REGULATION OF INTERLEUKIN 6 EXPRESSION BY CARDIOTROPHIN 1

doi:10.1006/cyto.1997.0220

Cytokine

Volume 9, Issue 9, September 1997, Pages 666-671

https://doi.org/10.1006/cyto.1997.0220 Get rights and content

Abstract

Cardiotrophin 1 (CT-1) is a recently described cytokine sharing many biological properties with those reported previously for leukaemia inhibitory factor (LIF). In the present study was show that CT-1 binds to the KB epidermoid cancer cell surface through a tripartite receptor complex which includes the gp130 signal transducing protein, LIF receptor β (LIFRβ) and a third component displaying a molecular weight of 80 kDa. CT-1 activated gp130 and LIFRβ transducing components, as attested by analysing their tyrosine phosphorylation level. The activation process is relayed to the nucleus by the recruitment of the STAT3 transcription factor. Analysis of KB cell line culture supernatants after CT-1 treatment indicates that CT-1 stimulates the production of interleukin 6 (IL-6) in a time- and dose-dependent manner. This stimulation of IL-6 production by CT-1 is associated with an increase in intracellular levels of IL-6 mRNA. This study suggests that at least in some pathological situations CT-1 might represent an immunomodulator regulating cytokine-induced gene products.

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Cited by (13)

