CARDIOTROPHIN-1 - BIOLOGICAL-ACTIVITIES AND BINDING TO THE LEUKEMIA INHIBITORY FACTOR-RECEPTOR GP130 SIGNALING COMPLEX

Cardiotrophin-1 (CT-1) is a newly isolated cytokine that was identifie d 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 o ncostatin M, These cytokines induce a pleiotropic set of growth and di fferentiation activities via receptors that use a common signaling sub unit, gp130. In this work we determine the activity of CT-1 in six in vitro biological assays and examine the composition of its cell surfac e 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 myel oid leukemia cell line, M1. CT-1 induces a phenotypic switch in rat sy mpathetic neurons and promotes the survival of rat dopaminergic and ch ick ciliary neurons. CT-1 also inhibits the differentiation of mouse e mbryonic stem cells. CT-1 and LIF cross-compete for binding to M1 cell s, K-d [CT-1] similar to 0.7 nM, and this binding is inhibited by an a nti-gp130 monoclonal antibody, Both ligands can be specifically crossl inked to a protein on M1 cells with the mobility of the LIF receptor ( similar to 200 kDa), In addition, CT-1 binds directly to a purified, s oluble form of the LIF receptor in solution K-d, similar to 211 nM). T hese 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.