Generation and functional significance of CXC chemokines for neutrophil-induced liver injury during endotoxemia

2005 ◽  
Vol 288 (5) ◽  
pp. G880-G886 ◽  
Author(s):  
Robert B. Dorman ◽  
Jaspreet S. Gujral ◽  
Mary Lynn Bajt ◽  
Anwar Farhood ◽  
Hartmut Jaeschke
Keyword(s):  
Liver Injury ◽  
Functional Significance ◽  
Cell Injury ◽  
Apoptotic Cell ◽  
Gene Knockout ◽  
Mrna Levels ◽  
Wild Type ◽  
Neutrophil Sequestration ◽  
Neutrophil Extravasation ◽  
Cxc Chemokine

Generation and functional significance of CXC chemokines for neutrophil-induced liver injury during endotoxemia. Am J Physiol Gastrointest Liver Physiol 288: G880–G886, 2005. First published December 2, 2004;.—The hypothesis that the neutrophil chemoattractant CXC chemokines KC and macrophage inflammatory protein-2 (MIP-2) are involved in neutrophil transmigration and liver injury was tested in C3Heb/FeJ mice treated with galactosamine (Gal, 700 mg/kg), endotoxin (ET, 100 μg/kg), or Gal + ET (Gal/ET). Hepatic KC and MIP-2 mRNA levels and plasma CXC chemokine concentrations were dramatically increased 1.5 h after Gal/ET or ET alone and gradually declined up to 7 h. Murine recombinant cytokines (TNF-α, IL-1α, and IL-1β), but not Gal/ET, induced CXC chemokine formation in the ET-resistant C3H/HeJ strain. To assess the functional importance of KC and MIP-2, C3Heb/FeJ mice were treated with Gal/ET and control IgG or a combination of anti-KC and anti-MIP-2 antibodies. Anti-CXC chemokine antibodies did not attenuate hepatocellular apoptosis, sinusoidal neutrophil sequestration and extravasation, or liver injury at 7 h. Furthermore, there was no difference in liver injury between BALB/cJ wild-type and CXC receptor-2 gene knockout (CXCR2−/−) mice treated with Gal/ET. The higher neutrophil count in livers of CXCR2−/−than in wild-type mice after Gal/ET was caused by the elevated number of neutrophils located in sinusoids of untreated CXCR2−/−animals. The pancaspase inhibitor Z-Val-Ala-Asp-fluoromethylketone eliminated Gal/ET-induced apoptosis and neutrophil extravasation and injury but not CXC chemokine formation. Thus Gal/ET induced massive, cytokine-dependent CXC chemokine formation in the liver. However, neutrophil extravasation and injury occurred in response to apoptotic cell injury at 6–7 h and was independent of CXC chemokine formation.

scholarly journals Stem cell factor and c-kit are involved in hepatic recovery after acetaminophen-induced liver injury in mice

2008 ◽  
Vol 295 (1) ◽  
pp. G45-G53 ◽  
Author(s):  
Bin Hu ◽  
Lisa M. Colletti
Keyword(s):  
Stem Cell ◽  
Liver Injury ◽  
Stem Cell Factor ◽  
Cellular Proliferation ◽  
Hepatocyte Proliferation ◽  
Mrna Levels ◽  
Wild Type ◽  
Hepatocyte Apoptosis ◽  
Large Reservoir ◽  
A Cell

Stem cell factor (SCF) and its receptor c-kit are important in hematopoiesis and cellular proliferation. c-kit has also been identified as a cell surface marker for progenitor cells. We have previously shown that there is a large reservoir of hepatic SCF, and this molecule plays a significant role in liver regeneration after 70% hepatectomy. In the current study, we further examined the expression of SCF and c-kit in acetaminophen (APAP)-induced liver injury in C57BL/6J mice or SCF-deficient sl-sld mice and their appropriate wild-type controls. Following APAP-induced liver injury, c-kit mRNA expression increased, with peak levels detected 48 h postinjury. Hepatic SCF mRNA levels after APAP injury were also increased, with peak levels seen 16 h post-APAP. The mortality rate in SCF-deficient mice treated with APAP was significantly higher than that of wild-type mice; furthermore, administration of exogenous SCF significantly reduced the mortality of APAP-treated wild-type mice. Bromodeoxyuridine incorporation experiments showed that SCF significantly increased hepatocyte proliferation at 48 and 72 h in APAP-treated mice. SCF inhibited APAP-induced hepatocyte apoptosis and increased Bcl-2 and Bcl-xL expression, suggesting that this decrease in hepatocyte apoptosis is mediated through Bcl-2 and Bcl-xL. In summary, SCF and c-kit expression was increased after APAP-induced liver injury. Administration of exogenous SCF reduces mortality in APAP-treated mice, increases hepatocyte proliferation, and prevents hepatocyte apoptosis induced by APAP, suggesting that these molecules are important in the liver's recovery from these injuries.