Cardiotrophin-1 reduces ischemia/reperfusion injury during liver transplant
2013, Journal of Surgical Research
Citation Excerpt :
Interestingly, whereas CT reduced IL-1β and TNF-α expression, it enhanced IL-6 production. The induction of IL-6 expression by CT has already been reported [29,30]. IL-6 participates in the orchestration of inflammation, but it is endowed with potent cytoprotective properties.
Orthotopic liver transplantation (OLT) is currently the elective treatment for advanced liver cirrhosis and acute liver failure. Ischemia/reperfusion damage may jeopardize graft function during the postoperative period. Cardiotrophin-1 (CT-1) has demonstrated cytoprotective properties in different experimental models of liver injury. There is no evidence to demonstrate its potential use in the prevention of the ischemia/reperfusion injury that occurs during OLT. The present study is the first report to show that the administration of CT-1 to donors would benefit the outcome of OLT.
We tested the cytoprotective effect of CT-1 administered to the donor prior to OLT in an experimental pig model. Hemodynamic changes, hepatic histology, cell death parameters, activation of cell signaling pathways, oxidative and nitrosative stress, and animal survival were analyzed.
Our data showed that CT-1 administration to donors increased animal survival, improved cardiac and respiratory functions, and reduced hepatocellular injury as well as oxidative and nitrosative stress. These beneficial effects, related to the activation of AKT, ERK, and STAT3, reduced caspase-3 activity and diminished IL-1β and TNF-α expression together with IL-6 upregulation in liver tissue.
The administration of CT-1 to donors reduced ischemia/reperfusion injury and improved survival in an experimental pig model of OLT.
Cardiotrophin-1 in cardiovascular regulation
2010, Advances in Clinical Chemistry
Citation Excerpt :
Other investigators also reported that CT-1 induces ICAM-1 and MCP-1 synthesis by NFκB in human umbilical vein endothelial cells [71,72]. CT-1 stimulates the production of IL-6 in a time- and dose-dependent manner in KB epidermoid cancer cells [73], human umbilical vein endothelial cells [74], and monocytes [75]. Intravenous injection of CT-1 in conscious rats augmented expression of iNOS in the lung and aorta, but not in the heart or liver [34].
Cardiotrophin (CT)-1 was discovered by coupling expression cloning with an embryonic stem cell-based model of cardiogenesis. Comparison of similarity in amino acid sequence and conformational structure indicates that CT-1 is a member of the interleukin (IL)-6 type cytokine family that shares the transmembrane signaling protein, glycoprotein (gp) 130 as a receptor. These cytokines mediate overlapping pleiotropic actions on a variety of cell types including cardiac myocytes, hepatocytes, megakaryocytes, osteoclasts, and neuronal cells. CT-1mediates its hypertrophic and cytoprotective properties through the Janus kinase/signal transducers and activators of transcription (JAK/STAT), mitogen-activated protein (MAP) kinase, phosphatidylinositol (PI) 3 kinase, and nuclear factor kappa B (NFκB) pathways. CT-1 gene and protein are distributed not only in the heart, but also in the pulmonary, renal, gastrointestinal, cerebral, and muscular tissues. CT-1 could also be synthesized and secreted from vascular endothelial cells and adipocytes. CT-1 has hypertrophic actions on the cardiac myocytes, skeletal muscle cells, and smooth muscle cells as well as cytoprotective actions on the cardiac myocytes, neuronal cells, and hepatocytes. CT-1 is circulating in the body, and its plasma concentration is increased in various cardiovascular and renal diseases such as hypertension, congestive heart failure, myocardial infarction, valvular heart disease, metabolic syndrome, and chronic kidney disease. Treatment with CT-1 is beneficial in experimental animal models of cardiovascular diseases. CT-1 specifically protects the cardiac myocytes from ischemic damage when CT-1 is given not only prior to the ischemia, but also given at the time of reoxygenation. Current evidence suggests that CT-1 plays an important role in the regulation of the cardiovascular system.
Cardiotrophin-1 induces interleukin-6 synthesis in human monocytes
2007, Cytokine
Background. Patients with congestive heart failure (CHF) show increased serum concentrations of cytokines like interleukin-6 (IL-6) and cardiotrophin-1 (CT-1). Additionally, monocyte function is modulated in CHF. The aim of this study was to examine if CT-1 is able to induce IL-6 in human monocytes and to investigate the underlying pathway. Methods. Separated peripheral blood monocytes of healthy volunteers were cultured with increasing concentrations of CT-1 for different periods. IL-6 mRNA was determined by RT-PCR or real-time PCR and IL-6 protein concentration in the supernatant by ELISA. Phosphorylation of signal transducer and activation of transcription (STAT) 3 was analyzed by western blot or by FACS analysis. To clarify the signalling pathway of CT-1 induced IL-6 expression various inhibitors of possible signal transducing molecules were used. Results. CT-1 induced IL-6 mRNA in monocytes in a time- and concentration-dependent manner. Maximal mRNA induction was detectable after 6 h with 100 ng/ml CT-1. IL-6 protein also increased in a time- and concentration-dependent manner with a maximum after 48 h with 100 ng/ml CT-1. AG490 as well as SB 203580 and parthenolide blocked CT-1 induced IL-6 expression completely. AG 490 was able to inhibit STAT3 phosphorylation in western blot analysis completely. This indicates that JAK2/STAT3, p38 and nuclear factor κB (NFκB) are involved in this pathway. To exclude a possible influence of plastic adherence of monocytes on CT-1 induced IL-6 expression, we determined intracellular STAT3 phosphorylation in whole blood samples by FACS analysis and observed independently of culture conditions a CT-1 concentration-dependent STAT3 phosphorylation. Conclusion. CT-1 induces IL-6 mRNA and protein expression in a time- and concentration-dependent manner. The underlying pathway is Janus kinase (JAK)2/STAT3, p38 and NFκB dependent. These data may explain increased IL-6 serum concentrations and altered monocyte function found in patients with CHF. Modulation of the CT-1 pathway might be a interesting strategy in the treatment of CHF.
Cardiotrophin-1 induces interleukin-6 synthesis in human umbilical vein endothelial cells
2006, Cytokine
In patients with chronic heart failure (CHF) increased plasma concentrations of proinflammatory cytokines are found. For example, the plasma interleukin-6 (IL-6) concentration correlates with disease severity. Beside IL-6 cardiotrophin-1 (CT-1), a member of the IL-6 superfamily, is also increased in CHF. We examined whether CT-1 is able to induce IL-6 in human umbilical vein endothelial cells (HUVEC) and characterised the underlying pathway. IL-6 mRNA was determined by real-time PCR and by RT-PCR in HUVEC which were stimulated with different CT-1 concentrations and for different time periods. IL-6 concentration in the supernatant was determined by ELISA. For the pathway determination following inhibitors were used: piceatannol (signal transducer and activation of transcription (STAT)3 phosphorylation), wortmannin (phosphatiylinositol 3-kinase (PI3K)), SB203580 (p38 mitogen-activated protein kinase (MAPK)), AG490 (Janus kinase (JAK)2), PD98059 (mitogen-activated protein kinase kinase (MEK) 1/2), parthenolide (nuclear factor κB) and cycloheximide (protein biosynthesis). CT-1 caused a concentration- and time-dependent increase in IL-6 mRNA in HUVEC with a maximal induction seen after 6 h (2-fold compared to control) with 100 ng/ml CT-1. In the supernatant of HUVEC a concentration- and time-dependent increase of IL-6 protein was found. A maximum effect with 100 ng/ml CT-1 was found after 24 h (11-fold compared to control). AG490, SB203580, piceatannol, parthenolide and cycloheximide inhibit CT-1 induced IL-6 mRNA and protein expression whereas wortmannin and PD98059 did not inhibit IL-6 expression. CT-1 induced both IL-6 mRNA and protein in a concentration- and time-dependent manner in HUVEC. The underlying pathway includes activation of JAK2, STAT3, p38 and NFκB. CT-1 induced IL-6 expression and requires protein synthesis and IL-6 is not stored intracellularly. We speculate that in CHF CT-1 might be in part responsible for increased IL-6 plasma concentrations. Modulation of the CT-1 pathway may be a further strategy in CHF treatment.
Neuronal targeting of cardiotrophin-1 by coupling with tetanus toxin C fragment
2001, Molecular and Cellular Neuroscience
Cardiotrophin-1 (CT-1) is a potent neurotrophic factor for motoneurons but its clinical use in motor neuron diseases is precluded by side effects on the heart and liver. We explored the possibility of targeting CT-1 to neurons by coupling with the tetanus toxin fragment TTC. Genetic fusion proteins between CT-1 or GFP and TTC were produced in Escherichia coli and assayed in vitro. In contrast to uncoupled CT-1 or GFP, TTC-coupled proteins bound with high affinity to cerebral neurons and spinal cord motoneurons and were rapidly internalized. Glia, hepatocytes, or cardiomyocytes did not show detectable binding or uptake of TTC-coupled proteins. Similar to CT-1, TTC-coupled CT-1 induced IL-6 secretion by KB cells, activated Reg-2 gene expression, and promoted motoneuron survival in a dose-dependent manner. In vivo studies will test whether TTC-coupled CT-1 might be targeted to degenerating spinal cord or brain-stem motoneurons and migrate trans-synaptically to cortical motoneurons, which are also affected in amyotrophic lateral sclerosis.
Transcriptomic Analysis of Breast Cancer Patients Sensitive and Resistant to Chemotherapy: Looking for Overall Survival and Drug Resistance Biomarkers
2022, Technology in Cancer Research and Treatment

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^f1: Correspondence to: Hugues Gascan, Laboratoire de Biologie Cellulaire, 4 rue Larrey, CHU Angers, 49033 Angers Cedex, France

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Regular articleREGULATION OF INTERLEUKIN 6 EXPRESSION BY CARDIOTROPHIN 1

Abstract

Regular article
REGULATION OF INTERLEUKIN 6 EXPRESSION BY CARDIOTROPHIN 1