| HOME | HELP | FEEDBACK | SUBSCRIPTIONS | ARCHIVE | SEARCH | TABLE OF CONTENTS |
|
|
|
|||||||
|
|||||||||
J Biol Chem, Vol. 274, Issue 3, 1257-1266, January 15, 1999
,, and
From the Department of Gastroenterology and Hepatology,
Medizinische Hochschule, Hannover, Federal Republic of Germany and
Interleukin-6 (IL-6) triggers pivotal pathways
in vivo. The designer protein hyper-IL-6 (H-IL-6) fuses the
soluble IL-6 receptor (sIL-6R) through an intermediate linker with
IL-6. The intracellular pathways that are triggered by H-IL-6 are not
defined yet. Therefore, we studied the molecular mechanisms leading to
H-IL-6-dependent gene activation. H-IL-6 stimulates
haptoglobin mRNA expression in HepG2 cells, which is
transcriptionally mediated as assessed by run-off experiments. The
increase in haptoglobin gene transcription correlates with higher
nuclear translocation of tyrosine-phosphorylated STAT3 and its DNA
binding. As H-IL-6 stimulates STAT3-dependent gene
transcription, we compared the molecular mechanism between IL-6 and
H-IL-6. Transfection experiments were performed with a
STAT3-dependent luciferase construct. The same amount of
H-IL-6 stimulated luciferase activity faster, stronger, and for a
longer period of time. Dose response experiments showed that a 10-fold lower dose of H-IL-6 stimulated STAT3-dependent gene
transcription comparable with the higher amount of IL-6. Cotransfection
with the gp80 and/or gp130 receptor revealed that the effect of H-IL-6 on STAT3-dependent gene transcription is restricted to the
gp80/gp130 receptor ratio. High amounts of gp130 increased and high
amounts of gp80 decreased the effect on H-IL-6-dependent
gene transcription. To investigate the in vivo effect of
H-IL-6 on gene transcription in the liver, H-IL-6 and IL-6 were
injected into C3H mice. H-IL-6 was at least 10-fold more effective in
stimulating the DNA binding and nuclear translocation of STAT3, which
enhances haptoglobin mRNA and protein expression. Thus H-IL-6
stimulates STAT3-dependent gene transcription in liver
cells in vitro and in vivo at least 10-fold
more effectively than IL-6. Our results provide evidence that H-IL-6 is
a promising designer protein for therapeutic intervention during
different pathophysiological conditions also in humans.
I. Medical Clinic, Section of Pathophysiology, University
of Mainz, Federal Republic of Germany
This article has been cited by other articles:
|
|
 |
|
  T. Owaki, M. Asakawa, N. Morishima, I. Mizoguchi, F. Fukai, K. Takeda, J. Mizuguchi, and T. Yoshimoto STAT3 Is Indispensable to IL-27-Mediated Cell Proliferation but Not to IL-27-Induced Th1 Differentiation and Suppression of Proinflammatory Cytokine Production J. Immunol., March 1, 2008; 180(5): 2903 - 2911. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 N. Venteclef, J. C. Smith, B. Goodwin, and P. Delerive Liver receptor homolog 1 is a negative regulator of the hepatic acute-phase response. Mol. Cell. Biol., September 1, 2006; 26(18): 6799 - 6807. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 V. von Felbert, F. Cordoba, J. Weissenberger, C. Vallan, M. Kato, I. Nakashima, L. R. Braathen, and J. Weis Interleukin-6 Gene Ablation in a Transgenic Mouse Model of Malignant Skin Melanoma Am. J. Pathol., March 1, 2005; 166(3): 831 - 841. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 S. L. Mackey and G. J. Darlington CCAAT Enhancer-binding Protein {alpha} Is Required for Interleukin-6 Receptor {alpha} Signaling in Newborn Hepatocytes J. Biol. Chem., April 16, 2004; 279(16): 16206 - 16213. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 S. Smola-Hess, U. Sandaradura de Silva, D. Hadaschik, and H. J. Pfister Soluble interleukin-6 receptor activates the human papillomavirus type 18 long control region in SW756 cervical carcinoma cells in a STAT3-dependent manner J. Gen. Virol., October 1, 2001; 82(10): 2335 - 2339. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
K. Streetz, B. Fregien, J. Plumpe, K. Korber, S. Kubicka, G. Sass, S. C. Bischoff, M. P. Manns, G. Tiegs, and C. Trautwein Dissection of the Intracellular Pathways in Hepatocytes Suggests a Role for Jun Kinase and IFN Regulatory Factor-1 in Con A-Induced Liver Failure J. Immunol., July 1, 2001; 167(1): 514 - 523. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 J. Audet, C. L. Miller, S. Rose-John, J. M. Piret, and C. J. Eaves Distinct role of gp130 activation in promoting self-renewal divisions by mitogenically stimulated murine hematopoietic stem cells PNAS, February 13, 2001; 98(4): 1757 - 1762. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 R. Reljic, S. D. Wagner, L. J. Peakman, and D. T. Fearon Suppression of Signal Transducer and Activator of Transcription 3-dependent B Lymphocyte Terminal Differentiation by BCL-6 J. Exp. Med., December 18, 2000; 192(12): 1841 - 1848. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 E. GALUN, E. ZEIRA, O. PAPPO, M. PETERS, and S. ROSE-JOHN Liver regeneration induced by a designer human IL-6/sIL-6R fusion protein reverses severe hepatocellular injury FASEB J, October 1, 2000; 14(13): 1979 - 1987. [Abstract] [Full Text]
|
|
|
|
|
|
S. Hess, H. Smola, U. Sandaradura de Silva, D. Hadaschik, D. Kube, S. E. Baldus, U. Flucke, and H. Pfister Loss of IL-6 Receptor Expression in Cervical Carcinoma Cells Inhibits Autocrine IL-6 Stimulation: Abrogation of Constitutive Monocyte Chemoattractant Protein-1 Production J. Immunol., August 15, 2000; 165(4): 1939 - 1948. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 K L STREETZ, T LUEDDE, M P MANNS, and C TRAUTWEIN Interleukin 6 and liver regeneration Gut, August 1, 2000; 47(2): 309 - 312. [Full Text] [PDF]
|
|
|
|
|
|
M. Niehof, K. Streetz, T. Rakemann, S. C. Bischoff, M. P. Manns, F. Horn, and C. Trautwein Interleukin-6-induced Tethering of STAT3 to the LAP/C/EBPbeta Promoter Suggests a New Mechanism of Transcriptional Regulation by STAT3 J. Biol. Chem., March 16, 2001; 276(12): 9016 - 9027. [Abstract] [Full Text] [PDF]
|
|
| HOME | HELP | FEEDBACK | SUBSCRIPTIONS | ARCHIVE | SEARCH | TABLE OF CONTENTS |
| All ASBMB Journals | Molecular and Cellular Proteomics |
| Journal of Lipid Research | ASBMB Today |
