Proinflammatory cytokines interleukin 1β and tumor necrosis factor α inhibit growth hormone stimulation of insulin-like growth factor I synthesis and growth hormone receptor mRNA levels in cultured rat liver cells

1996 ◽  
Vol 135 (6) ◽  
pp. 729-737 ◽  
Author(s):  
Matthias Wolf ◽  
Sebastian Böhm ◽  
Marcus Brand ◽  
Georg Kreymann
Keyword(s):  
Growth Hormone ◽  
Tumor Necrosis Factor ◽  
Proinflammatory Cytokines ◽  
Tumor Necrosis ◽  
Tumor Necrosis Factor Α ◽  
Mrna Levels ◽  
Receptor Mrna ◽  
Gh Receptor ◽  
Tnf Α ◽  
Igf I

Wolf M, Böhm S, Brand M, Kreymann G. Proinflammatory cytokines interleukin 1β and tumor necrosis factor α inhibit growth hormone stimulation of insulin-like growth factor I synthesis and growth hormone receptor mRNA levels in cultured rat liver cells. Eur J Endocrinol 1996;135:729–37. ISSN 0804–4643 Low levels of insulin-like growth factor I (IGF-I) in critical illness are observed despite increased or normal levels of growth hormone (GH). The mechanisms for this apparent GH resistance have not been elucidated. As many of the acute inflammatory responses in critical illness are mediated by the proinflammatory cytokines interleukin 1β (IL-1β) and tumor necrosis factor α (TNF-α), the present studies evaluated IL-1β and TNF-α effects on steady-state and GH-stimulated IGF-I synthesis and GH receptor mRNA levels. In rat hepatocytes in primary culture, IGF-I released into culture medium was determined by radioimmunoassay, and quantitative competitive polymerase chain reaction was used to measure IGF-I mRNA and GH receptor mRNA concentrations. Growth hormone increased GH receptor mRNA, IGF-I mRNA and IGF-I protein secreted into the culture medium. In cells not stimulated with GH, modest inhibitory effects of IL-1β on GH receptor mRNA, IGF-I mRNA and IGF-I protein levels were seen. However, the stimulatory effects of GH were inhibited in a dose-dependent manner both by IL-1β and TNF-α, and at higher cytokine concentrations no stimulatory effects of GH were observed. Both IL-1β and TNF-α in submaximal dose had additive inhibitory effects on IGF-I protein concentrations but these effects did not result in irreversible damage to cells, as indicated by restoration of IGF-I and GH receptor mRNA levels to normal after withdrawal of cytokines. In conclusion, we demonstrated that in rat hepatocytes in primary culture IL-1β and TNF-α inhibited GH-stimulated IGF-I synthesis. Diminished GH receptor mRNA concentrations in response to IL-1β and TNF-α indicate that low IGF-I levels during severe illness, despite high circulating GH levels, may at least partially be a consequence of suppression of hepatic GH receptor synthesis by IL-1β and TNF-α. Matthias Wolf, Medizinische Kern- und Poliklinik, Universitäts-Krankenhaus Eppendorf, Martinistrasse 52, 20246 Hamburg, Germany

Interleukin-1 and tumor necrosis factor-α increase insulin-like growth factor-binding protein-3 (IGFBP-3) production and IGFBP-3 protease activity in human articular chondrocytes

1995 ◽  
Vol 146 (2) ◽  
pp. 279-286 ◽  
Author(s):  
R C Olney ◽  
D M Wilson ◽  
M Mohtai ◽  
P J Fielder ◽  
R L Smith
Keyword(s):  
Tumor Necrosis Factor ◽  
Tumor Necrosis ◽  
Tumor Necrosis Factor Α ◽  
Articular Chondrocytes ◽  
Tnf Α ◽  
Igf I ◽  
Matrix Production ◽  
Factor Α ◽  
Necrosis Factor ◽  
Igfbp 3

