Anne Angelillo-Scherrer, Laurent Burnier, Diether Lambrechts, Richard J. Fish, Marc Tjwa, Stéphane Plaisance, Rocco Sugamele, Maria DeMol, Eduardo Martinez-Soria, Patrick H. Maxwell, Greg Lemke, Stephen P. Goff, Glenn K. Matsushima, H. Shelton Earp, Marc Chanson, Désiré Collen, Shozo Izui, Marc Schapira, Edward M. Conway, Peter Carmeliet
J Clin Invest.
2008;
118(2):583–596
doi:10.1172/JCI30375
This article Copyright © 2008, The American Society for Clinical Investigation
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any patients with anemia fail to respond to treatment with erythropoietin (Epo), a commonly used hormone that stimulates erythroid progenitor production and maturation by human BM or by murine spleen. The protein product of growth arrest–specific gene 6 (Gas6) is important for cell survival across several cell types, but its precise physiological role remains largely enigmatic. Here, we report that murine erythroblasts released Gas6 in response to Epo and that Gas6 enhanced Epo receptor signaling by activating the serine-threonine kinase Akt in these cells. In the absence of Gas6, erythroid progenitors and erythroblasts were hyporesponsive to the survival activity of Epo and failed to restore hematocrit levels in response to anemia. In addition, Gas6 may influence erythropoiesis via paracrine erythroblast-independent mechanisms involving macrophages. When mice with acute anemia were treated with Gas6, the protein normalized hematocrit levels without causing undesired erythrocytosis. In a transgenic mouse model of chronic anemia caused by insufficient Epo production, Gas6 synergized with Epo in restoring hematocrit levels. These findings may have implications for the treatment of patients with anemia who fail to adequately respond to Epo.
Figure 9
Relative cytokine levels in plasma and BM-derived macrophage releasate in WT and Gas6–/– mice.
A cytokine antibody array was performed in a pool of plasma of 8 mice in steady-state condition (A) and a pool of releasate of 8 macrophage culture samples (B). Relative cytokine expression is shown in AU. Cytokines known to inhibit erythropoiesis are indicated in red. 1, Axl; 2, B lymphocyte chemoattractant; 3, CD40; 4, CD80L; 5, CD80T; 6, cytokine responsive gene–2; 7, cutaneous T cell–attracting chemokine; 8, CXC–chemokine ligand–16; 9, eotaxin; 10, eotaxin-2; 11, FasL; 12, fractalkine; 13, G-CSF; 14, GM-CSF; 15, IFN-γ; 16, IGF-binding protein 3 (IGFBP-3); 17, IGFBP-5; 18, IGFBP-6; 19, IL-10; 20, IL-12p40/p70; 21, IL-12p70; 22, IL-13; 23, IL-17; 24, IL-1α; 25, IL-1β; 26, IL-2; 27, IL-3; 28, IL-3Rβ; 29, IL-4; 30, IL-5; 31, IL-6; 32, IL-9; 33, mouse IL-8 ortholog (KC or Gro-alpha); 34, leptin; 35, leptin receptor; 36, LPS-induced CXC chemokine; 37, L-selectin; 38, lymphotactin; 39, monocyte chemotactic protein–1 (MCP1); 40, MCP5; 41, M-CSF; 42, monokine induced by IFNγ; 43, macrophage inflammatory protein 1α (MIP1α); 44, MIP1γ; 45, MIP2; 46, MIP3α; 47, MIP3β; 48, platelet factor 4; 49, P-selectin; 50, RANTES; 51, SCF; 52, SCF1α; 53, soluble TNF-receptor 1 (sTNF-R1); 54, sTNF-R2; 55, thymus activation regulated chemokine; 56, T cell activation gene 3; 57, thymus expressed chemokine; 58, tissue inhibitor of metalloproteinase 1; 59, TNF-α; 60, thrombopoietin; 61, VCAM-1; 62, VEGF.
