In vivo and in vitro activities of the gp130-stimulating designer cytokine Hyper-IL-6.
IL-6 is a multifactorial cytokine mediating acute inflammatory responses in the liver. When IL-6 binds to a specific receptor (IL-6R), the IL-6/IL-6R complex associates with the signal transducer gp130, initiating intracellular signaling. A soluble form of the IL-6R (sIL-6R) renders target cells sensitive to IL-6 that do not express the IL-6R on their surfaces. A designer cytokine, termed Hyper-IL-6, consisting of IL-6 covalently linked to the sIL-6R was fully active on gp130-expressing cells at 100- to 1000-fold lower concentrations than unlinked IL-6 and IL-6R. Mice were injected i.p. with Hyper-IL-6 or IL-6. Upon injection of Hyper-IL-6 into mice, the acute phase response, as measured by haptoglobin mRNA expression in the liver, was markedly increased and lasted significantly longer compared with that in mice injected with a 10-fold higher dose of IL-6 alone. On human hepatoma cells, Hyper-IL-6 caused similar effects, indicating that the longer lasting response to the fusion protein could not only be explained by the longer plasma half-life of the fusion protein. Experiments using iodinated IL-6 and Hyper-IL-6 revealed that Hyper-IL-6 bound with high affinity to gp130 and was less efficiently internalized. This effect might explain the longer lasting activity of this protein on cells. The highly active IL-6/sIL-6R designer protein might be of significant clinical importance for the stimulation of cells that are more responsive to the IL-6/sIL-6R complex than to IL-6 alone. Such cells include hemopoietic progenitor cells and hepatocytes.
Peters
M
M
First Department of Medicine, University of Mainz, Germany.
Blinn
G
G
Solem
F
F
Fischer
M
M
Meyer zum Büschenfelde
K H
KH
Rose-John
S
S
D000210:Acute-Phase Reaction / Q000097:blood / Q000235:genetics; D000818:Animals; D015703:Antigens, CD / Q000378:metabolism*; D002460:Cell Line; D050822:Cytokine Receptor gp130; D015195:Drug Design; D015870:Gene Expression / Q000187:drug effects; D006242:Haptoglobins / Q000235:genetics; D006801:Humans; D007274:Injections, Intraperitoneal; D015850:Interleukin-6 / Q000008:administration & dosage* / Q000032:analysis* / Q000097:blood; D007457:Iodine Radioisotopes / Q000378:metabolism; D008099:Liver / Q000187:drug effects / Q000378:metabolism; D008562:Membrane Glycoproteins / Q000378:metabolism*; D051379:Mice; D011485:Protein Binding; D012333:RNA, Messenger / Q000096:biosynthesis; D018123:Receptors, Interleukin / Q000008:administration & dosage* / Q000032:analysis* / Q000097:blood; D019947:Receptors, Interleukin-6; D011993:Recombinant Fusion Proteins / Q000008:administration & dosage / Q000032:analysis / Q000097:blood; D015398:Signal Transduction / Q000187:drug effects; D013997:Time Factors; D014407:Tumor Cells, Cultured
D015703:Antigens, CD; D006242:Haptoglobins; C494199:IL6ST protein, human; C494200:Il6st protein, mouse; D015850:Interleukin-6; D007457:Iodine Radioisotopes; D008562:Membrane Glycoproteins; D012333:RNA, Messenger; D018123:Receptors, Interleukin; D019947:Receptors, Interleukin-6; D011993:Recombinant Fusion Proteins; C104543:interleukin 6-interleukin 6 receptor fusion protein, recombinant; D050822:Cytokine Receptor gp130