Abstract IGF-I is the major anabolic factor for cartilage matrix production. Chondrocytes and cartilage treated with interleukin-1α (IL-1α), and chondrocytes from several models of inflammatory joint disease, exhibit reduced responsiveness to IGF-I. Since the IGF-binding proteins (IGFBPs) modulate the effects of IGF-I, we examined the effect of IL-1α and tumor necrosis factor-α (TNF-α) on IGFBP production by normal human articular chondrocytes in primary culture. Western ligand blots and immunoprecipitation of conditioned medium samples showed that articular chondrocytes produced IGFBPs-2, −3 and −4 and glycosylated IGFBP-4. Both IL-1α and TNF-α increased chondrocyte production of IGFBP-3, but did not alter IGFBP-4 production. The activity of a neutral metalloprotease with the ability to cleave IGFBP-3 was also increased by IL-1α. These data suggest that the cytokines IL-1α and TNF-α may act to reduce IGF-I access to chondrocytes by increasing production of IGFBP-3. This may be a factor in the decreased matrix production in the inflammatory arthritides. Journal of Endocrinology (1995) 146, 279–286

Regulation of porcine insulin-like growth factor I and growth hormone receptor mRNA expression by energy status

1994 ◽  
Vol 266 (5) ◽  
pp. E776-E785 ◽  
Author(s):  
P. A. Weller ◽  
M. J. Dauncey ◽  
P. C. Bates ◽  
J. M. Brameld ◽  
P. J. Buttery ◽  
...  
Keyword(s):  
Growth Hormone ◽  
Growth Factor ◽  
Growth Rates ◽  
Mrna Levels ◽  
Energy Status ◽  
Factor I ◽  
Receptor Mrna ◽  
Gh Receptor ◽  
Igf I ◽  
Class 1

Regulation of insulin-like growth factor I (IGF-I) and growth hormone (GH) receptor mRNA in liver and muscle by energy status was assessed in 2-mo-old pigs by altering thermoregulatory demand and energy intake over a 5-wk period to produce a range of plasma IGF-I concentrations from 3.5 +/- 0.7 to 28.9 +/- 6.2 nmol/l. These values were related directly to growth rates (0.06 +/- 0.02 to 0.44 +/- 0.01 kg/day) and total hepatic IGF-I mRNA levels. Increased growth rates were accompanied by an increase in hepatic class 1 and class 2 IGF-I mRNA levels and an increase in the ratio of class 2 to class 1 IGF-I mRNA in liver, suggesting a distinct role for class 2 expression in the endocrine growth response. High levels of class 1 transcripts and a virtual absence of class 2 transcripts characterized all muscle tissues examined, and there was no correlation with plasma IGF-I levels. This suggests that growth promotion in response to increased energy status is regulated via endocrine hepatic IGF-I rather than via a paracrine response. The levels of GH receptor mRNA were positively correlated with overall growth rate (P < 0.005) in liver and negatively correlated (P < 0.05) in muscle, indicating distinct tissue-specific effects of energy status.

scholarly journals Inhibition by Interleukin-1β and Tumor Necrosis Factor-α of the Insulin-Like Growth Factor I Messenger Ribonucleic Acid Response to Growth Hormone in Rat Hepatocyte Primary Culture*

Endocrinology ◽  
1997 ◽  
Vol 138 (3) ◽  
pp. 1078-1084 ◽  
Author(s):  
Jean-Paul Thissen ◽  
Josiane Verniers
Keyword(s):  
Gene Expression ◽  
Growth Factor ◽  
Tumor Necrosis Factor ◽  
Tumor Necrosis ◽  
Mrna Levels ◽  
Factor I ◽  
Tnf Α ◽  
Igf I ◽  
Necrosis Factor ◽  
I Gene

