Interleukin-6 and soluble interleukin-6 receptor: direct stimulation of gp130 and hematopoiesis

M Peters, AM Müller… - Blood, The Journal of the …, 1998 - ashpublications.org
M Peters, AM Müller, S Rose-John
Blood, The Journal of the American Society of Hematology, 1998ashpublications.org
THE INTERLEUKIN-6 (IL-6) family of cytokines acts via receptor complexes that contain at
least one subunit of the signal transducing protein gp130. 1 The family comprises IL-6, IL-11,
ciliary neurotrophic factor (CNTF), cardiotrophin-1 (CT-1), leukemia inhibitory factor (LIF),
and oncostatin M (OSM). 1 IL-6, IL-11, and CNTF first bind to specific receptors, and these
complexes associate with a homodimer of gp130 in the case of IL-6 and IL-11 or,
alternatively, with a heterodimer of gp130 and the related protein LIF receptor (LIF-R) in the …
THE INTERLEUKIN-6 (IL-6) family of cytokines acts via receptor complexes that contain at least one subunit of the signal transducing protein gp130. 1 The family comprises IL-6, IL-11, ciliary neurotrophic factor (CNTF), cardiotrophin-1 (CT-1), leukemia inhibitory factor (LIF), and oncostatin M (OSM). 1 IL-6, IL-11, and CNTF first bind to specific receptors, and these complexes associate with a homodimer of gp130 in the case of IL-6 and IL-11 or, alternatively, with a heterodimer of gp130 and the related protein LIF receptor (LIF-R) in the case of CNTF. OSM and LIF first bind directly to gp130 and LIF-R, respectively, and form heterodimers with LIF-R and gp130. Recently, a gp130-related protein was described that can heterodimerize with gp130 and that acts as an alternative OSM receptor. 2 CT-1 binds directly to the LIF-R and induces gp130/LIF-R heterodimer formation. 3 Recently, the presence of a specific glycosylphosphatidylinositol (GPI)-anchored CT-1 receptor on neuronal cells was implicated. 4 Cytokines of the IL-6 family are involved in various steps of hematopoiesis and have been used for the ex vivo expansion of hematopoietic cells. 5-7 Whereas recent reviews have concentrated on soluble cytokine receptors in general, 8 on the mechanisms of generation of soluble receptors, 9, 10 and on various aspects of the IL-6 cytokine family, 11 this review will mainly focus on the consequences of direct stimulation of gp130 on hematopoietic cells, through the complex of IL-6 and a soluble form of the IL-6R, in vivo and in vitro.
GENERATION AND OCCURRENCE OF SOLUBLE RECEPTORS Many if not all transmembrane proteins occur also in a soluble form that consists of the major part of the extracellular domain. This phenomenon has been observed for type I and type II transmembrane proteins. 9, 10 Two independent mechanisms lead to the generation of such soluble proteins. Firstly, transmembrane proteins can be cleaved by a transmembrane metalloproteinase that most likely is a protease distinct from matrix-type metalloproteinases to yield the soluble extracellular domain of the proteins. This mechanism has been studied in detail for the human IL-6R. 12-16 Cleavage is controlled by protein kinase C and occurs at a distinct site that is not strictly sequence specific. 15 The generation of the soluble IL-6R can be prevented by hydroxamic acid compounds16 that previously have been shown to inhibit the processing of the membrane form of tumor necrosis factor (TNF). 17, 18 A TNF
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