Altered responsiveness to chemokines due to targeted disruption of SHIP
Chang H. Kim, … , Gerald Krystal, Hal E. Broxmeyer
Chang H. Kim, … , Gerald Krystal, Hal E. Broxmeyer
Published December 15, 1999
Citation Information: J Clin Invest. 1999;104(12):1751-1759. https://doi.org/10.1172/JCI7310.
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Article

Altered responsiveness to chemokines due to targeted disruption of SHIP

Abstract

SHIP has been implicated in negative signaling in a number of hematopoietic cell types and is postulated to downregulate phosphatidylinositol-3-kinase– (PI-3K–) initiated events in diverse receptor signaling pathways. Because PI-3K is implicated in chemokine signaling, we investigated whether SHIP plays any role in cellular responses to chemokines. We found that a number of immature and mature hematopoietic cells from SHIP-deficient mice manifested enhanced directional migration (chemotaxis) in response to the chemokines stromal cell–derived factor-1 (SDF-1) and B-lymphocyte chemoattractant (BLC). SHIP–/– cells were also more active in calcium influx and actin polymerization in response to SDF-1. However, colony formation by SHIP-deficient hematopoietic progenitor cell (HPCs) was not inhibited by 13 myelosuppressive chemokines that normally inhibit proliferation of HPCs. These altered biologic activities of chemokines on SHIP-deficient cells are not caused by simple modulation of chemokine receptor expression in SHIP-deficient mice, implicating SHIP in the modulation of chemokine-induced signaling and downstream effects.

Authors

Chang H. Kim, Giao Hangoc, Scott Cooper, Cheryl D. Helgason, Sandie Yew, R. Keith Humphries, Gerald Krystal, Hal E. Broxmeyer

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Figure 1

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Bone marrow HPC, macrophages and B cells from SHIP-deficient mice have e...
Bone marrow HPC, macrophages and B cells from SHIP-deficient mice have enhanced chemotaxis to SDF-1. (a) Bone marrow cells were examined for their ability to transmigrate from the upper chamber toward SDF-1 at indicated concentrations in the lower chamber. After chemotaxis, myeloid progenitors in input and the lower chamber were assayed by methylcellulose colony assay. HPC (CFU-GM) migration was normalized for the number of input colony-forming HPCs to obtain HPC migration rate (% of input ± SD). Chemotaxis of CD11b/Mac-1+ F4/80+ bone marrow macrophages (b) and bone marrow B220+ B cells (c) in response to SDF-1. Data are expressed as the mean (± SD) of percent cell migration obtained from triplicated points. Results are each 1 representative of 5 independent experiments with consistent results. *Significant differences were observed between the wild-type and SHIP-deficient cells (P < 0.03).