of transcription (JAK/STAT) signaling is involved in GH signal transduction. This study examined the role of JAK/STAT signaling in GH resistance of SGA rats. Methods: NCG-SGA was induced by uterine artery ligation in pregnant rats. NCG-SGA rats were treated with GH for 7 days and rats appropriate for gestational age (AGA) served as controls. Phosphorylation of JAK2/STAT5 and expression of GH receptor, suppressor of cytokine signaling 2 (SOCS-2) and cytokine-inducible SH2-containing protein (CIS) in the liver were determined by Western blotting. The expression of insulin-like growth factor 1 (IGF-1) mRNA was examined by the reverse transcription-polymerase chain reaction. Results: GH treatment significantly increased body weight and length growth rate in AGA but not in NCG-SGA rats. The increase in serum IGF-1 level and expression of IGF-1 mRNA in response to GH treatment in NCG-SGA rats was significantly less than in AGA rats. GH-induced increase in phosphorylation of JAK2/STAT5 in response to acute GH stimulation was significantly lower in NCG-SGA rats compared to AGA controls. SOCS-2 and CIS expressions significantly increased in NCG-SGA rats following GH treatment. Conclusion: GH resistance in NCG-SGA rats is associated with impaired JAK/STAT signaling and upregulated SOCS-2 and CIS expression.

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Section: Discussionmentioning

confidence: 91%

Impaired Growth Hormone Receptor Signaling during Non-Catch-Up Growth in Rats Born Small for Gestational Age

Huang

Du²,

Zhuang³

et al. 2010

Horm Res Paediatr

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“…Impaired STAT5 activation has also been observed in sepsis with an accompanying endotoxin release. In these patients hepatic expression of SOCS-1, SOCS-3, and CIS was transiently increased during sepsis and temporally associated with the development of hepatic GH resistance (10,99). It is likely that increased SOCS/CIS expression is the result of elevated IL-6 levels that accompany severe inflammation.…”

Section: Contribution Of Stat5 In Liver To Human Physiology and Diseasementioning

confidence: 92%

“…1). Denson's work demonstrates that IL-6 inhibits hepatic GH signaling through an increase of CIS and SOCS3, and thus causes acquired GH resistance in patients with inflammatory diseases or sepsis (10,21).…”

Section: Stat3 Target Genesmentioning

confidence: 99%

Genomic dissection of the cytokine-controlled STAT5 signaling network in liver

Hosui

Hennighausen

2008

Physiological Genomics

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Hosui A, Hennighausen L. Genomic dissection of the cytokine-controlled STAT5 signaling network in liver. Physiol Genomics 34: 135-143, 2008. First published May 6, 2008 doi:10.1152/physiolgenomics.00048.2008.-Growth hormone (GH) controls the physiology and pathophysiology of the liver, and its signals are conducted by two members of the family of signal transducers and activators of transcription, STAT5A and STAT5B. Mice in which the Stat5a/b locus has been inactivated specifically in hepatocytes display GH resistance, the sex-specific expression of genes associated with liver metabolism and the cytochrome P-450 system is lost, and they develop hepatosteatosis. Several groups have shown by global gene expression profiling that a cadre of STAT5A/B target genes identify genetic cascades induced by GH and other cytokines. Evidence is accumulating that in the absence of STAT5A/B GH aberrantly activates STAT1 and STAT3 and their downstream target genes and thereby offers a partial explanation of some of the physiological alterations observed in Stat5a/b-null mice and human patients. We hypothesize that phenotypic changes observed in the absence of STAT5A/B are due to two distinct molecular consequences: first, the failure of STAT5A/B target genes to be activated by GH and second, the rerouting of GH signaling to other members of the STAT family. Rerouting of GH signaling to STAT1 and STAT3 might partially compensate for the loss of STAT5A/B, but it certainly activates biological programs distinct from STAT5A/B. Here we discuss the extent to which studies on global gene expression profiling have fostered a better understanding of the biology behind cytokine-STAT5A/B networks in hepatocytes. We also explore whether this wealth of information on gene activity can be used to further understand the roles of cytokines in liver disease.signal transducers and activators of transcription; knockout; metabolism THE ABILITY TO MUTATE individual genes in the mouse has permitted detailed studies on their roles in development, physiology, and disease. In particular, gene knockout mice have provided in-depth insight into the molecular structure and dynamics of signal transduction networks. However, in many cases the physiological consequences observed in mutant mice, or lack thereof, were unexpected and irreconcilable with the proposed functions of the protein under investigation. Genomewide gene expression profiling from gene knockout mice should provide an inroad into better understanding of the molecular consequences of disrupting complex information networks. The application of global approaches to the analysis of complex biological systems including organ development, physiology, and disease has gained considerable strength. Characterization of molecular networks that drive these biological processes has been facilitated by the emergence of affordable high-throughput technologies, including DNA microarrays that can monitor the activity of an entire genome. Such approaches have the promise to facilitate an understanding of mole...

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“…36 Conversely, GH does stimulate cytokine production in human monocytes 37 and in liver of endotoxin-treated rat. 38 ; therefore, further study in humans with ESRD is indicated. Whereas GH had no impact on serum creatinine, urea nitrogen, albuminuria, or elevated BP levels in the CRF rats, it had a notable impact on cardiac morphology.…”

Section: Discussionmentioning

confidence: 99%

Low-Dose Growth Hormone is Cardioprotective in Uremia

Rabkin

Awwad

Chen

et al. 2008

Journal of the American Society of Nephrology

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Growth hormone (GH) is required to maintain normal cardiac structure and function and has a positive effect on cardiac remodeling in experimental and possibly human disease. Cardiac resistance to GH develops in the uremic state, perhaps predisposing to the characteristic cardiomyopathy associated with uremia. It was hypothesized that administration of low-dosage GH may have a salutary effect on the cardiac remodeling process in uremia, but because high levels of GH have adverse cardiac effects, administration of high-dosage GH may worsen uremic cardiomyopathy. In rats with chronic renal failure, quantitative cardiac morphology revealed a decrease in total capillary length and capillary length density and an increase in mean intercapillary distance and fibroblast volume density evident. Low-dosage GH prevented these changes. Collagen and TGF-␤ immunostaining, increased in chronic renal failure, were also reduced by GH, suggesting a mechanism for its salutary action. Low-dosage GH also prevented thickening of the carotid artery but did not affect aortic pathology. In contrast, high-dosage GH worsened several of these variables. These results suggest that low-dosage GH may benefit the heart and possibly the carotid arteries in chronic renal failure.

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Endotoxin attenuates growth hormone-induced hepatic insulin-like growth factor I expression by inhibiting JAK2/STAT5 signal transduction and STAT5b DNA binding

Cited by 40 publications

References 44 publications

Impaired Growth Hormone Receptor Signaling during Non-Catch-Up Growth in Rats Born Small for Gestational Age

Impaired Growth Hormone Receptor Signaling during Non-Catch-Up Growth in Rats Born Small for Gestational Age

Genomic dissection of the cytokine-controlled STAT5 signaling network in liver

Low-Dose Growth Hormone is Cardioprotective in Uremia

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