scholarly journals Intestinal Resistance to 1,25 Dihydroxyvitamin D in Mice Heterozygous for the Vitamin D Receptor Knockout Allele

Endocrinology ◽  
2007 ◽  
Vol 148 (3) ◽  
pp. 1396-1402 ◽  
Author(s):  
Yurong Song ◽  
James C. Fleet
Keyword(s):  
Vitamin D ◽  
Vitamin D Receptor ◽  
Time Course ◽  
Transient Receptor Potential ◽  
Gene Knockout ◽  
Mrna Levels ◽  
Wild Type ◽  
Calcium Diet ◽  
Low Calcium Diet ◽  
Low Calcium

We tested the hypothesis that low vitamin D receptor (VDR) level causes intestinal vitamin D resistance and intestinal calcium (Ca) malabsorption. To do so, we examined vitamin D regulated duodenal Ca absorption and gene expression [transient receptor potential channel, vallinoid subfamily member 6 (TRPV6), 24-hydroxylase, calbindin D9k (CaBP) mRNA, and CaBP protein] in wild-type mice and mice with reduced tissue VDR levels [i.e. heterozygotes for the VDR gene knockout (HT)]. Induction of 24-hydroxylase mRNA levels by 1,25 dihydroxyvitamin D3 [1,25(OH)2 D3] injection was significantly reduced in the duodenum and kidney of HT mice in both time-course and dose-response experiments. TRPV6 and CaBP mRNA levels in duodenum were significantly induced after 1,25(OH)2 D3 injection, but there was no difference in response between wild-type and HT mice. Feeding a low-calcium diet for 1 wk increased plasma PTH, renal 1α-hydroxylase (CYP27B1) mRNA level, and plasma 1,25(OH)2 D3, and this response was greater in HT mice (by 88, 55, and 37% higher, respectively). In contrast, duodenal TRPV6 and CaBP mRNA were not higher in HT mice fed the low-calcium diet. However, the response of duodenal Ca absorption and CaBP protein to increasing 1,25(OH)2 D3 levels was blunted by 40% in HT mice. Our data show that low VDR levels lead to resistance of intestinal Ca absorption to 1,25(OH)2 D3, and this resistance may be due to a role for the VDR (and VDR level) in the translation of CaBP.

Wild-type levels of the mouseForkhead Box f1gene are essential for lung repair

2002 ◽  
Vol 282 (6) ◽  
pp. L1253-L1265 ◽  
Author(s):  
Vladimir V. Kalinichenko ◽  
Yan Zhou ◽  
Brian Shin ◽  
Donna Beer Stolz ◽  
Simon C. Watkins ◽  
...  
Keyword(s):  
Endothelial Cell ◽  
Cellular Proliferation ◽  
Cell Injury ◽  
Surfactant Protein ◽  
Butylated Hydroxytoluene ◽  
Normal Lung ◽  
Mrna Levels ◽  
Wild Type ◽  
Lung Repair ◽  
Lung Hemorrhage

The Forkhead Box (Fox) family of transcription factors plays important roles in regulating expression of genes involved in cellular proliferation and differentiation. In a previous study, we showed that newborn foxf1(+/−) mice with diminished Foxf1 levels exhibited abnormal formation of pulmonary alveoli and capillaries and died postnatally. Interestingly, surviving newborn foxf1(+/−) mice exhibited increased pulmonary Foxf1 levels and normal adult lung morphology, suggesting that wild-type Foxf1 levels are required for lung development and function. The present study was conducted to determine whether adult foxf1(+/−) mice were able to undergo lung repair similar to that observed in wild-type mice. We demonstrated that adult foxf1(+/−) mice died from severe lung hemorrhage after butylated hydroxytoluene (BHT) lung injury and that this phenotype was associated with a 10-fold decrease in pulmonary Foxf1 expression and increased alveolar endothelial cell apoptosis that disrupted capillary integrity. Furthermore, BHT-induced lung hemorrhage of adult foxf1(+/−) mice was associated with a drastic reduction in expression of the Flk-1, bone morphogenetic protein-4, surfactant protein B, platelet endothelial cell adhesion molecule, and vascular endothelial cadherin genes, whereas the expression of these genes was either transiently diminished or increased in wild-type lungs after BHT injury. Because these proteins are critical for lung morphogenesis and endothelial homeostasis, their decreased mRNA levels are likely contributing to BHT-induced lung hemorrhage in foxf1(+/−) mice. Collectively, our data suggest that sustained expression of Foxf1 is essential for normal lung repair and endothelial cell survival in response to pulmonary cell injury.