Abstract The cytokines are the putative mediators of the catabolic reaction that accompanies infection and trauma. Evidence suggests that their catabolic actions are indirect and potentially mediated through changes in hormonal axis such as the hypothalamo-pituitary-adrenal axis. Insulin-like growth factor I (IGF-I) is a GH-dependent growth factor that regulates the protein metabolism. To determine whether cytokines can directly inhibit the production of IGF-I by the liver, we investigated the regulation of IGF-I gene expression by interleukin (IL)-1β, IL-6, and tumor necrosis factor (TNF)-α (10 ng/ml) in a model of rat primary cultured hepatocytes. Hepatocytes were isolated by liver collagenase perfusion and cultured on Matrigel 48 h before experiments. Each experiment was performed in at least three different animals. In the absence of GH, IL-1β and TNF-α did not affect the IGF-I messenger RNA (mRNA) basal levels, whereas IL-6 increased it by a factor of 2.5 after 24 h (P &lt; 0.05). GH (500 ng/ml) alone stimulated the IGF-I gene expression markedly (5- to 10-fold increase) after 24 h (P &lt; 0.001). IL-1β, and TNF-α to a lesser extent, dramatically inhibited the IGF-I mRNA response to GH (IL-1β: −82%, P &lt; 0.001 and TNF-α: −47%, P &lt; 0.01). The half-maximal inhibition of the IGF-I mRNA response to GH was observed for a concentration of IL-1β between 0.1 and 1 ng/ml. Moreover, IL-1β abolished the IL-6-induced IGF-I mRNA response. In contrast, IL-6 did not impair the IGF-I mRNA response to GH. To determine the potential role of the GH receptor (GHR) and the GH-binding protein (GHBP) in this GH resistance, we assessed the GHR and GHBP mRNAs response to these cytokines. GH alone did not affect the GHR/GHBP mRNA levels. IL-1β markedly decreased the GHR and GHBP mRNA levels (respectively, −68% and −60%, P &lt; 0.05). Neither TNF-α nor IL-6 affected the GHR/GHBP gene expression. In conclusion, our results show that IL-1β, and TNF-α to a lesser extent, blunt the IGF-I mRNA response to GH. The resistance to GH induced by IL-1β might be mediated by a decrease of GH receptors, as suggested by the marked reduction of GHR mRNA. These findings suggest that decreased circulating IGF-I, in response to infection and trauma, may be caused by a direct effect of cytokines at the hepatocyte level.

The cytokines interleukin-1β and tumor necrosis factor-α stimulate CFTR-mediated fluid secretion by swine airway submucosal glands

2012 ◽  
Vol 303 (4) ◽  
pp. L327-L333 ◽  
Author(s):  
Nicholas Baniak ◽  
Xiaojie Luan ◽  
Amber Grunow ◽  
Terry E. Machen ◽  
Juan P. Ianowski
Keyword(s):  
Tumor Necrosis Factor ◽  
Proinflammatory Cytokines ◽  
Tumor Necrosis ◽  
Tumor Necrosis Factor Α ◽  
Interleukin 1Β ◽  
Tnf Α ◽  
Submucosal Glands ◽  
Factor Α ◽  
Airway Defense ◽  
Necrosis Factor

The airway is kept sterile by an efficient innate defense mechanism. The cornerstone of airway defense is mucus containing diverse antimicrobial factors that kill or inactivate pathogens. Most of the mucus in the upper airways is secreted by airway submucosal glands. In patients with cystic fibrosis (CF), airway defense fails and the lungs are colonized by bacteria, usually Pseudomonas aeruginosa . Accumulating evidence suggests that airway submucosal glands contribute to CF pathogenesis by failing to respond appropriately to inhalation of bacteria. However, the regulation of submucosal glands by the innate immune system remains poorly understood. We studied the response of submucosal glands to the proinflammatory cytokines interleukin-1β and tumor necrosis factor-α. These are released into the airway submucosa in response to infection with the bacterium P. aeruginosa and are elevated in CF airways. Stimulation with IL-1β and TNF-α increased submucosal gland secretion in a concentration-dependent manner with a maximal secretion rate of 240 ± 20 and 190 ± 40 pl/min, respectively. The half maximal effective concentrations were 11 and 20 ng/ml, respectively. The cytokine effect was dependent on cAMP but was independent of cGMP, nitric oxide, Ca2+, or p38 MAP kinase. Most importantly, IL-1β- and TNF-α-stimulated secretion was blocked by the CF transmembrane conductance regulator (CFTR) blocker, CFTRinh172 (100 μmol/l) but was not affected by the Ca2+-activated Cl− channel blocker, niflumic acid (1 μmol/l). The data suggest, that during bacterial infections and resulting release of proinflammatory cytokines, the glands are stimulated to secrete fluid, and this response is mediated by cAMP-activated CFTR, a process that would fail in patients with CF.

