Harlequin granulocyte-colony stimulating factor interleukin 6 molecules with bifunctional and antagonistic activities.

BACKGROUND: The granulocyte-colony stimulating factor (G-CSF) and the interleukin 6 (IL-6) are part of a large family of cytokines that regulate the production and the functional activity of hemopoietic cells. Recent studies have shown that IL-6 and G-CSF share structure homology and have partially overlapping functions. OBJECTIVES: Our research gives some information for planning the production of new artificial cytokines in order to establish whether we could obtain molecules that had two functions or an inhibitory function. STUDY DESIGN: Fourteen different chimeric molecules (called Harlequin molecules) of human IL-6 and G-CSF have been produced exchanging the sequence encoded by the 2nd to the 5th exon of the genes of the two cytokines. RESULTS: In order to test their biological activity we performed different assays: proliferation of murine B9-cells and immunoglobulin production from human Epstein-Barr virus (EBV)-transformed B-cell lines for IL-6; induction of granulocytic differentiation of the murine 32DC13(G) cell line and normal bone marrow progenitor cells for G-CSF. Some chimeric molecules maintain the activity of either IL-6 and G-CSF and at least one (Harlequin 11) has both biological activities. One chimeric protein has no biological activity but competes, presumably at the receptor level, for the activity of the intact cytokine. CONCLUSION: These studies can provide important information on the structure/function of the two cytokines. The bifunctional Harlequin molecule 11 could be a potential candidate as therapeutic agent.