Dual functional significance of calcineurin homologous protein 1 binding to Na+/H+ exchanger isoform 1

2011 ◽  
Vol 301 (2) ◽  
pp. C280-C288 ◽  
Author(s):  
Masafumi Matsushita ◽  
Hiroo Tanaka ◽  
Keiji Mitsui ◽  
Hiroshi Kanazawa
Keyword(s):  
Plasma Membrane ◽  
Binding Site ◽  
Functional Significance ◽  
Gene Knockout ◽  
Membrane Localization ◽  
Wild Type ◽  
Homologous Protein ◽  
Plasma Membrane Localization ◽  
Dual Functional ◽  
Associated Proteins

Calcineurin homologous protein 1 (CHP1) binds to the hydrophilic tail of the Na+/H+ exchanger isoform 1 (NHE1). Previous gene knockout of CHP1 revealed that the loss of CHP1 caused a decrease in the total amount of NHE1, suggesting the destabilization of NHE1 molecules without CHP1 (Matsushita et al., Am J Physiol Cell Physiol 293: C246–C254, 2007). However, Pang et al. ( J Biol Chem 276: 17367–17372, 2001) reported that NHE1 without a CHP1 binding site was found in the plasma membrane, suggesting no requirement of CHP1 binding for plasma membrane localization of NHE1. Here, the functional significance of CHP1 binding to NHE1 was examined to resolve these contradictory results. In CV1 cells, which overexpressed wild-type NHE1, overexpression of CHP1 caused an increase in both the total amount of NHE1 and the colocalization of NHE1 and CHP1 at the plasma membrane. This provided new visual evidence of the localization of NHE1 from endoplasmic reticulum to the plasma membrane upon CHP1 binding. An immunoprecipitation assay showed that the expression of CHP1 reduced the ubiquitination of NHE1 and/or its associated proteins. Mutant NHE1s without CHP1 binding site exhibited a modest localization to the plasma membrane. After reaching the plasma membrane, these mutant NHE1s exhibited shorter half-lives than the wild-type NHE1 with CHP1. The results suggest a dual functional significance of CHP1 and its binding region: 1) binding of CHP1 stabilizes NHE1 and increases its plasma membrane localization by masking a NHE1 disposal signal, and 2) CHP1 binding is required for the antiporter activity.

scholarly journals Plasma Kallikrein as a Modulator of Liver Injury/Remodeling

2021 ◽  
Vol 12 ◽  
Author(s):  
Ibrahim A Ahmed ◽  
Miran A Jaffa ◽  
Mayssam Moussa ◽  
Duaa Hatem ◽  
Ghewa A El-Achkar ◽  
...  
Keyword(s):  
Gene Expression ◽  
Cell Death ◽  
Liver Injury ◽  
Cell Injury ◽  
Tissue Injury ◽  
Interleukin 1 ◽  
Temporal Variations ◽  
Plasma Kallikrein ◽  
Mrna Levels ◽  
Kinin System