scholarly journals Tumor necrosis factor-α induces a biphasic change in claudin-2 expression in tubular epithelial cells: role in barrier functions

2015 ◽  
Vol 309 (1) ◽  
pp. C38-C50 ◽  
Author(s):  
Yasaman Amoozadeh ◽  
Qinghong Dan ◽  
Jenny Xiao ◽  
Faiza Waheed ◽  
Katalin Szászi
Keyword(s):  
Tumor Necrosis Factor ◽  
Tumor Necrosis ◽  
Tumor Necrosis Factor Α ◽  
Mrna Levels ◽  
Tnf Α ◽  
Biphasic Effect ◽  
Early Increase ◽  
Factor Α ◽  
The Impact ◽  
Necrosis Factor

The inflammatory cytokine tumor necrosis factor-α (TNF-α) is a pathogenic factor in acute and chronic kidney disease. TNF-α is known to alter expression of epithelial tight junction (TJ) proteins; however, the underlying mechanisms and the impact of this effect on epithelial functions remain poorly defined. Here we describe a novel biphasic effect of TNF-α on TJ protein expression. In LLC-PK1 tubular cells, short-term (1–6 h) TNF-α treatment selectively elevated the expression of the channel-forming TJ protein claudin-2. In contrast, prolonged (>8 h) TNF-α treatment caused a marked downregulation in claudin-2 and an increase in claudin-1, -4, and -7. The early increase and the late decrease in claudin-2 expression involved distinct mechanisms. TNF-α slowed claudin-2 degradation through ERK, causing the early increase. This increase was also mediated by the EGF receptor and RhoA and Rho kinase. In contrast, prolonged TNF-α treatment reduced claudin-2 mRNA levels and promoter activity independent from these signaling pathways. Electric Cell-substrate Impedance Sensing measurements revealed that TNF-α also exerted a biphasic effect on transepithelial resistance (TER) with an initial decrease and a late increase. Thus there was a good temporal correlation between TNF-α-induced claudin-2 protein and TER changes. Indeed, silencing experiments showed that the late TER increase was at least in part caused by reduced claudin-2 expression. Surprisingly, however, claudin-2 silencing did not prevent the early TER drop. Taken together, the TNF-α-induced changes in claudin-2 levels might contribute to TER changes and could also play a role in newly described functions of claudin-2 such as proliferation regulation.

Effect of tumor necrosis factor-α on the expression of insulin-like growth factor I and insulin-like growth factor binding protein 4 in mouse osteoblasts

1994 ◽  
Vol 131 (3) ◽  
pp. 293-301 ◽  
Author(s):  
Stephan H Scharla ◽  
Donna D Strong ◽  
Subburaman Mohan ◽  
Thierry Chevalley ◽  
Thomas A Linkhart
Keyword(s):  
Growth Factor ◽  
Tumor Necrosis Factor ◽  
Tumor Necrosis ◽  
Tumor Necrosis Factor Α ◽  
Insulin Like Growth Factor ◽  
Factor I ◽  
Tnf Α ◽  
Igf I ◽  
Factor Α ◽  
Necrosis Factor

