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Interleukin-6 receptor-interleukin-6 fusion proteins with enhanced interleukin-6 type pleiotropic activities |
European Cytokine Network. Volume 8, Number 4, 359-65, December 1997, Review
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 Summary
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Author(s) : Judith Chebath, Dina Fischer, Anil Kumar, Jae-Wook Oh, Orit Kolett, Tsvee Lapidot, Martina Fischer, Stefan Rose-John, Arnon Nagler, Shimon Slavin, Michel Revel, Department of Molecular Genetics, Weizmann Institute of Science, Rehovot 76100, Israel, InterPharm Laboratories, Weizmann Industrial Park, Ness Ziona 76110, Israel, Department of Immunology, Weizmann Institute of Science, Rehovot 76100, Israel, Department of Medicine-Section-Pathophysiology, Mainz University D-55101, Germany, Bone Marrow Transplantation Center, Hadassa Medical Center, Jerusalem 91120, Israel. |
Summary : An sIL-6R/IL-6 chimera, directly fusing the natural forms of soluble IL-6 receptor and IL-6, as found in human body fluids, was produced in transfected human cells. The secreted p85 glycoprotein was active at a concentration of 120 pM to produce growth-arrest and spindleoid differentiation of murine melanoma F 10.9 cells, which do not respond to IL-6 alone. This fusion protein was as active as the yeast-produced p56 fusion protein containing a shortened sIL-6R, linked through a flexible peptide chain to IL-6 (Hyper IL-6). The concentration of Hyper IL-6 needed to arrest the growth of F10.9 cells was much lower than that needed of a combination of IL-6 and sIL-6R, added separately. Hyper IL-6 was also more active than IL-6 in stimulating growth of murine plasmacytoma T1165 cells, the half maximal stimulation being obtained at 2 pM Hyper IL-6 versus 23 pM for IL-6. In order to evaluate the effect of the fused sIL-6R/IL-6 proteins on human hematopoietic primitive progenitor cells, they were added to suspension cultures of CD34+ cells from human cord blood in addition to both flt3/flk2 ligand (FL) and stem cell factor (SCF). Fused sIL-6R/IL-6 produced a marked stimulation of cell expansion and a marked increase in the number of colony forming units when subsequently plated in semi-solid medium with IL-3, GM-CSF, SCF and erythropoietin. Ex-vivo maintenance and expansion of early progenitor cells in bone marrow transplantation protocols may be a potential application for the sIL-6R/IL-6 chimeric glycoproteins. |
Keywords : growth inhibition, melanoma, hematopoiesis, interleukin-6. |
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