The occurrence and persistence of hepatic injury which arises from cell death and inflammation result in liver disease. The processes that lead to liver injury progression and resolution are still not fully delineated. The plasma kallikrein-kinin system (PKKS) has been shown to play diverse functions in coagulation, tissue injury, and inflammation, but its role in liver injury has not been defined yet. In this study, we have characterized the role of the PKKS at various stages of liver injury in mice, as well as the direct effects of plasma kallikrein on human hepatocellular carcinoma cell line (HepG2). Histological, immunohistochemical, and gene expression analyses were utilized to assess cell injury on inflammatory and fibrotic factors. Acute liver injury triggered by carbon tetrachloride (CCl4) injection resulted in significant upregulation of the plasma kallikrein gene (Klkb1) and was highly associated with the high mobility group box 1 gene, the marker of cell death (r = 0.75, p < 0.0005, n = 7). In addition, increased protein expression of plasma kallikrein was observed as clusters around necrotic areas. Plasma kallikrein treatment significantly increased the proliferation of CCl4-induced HepG2 cells and induced a significant increase in the gene expression of the thrombin receptor (protease activated receptor-1), interleukin 1 beta, and lectin–galactose binding soluble 3 (galectin-3) (p < 0.05, n = 4). Temporal variations in the stages of liver fibrosis were associated with an increase in the mRNA levels of bradykinin receptors: beta 1 and 2 genes (p < 0.05; n = 3–10). In conclusion, these findings indicate that plasma kallikrein may play diverse roles in liver injury, inflammation, and fibrosis, and suggest that plasma kallikrein may be a target for intervention in the states of liver injury.

scholarly journals Surfactant protein A reduces TLR4 and inflammatory cytokine mRNA levels in neonatal mouse ileum

2021 ◽  
Vol 11 (1) ◽  
Author(s):  
Lidan Liu ◽  
Chaim Z. Aron ◽  
Cullen M. Grable ◽  
Adrian Robles ◽  
Xiangli Liu ◽  
...  
Keyword(s):  
Proinflammatory Cytokine ◽  
Inflammatory Cytokine ◽  
Protein A ◽  
Surfactant Protein ◽  
Surfactant Protein A ◽  
Mrna Levels ◽  
Wild Type ◽  
Cytokine Mrna ◽  
Protein Levels ◽  
Cytokine Levels

AbstractLevels of intestinal toll-like receptor 4 (TLR4) impact inflammation in the neonatal gastrointestinal tract. While surfactant protein A (SP-A) is known to regulate TLR4 in the lung, it also reduces intestinal damage, TLR4 and inflammation in an experimental model of necrotizing enterocolitis (NEC) in neonatal rats. We hypothesized that SP-A-deficient (SP-A−/−) mice have increased ileal TLR4 and inflammatory cytokine levels compared to wild type mice, impacting intestinal physiology. We found that ileal TLR4 and proinflammatory cytokine levels were significantly higher in infant SP-A−/− mice compared to wild type mice. Gavage of neonatal SP-A−/− mice with purified SP-A reduced ileal TLR4 protein levels. SP-A reduced expression of TLR4 and proinflammatory cytokines in normal human intestinal epithelial cells (FHs74int), suggesting a direct effect. However, incubation of gastrointestinal cell lines with proteasome inhibitors did not abrogate the effect of SP-A on TLR4 protein levels, suggesting that proteasomal degradation is not involved. In a mouse model of experimental NEC, SP-A−/− mice were more susceptible to intestinal stress resembling NEC, while gavage with SP-A significantly decreased ileal damage, TLR4 and proinflammatory cytokine mRNA levels. Our data suggests that SP-A has an extrapulmonary role in the intestinal health of neonatal mice by modulating TLR4 and proinflammatory cytokines mRNA expression in intestinal epithelium.

scholarly journals Lemon Balm and Dandelion Leaf Extracts Synergistically Protect against Carbon Tetrachloride-Induced Acute Liver Injury in Mice

2021 ◽  
Vol 11 (1) ◽  
pp. 390
Author(s):  
Beom-Rak Choi ◽  
Il-Je Cho ◽  
Su-Jin Jung ◽  
Jae-Kwang Kim ◽  
Dae-Geon Lee ◽  
...  
Keyword(s):  
Carbon Tetrachloride ◽  
Liver Injury ◽  
Acute Liver Injury ◽  
Antioxidant Activities ◽  
Body Weight Gain ◽  
Histopathological Analysis ◽  
Related Factor ◽  
Mrna Levels ◽  
Protective Effects ◽  
Lemon Balm