Scharla SH, Strong DD, Mohan S, Chevalley T, Linkhart TA. Effect of tumor necrosis factor-α on the expression of insulin-like growth factor I and insulin-like growth factor binding protein 4 in mouse osteoblasts. Eur J Endocrinol 1994;131:293–301. ISSN 0804–4643 Tumor necrosis factor-α (TNF-α) is a cytokine produced by immune cells, which has multiple effects on bone cells and is therefore thought to mediate changes in bone metabolism occurring during inflammation. In the present study we have investigated the effect of TNF-α on the secretion of insulin-like growth factor I (IGF-I) and IGF binding protein 4 (IGFBP-4) by clonal mouse osteoblasts (MC3T3-E1 cells) using subconfluent in vitro cultures and serum-free conditions. The IGF-I was determined by radioimmunoassay under conditions eliminating the interference of IGFBPs. Treatment of MC3T3-E1 cultures with TNF-α for 24 h resulted in a dose-dependent decrease in IGF-I secretion (maximally to 34 ± 9.7% of control with 60 pmol/l TNF-α; mean ± sd). The TNF-α treatment also resulted in decreased messenger ribonucleic acid (mRNA) levels of IGF-I at 4 and 24 h, as detected by Northern analysis. Because basal secretion of IGFBPs is very low in MC3T3-E1 cells, effects of TNF-α on IGFBP secretion were studied in cultures in which IGFBP-4 expression was increased by calcitriol (1,25(OH)2D3) treatment. The presence of TNF-α (600 pmol/l) inhibited this calcitriol-induced stimulation of IGFBP-4 mRNA levels from 4 h onwards, with complete inhibition of the calcitriol effect occurring at 24 h. We also observed a dose-dependent inhibition of calcitriol-stimulated IGFBP-4 secretion into the culture medium (as detected by Western ligand blot), with the maximal inhibition occurring with 600 pmol/l TFN-α to 25 ± 7% of control levels. These TNF-α effects were not prevented by indomethacin treatment, suggesting that they are not dependent on prostaglandins. The DNA synthesis was reduced to 62 ± 8% of the control value by 600 pmol/l TNF-α. We conclude that secretion of IGFs and IGFBPs by osteoblasts can be modulated by TNF-α, which in turn may be responsible for some of the known effects of TNF-α on osteoblastic cell proliferation and differentiation. Stephan H Scharla, Klinik am Kurpark, Schussenrieder Strasse 5, D-88326 Anlendorf, Germany

scholarly journals Tumor necrosis factor-α, kidney function, and hypertension

2017 ◽  
Vol 313 (4) ◽  
pp. F1005-F1008 ◽  
Author(s):  
Eamonn Mehaffey ◽  
Dewan S. A. Majid
Keyword(s):  
Tumor Necrosis Factor ◽  
Proinflammatory Cytokines ◽  
Renal Injury ◽  
Tumor Necrosis ◽  
Tumor Necrosis Factor Α ◽  
Low Grade ◽  
Tnf Α ◽  
Factor Α ◽  
Necrosis Factor

Hypertension is considered to be a low-grade inflammatory condition characterized by the presence of various proinflammatory cytokines. Tumor necrosis factor-α (TNF-α) is a constituent of the proinflammatory cytokines that is associated with salt-sensitive hypertension (SSH) and related renal injury. Elevated angiotensin II (ANG II) and other factors such as oxidative stress conditions promote TNF-α formation. Many recent studies have provided evidence that TNF-α exerts a direct renal action by regulating hemodynamic and excretory function in the kidney. The cytokine incites a strong natriuretic response and plays a part in regulation of the intrarenal renin-angiotensin system. The exact mechanistic role of TNF-α in the development of SSH is as yet poorly understood. While TNF-α antagonism has been shown to attenuate hypertensive responses in many hypertensive animal models, contrasting findings demonstrate that the direct systemic administration of TNF-α usually induces hypotensive as well as natriuretic responses, indicating a counterregulatory role of TNF-α in SSH. Differential activities of two cell surface receptors of TNF-α (receptor type 1 and type 2) may explain the contradictory functions of TNF-α in the setting of hypertension. This short review will evaluate ongoing research studies that investigate the action of TNF-α within the kidney and its role as an influential pathophysiological variable in the development of SSH and renal injury. This information may help to develop specific TNF-α receptor targeting as an effective treatment strategy in this clinical condition.

#50 Gestational exposure of tumor necrosis factor-α (TNF-α) inhibitor drugs

2019 ◽  
Vol 88 ◽  
pp. 149-150 ◽  
Author(s):  
Erkoseoglu Ilknur ◽  
Kadioglu Mine ◽  
Cavusoglu Irem ◽  
Sisman Mulkiye ◽  
Aran Turhan ◽  
...  
Keyword(s):  
Tumor Necrosis Factor ◽  
Tumor Necrosis ◽  
Tumor Necrosis Factor Α ◽  
Gestational Exposure ◽  
Tnf Α ◽  
Factor Α ◽  
Necrosis Factor
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