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Blood, 15 June 2002, Vol. 99, No. 12, pp. 4307-4317
CHEMOKINES
Enhancement of intracellular signaling associated with
hematopoietic progenitor cell survival in response to SDF-1/CXCL12 in
synergy with other cytokines
Younghee Lee,
Akihiko Gotoh,
Hyung-Joo Kwon,
Minute You,
Lisa Kohli,
Charlie Mantel,
Scott Cooper,
Giao Hangoc,
Keisuke Miyazawa,
Kazuma Ohyashiki, and
Hal E. Broxmeyer
From the Departments of Microbiology/Immunology,
Medicine, Biochemistry and Molecular Biology, and the Walther Oncology
Center, Indiana University School of Medicine, and the Walther Cancer
Institute, Indianapolis; and First Department of Internal Medicine,
Tokyo Medical University, Nishishinjuku, Shinjuku-ku, Tokyo, Japan.
Stromal cell-derived factor 1 (SDF-1/CXCL12) is a multifunctional
cytokine. We previously reported that myelopoiesis was enhanced in
SDF-1 transgenic mice, probably due in part to SDF-1 enhancement of myeloid progenitor cell (MPC) survival. To understand signaling pathways involved in this activity, we studied the effects on factor-dependent cell line MO7e cells incubated with SDF-1 alone or
in combination with other cytokines. SDF-1 induced transient activation of extracellular stress-regulated kinase (ERK1/2), ribosomal S6 kinase (p90RSK) and Akt, molecules implicated in cell
survival. Moreover, ERK1/2, p90RSK, and Akt were synergistically activated by SDF-1 in combination with granulocyte-macrophage colony-stimulating factor (GM-CSF), Steel factor (SLF), or
thrombopoietin (TPO). Similar effects were seen after pretreatment of
MO7e cells with SDF-1 followed by stimulation with the other
cytokines, suggesting a priming effect of SDF-1. Nuclear factor- B
(NF-B) did not appear to be involved in SDF-1 actions, alone or
in combination with other cytokines. These intracellular effects were
consistent with enhanced myeloid progenitor cell survival by SDF-1
after delayed addition of growth factors. SDF-1 alone supported
survival of highly purified human cord blood CD34+++ cells,
less purified human cord blood, and MO7e cells; this effect was
synergistically enhanced when SDF-1 was combined with low amounts of
other survival-promoting cytokines (GM-CSF, SLF, TPO, and FL). SDF-1
may contribute to maintenance of MPCs in bone marrow by enhancing cell
survival alone and in combination with other cytokines.
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