Abstract
Cardiotrophin-1 (CT-1) is a newly isolated cytokine that was identified based on its ability to induce cardiac myocyte hypertrophy. It is a member of the family of cytokines that includes interleukins-6 and -11, leukemia inhibitory factor (LIF), ciliary neurotrophic factor, and oncostatin M. These cytokines induce a pleiotropic set of growth and differentiation activities via receptors that use a common signaling subunit, gp130. In this work we determine the activity of CT-1 in six in vitro biological assays and examine the composition of its cell surface receptor. We find that CT-1 is inactive in stimulating the growth of the hybridoma cell line, B9 and inhibits the growth of the mouse myeloid leukemia cell line, M1. CT-1 induces a phenotypic switch in rat sympathetic neurons and promotes the survival of rat dopaminergic and chick ciliary neurons. CT-1 also inhibits the differentiation of mouse embryonic stem cells. CT-1 and LIF cross-compete for binding to M1 cells, Kd [CT-1] approximately 0.7 nM, and this binding is inhibited by an anti-gp130 monoclonal antibody. Both ligands can be specifically cross-linked to a protein on M1 cells with the mobility of the LIF receptor (approximately 200 kDa). In addition, CT-1 binds directly to a purified, soluble form of the LIF receptor in solution (Kd approximately 2 nM). These data show that CT-1 has a wide range of hematopoietic, neuronal, and developmental activities and that it can act via the LIF receptor and the gp130 signaling subunit.
Highlights
Cardiotrophin-l (CT-l) is a newly isolated cytokine that was identified based on its ability to induce cardiac myocyte hypertrophy
CT-I binds directly to a purified, soluble form of the leukemia inhibitory factor (LIF) receptor in solution (Kd - 2 1lM). These data show that CT-I has a wide range of hematopoietic, neuronal, and developmental activities and that it can act via the LIF receptor and the gpl30 signaling subunit
In the course of identifying factors that mediate the various phases of cardiac hypertrophy, we recently isolated by expression cloning a novel cytokine, cardiotrophin (CT-l)!, that induces cardiac myocyte hypertrophy in vitro [7]
Summary
Vol 270, No 18, Issue of May 5, pp. 10915-10922, 1995 Printed in U.S.A. BIOLOGICAL ACTIVITIES AND BINDING TO THE LEUKEMIA INHIBITORY FACTOR RECEPTORlgp130 SIGNALING COMPLEX*. Cardiotrophin-l (CT-l) is a newly isolated cytokine that was identified based on its ability to induce cardiac myocyte hypertrophy It is a member of the family of cytokines that includes interleukins-6 and -11, leukemia inhibitory factor (LIF), ciliary neurotrophic factor, and oncostatin M. These cytokines induce a pleiotropic set of growth and differentiation activities via receptors that use a common signaling subunit, gp130. CT·I and LIF cross-compete for binding to MI cells, K d [CT-I] - 0.71lM, and this binding is inhibited by an anti-gpl monoclonal antibody Both ligands can be crosslinked to a protein on MI cells with the mobility of the LIF receptor (-200 kDa). We show that CT-l can bind to and induce biological responses via the LIF receptor and its signaling subunit, gp130
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