Lemon balm and dandelion are commonly used medicinal herbs exhibiting numerous pharmacological activities that are beneficial for human health. In this study, we explored the protective effects of a 2:1 (w/w) mixture of lemon balm and dandelion extracts (MLD) on carbon tetrachloride (CCl4)-induced acute liver injury in mice. CCl4 (0.5 mL/kg; i.p.) injection inhibited body weight gain and increased relative liver weight. Pre-administration of MLD (50–200 mg/kg) for 7 days prevented these CCl4-mediated changes. In addition, histopathological analysis revealed that MLD synergistically alleviated CCl4-mediated hepatocyte degeneration and infiltration of inflammatory cells. MLD decreased serum aspartate aminotransferase and alanine transferase activities and reduced the number of liver cells that stained positive for cleaved caspase-3 and cleaved poly(ADP-ribose) polymerase, suggesting that MLD protects against CCl4-induced hepatic damage via the inhibition of apoptosis. Moreover, MLD attenuated CCl4-mediated lipid peroxidation and protein nitrosylation by restoring impaired hepatic nuclear factor erythroid 2-related factor 2 mRNA levels and its dependent antioxidant activities. Furthermore, MLD synergistically decreased mRNA and protein levels of tumor necrosis factor-α, interleukin-1β, and interleukin-6 in the liver. Together, these results suggest that MLD has potential for preventing acute liver injury by inhibiting apoptosis, oxidative stress, and inflammation.

scholarly journals TRPM2 Non-Selective Cation Channels in Liver Injury Mediated by Reactive Oxygen Species

Antioxidants ◽  
2021 ◽  
Vol 10 (8) ◽  
pp. 1243
Author(s):  
Eunus S. Ali ◽  
Grigori Y. Rychkov ◽  
Greg J. Barritt
Keyword(s):  
Reactive Oxygen Species ◽  
Liver Injury ◽  
Cell Injury ◽  
Ischemia Reperfusion ◽  
Reactive Oxygen ◽  
Cell Types ◽  
Chronic Liver ◽  
Oxygen Species ◽  
Alcoholic Fatty Liver ◽  
Trpm2 Channels

TRPM2 channels admit Ca2+ and Na+ across the plasma membrane and release Ca2+ and Zn2+ from lysosomes. Channel activation is initiated by reactive oxygen species (ROS), leading to a subsequent increase in ADP-ribose and the binding of ADP-ribose to an allosteric site in the cytosolic NUDT9 homology domain. In many animal cell types, Ca2+ entry via TRPM2 channels mediates ROS-initiated cell injury and death. The aim of this review is to summarise the current knowledge of the roles of TRPM2 and Ca2+ in the initiation and progression of chronic liver diseases and acute liver injury. Studies to date provide evidence that TRPM2-mediated Ca2+ entry contributes to drug-induced liver toxicity, ischemia–reperfusion injury, and the progression of non-alcoholic fatty liver disease to cirrhosis, fibrosis, and hepatocellular carcinoma. Of particular current interest are the steps involved in the activation of TRPM2 in hepatocytes following an increase in ROS, the downstream pathways activated by the resultant increase in intracellular Ca2+, and the chronology of these events. An apparent contradiction exists between these roles of TRPM2 and the role identified for ROS-activated TRPM2 in heart muscle and in some other cell types in promoting Ca2+-activated mitochondrial ATP synthesis and cell survival. Inhibition of TRPM2 by curcumin and other “natural” compounds offers an attractive strategy for inhibiting ROS-induced liver cell injury. In conclusion, while it has been established that ROS-initiated activation of TRPM2 contributes to both acute and chronic liver injury, considerable further research is needed to elucidate the mechanisms involved, and the conditions under which pharmacological inhibition of TRPM2 can be an effective clinical strategy to reduce ROS-initiated liver injury.

scholarly journals Eicosapentaenoic Acid Increases Browning Markers in Subcutaneous Adipose Tissue and Primary Adipocytes from Wild Type and UCP-1 Deficient Mice (P15-007-19)

2019 ◽  
Vol 3 (Supplement_1) ◽  
Author(s):  
Shasika Jayarathne ◽  
Mandana Pahlavani ◽  
Latha Ramalingam ◽  
Shane Scoggin ◽  
Naima Moustaid-Moussa
Keyword(s):  
Adipose Tissue ◽  
Eicosapentaenoic Acid ◽  
Subcutaneous Adipose Tissue ◽  
Uncoupling Protein ◽  
Fibroblast Growth Factor 21 ◽  
Chow Diet ◽  
Mrna Levels ◽  
Wild Type ◽  
Brown Adipose ◽  
Subcutaneous Adipose

