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Soluble Mannose 6-Phosphate/Insulin-Like Growth Factor II (IGF-II) Receptor Inhibits Interleukin-6-Type Cytokine-Dependent Proliferation by Neutralization of IGF-II

Groupe de Recherche Cytokines/Récepteurs/Transduction, Institut National de la Santé et de la Recherche Médicale, Unité 463, and Institut Féderatif de Recherche 26, Institut de Biologie, 44093 Nantes, France

Address all correspondence and requests for reprints to: Dr. Frédéric Blanchard, Institut National de la Santé et de la Recherche Médicale, Unité 463, Institut de Biologie, 9 Quai Moncousu, 44093 Nantes Cedex 01, France. E-mail: fblan{at}nantes.inserm.fr.

The calcium-independent mannose 6-phosphate receptor (CIMPR) is a receptor for multiple ligands, including leukemia inhibitory factor (LIF), an IL-6 type cytokine, and IGF-II. CIMPR targets newly synthesized ligands to lysosomes and induces internalization/degradation of secreted ligands. A natural soluble form of CIMPR (sCIMPR) neutralizes IGF-II mitogenic potency on hepatocytes and fibroblasts. Herein we show that sCIMPR also inhibits LIF-driven proliferation of myeloid and lymphoid cell lines. Similar inhibition was observed with IL-6 and IL-11, two other IL-6-type cytokines that do not interact with CIMPR. Neutralizing anti-IGF-II antibodies inhibited IL-6-, IL-11-, and LIF-driven cell proliferation to the same extent as sCIMPR, suggesting that neutralization of serum IGF-II by sCIMPR plays a major role in IL-6-type cytokine-dependent cell proliferation. Confirming this idea, ERK1/2 and AKT/protein kinase B, the kinases necessary for cell proliferation and survival, were activated by IGF-II alone or by the association of IL-6-type cytokines and IGF-II. IL-6-type cytokines alone (up to 10 ng/ml) did not activate ERK1/2 or AKT, but did activate STAT3 (signal transducer and activator of transcription 3), a transcription factor necessary for the G₁ to S phase cell cycle transition. Activation of ERK1/2 and AKT by IGF-II thus appears essential to sustain cellular expansion driven by IL-6-type cytokines.