Abstract Objectives Brown adipose tissue (BAT) regulates energy balance through thermogenesis, in part via uncoupling protein -1 (UCP-1). White adipose tissue (WAT), namely subcutaneous adipose tissue (SAT) can convert to a beige/brite adipose tissue phenotype (browning) under thermogenic conditions such as cold. We previously reported that eicosapentaenoic acid (EPA) reduced obesity and glucose intolerance, and increased UCP-1 in BAT of B6 mice at ambient temperature (22°C); and these effects were attenuated at thermoneutral environment (28–30°C). We hypothesized that EPA exerts anti-obesity effects on SAT, including increased browning, adipocyte hypotrophy; and these effects require UCP-1. Methods Six-week-old B6 wild type (WT) and UCP-1 knock-out (KO) male mice were maintained at thermoneutral environment and fed high fat diet (HF) with or without 36 g/kg of AlaskOmega EPA-enriched fish oil (800 mg/g) for 14 weeks; and SAT was collected for histological, gene and protein analyses. SAT was also prepared from chow diet-fed WT and KO mice at ambient environment to prepare stroma vascular cells, which were differentiated into adipocytes, treated with 100uM EPA for 48 hours then harvested for mRNA and protein analyses. Results KO mice fed HF diets had the highest body weight (P < 0.05) among all groups. EPA reduced fat cell size in both WT and KO mice fed the EPA diet. mRNA levels of fibroblast growth factor-21 (FGF-21) were higher in SAT of WT mice fed EPA compared to WT mice fed HF (P < 0.05), with no differences between the KO genotype. KO mice fed HF diets had lower levels of UCP-3 in SAT compared to WT mice fed HF (P < 0.05), which was rescued only in the KO mice fed EPA (P < 0.05). UCP-1 protein levels were very low in SAT tissues, and UCP-2 mRNA levels were similar across all groups in SAT. Interestingly, EPA significantly (P < 0.05) increased mRNA expression of UCP-2, UCP-3 and FGF21 in differentiated SAT adipocytes from both WT and KO compared to control. Furthermore, UCP-1 mRNA levels were significantly higher in WT adipocytes treated with EPA, compared to non-treated cells (P < 0.05). Additional mechanistic studies are currently underway to further dissect adipose depot differences in EPA effects in WT vs. KO mice. Conclusions Our data suggest that EPA increases SAT browning, independently of UCP-1. Funding Sources NIH/NCCIH.

scholarly journals Estrogen Up-Regulates Hepatic Expression of Suppressors of Cytokine Signaling-2 and -3 in Vivo and in Vitro

Endocrinology ◽  
2004 ◽  
Vol 145 (12) ◽  
pp. 5525-5531 ◽  
Author(s):  
Gary M. Leong ◽  
Sofia Moverare ◽  
Jesena Brce ◽  
Nathan Doyle ◽  
Klara Sjögren ◽  
...  
Keyword(s):  
Promoter Activity ◽  
Hepatoma Cells ◽  
Cytokine Signaling ◽  
Mrna Levels ◽  
Dependent Manner ◽  
Wild Type ◽  
Hepatic Expression ◽  
Suppressors Of Cytokine Signaling

Abstract Suppressors of cytokine signaling (SOCS) are important negative regulators of cytokine action. We recently reported that estrogen stimulates SOCS-2 expression and inhibits GH signaling in kidney cells. The effects of estrogen on SOCS expression in other tissues are unclear. The aim of this study was to investigate in vivo and in vitro whether estrogen affected SOCS expression in the liver, a major target organ of GH. The in vivo hepatic effects of estrogen on ovariectomized mice lacking estrogen receptor (ER)-α, ERβ, or both and their wild-type littermates were examined by DNA microarray analysis. In vitro, the effects of estrogen on SOCS expression in human hepatoma cells were examined by reverse transcription quantitative PCR. Long-term (3 wk) estrogen treatment induced a 2- to 3-fold increase in hepatic expression of SOCS-2 and -3 in wild-type and ERβ knockout mice but not in those lacking ERα or both ER subtypes. Short-term treatment (at 24 h) increased the mRNA level of SOCS-3 but not SOCS-2. In cultured hepatoma cells, estrogen increased SOCS-2 and -3 mRNA levels by 2-fold in a time- and dose-dependent manner (P &lt; 0.05). Estrogen induced murine SOCS-3 promoter activity by 2-fold (P &lt; 0.05) in constructs containing a region between nucleotides −1862 and −855. Moreover, estrogen and GH had additive effects on the SOCS-3 promoter activity. In summary, estrogen, via ERα, up-regulated hepatic expression of SOCS-2 and -3, probably through transcriptional activation. This indicates a novel mechanism of estrogen regulation of cytokine action.

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