The Journal of Experimental Medicine
StemCell Technologies
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Published online 12 January 2004 doi:10.1084/jem.20031193
Rockefeller University Press, 0022-1007 $8.00
JEM, Volume 199, Number 2, 243-254
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Src Homology 2–containing 5-Inositol Phosphatase (SHIP) Suppresses an Early Stage of Lymphoid Cell Development through Elevated Interleukin-6 Production by Myeloid Cells in Bone Marrow

Koji Nakamura1, Taku Kouro1, Paul W. Kincade1,2, Alexander Malykhin1, Kazuhiko Maeda1, and K. Mark Coggeshall1,2,3

1 Immunobiology and Cancer Program, Oklahoma Medical Research Foundation, Oklahoma City, OK 73104
2 Department of Microbiology and Immunology, University of Oklahoma, Oklahoma City, OK 73104
3 Department of Cell Biology, University of Oklahoma, Oklahoma City, OK 73104

Address correspondence to K. Mark Coggeshall, Oklahoma Medical Research Foundation, 825 NE 13th St., Oklahoma City, OK 73104. Phone: (405) 271-7209; Fax: (405) 271-8569; email: mark-coggeshall{at}omrf.ouhsc.edu

The Src homology (SH)2–containing inositol 5-phosphatase (SHIP) negatively regulates a variety of immune responses through inhibitory immune receptors. In SHIP-/- animals, we found that the number of early lymphoid progenitors in the bone marrow was significantly reduced and accompanied by expansion of myeloid cells. We exploited an in vitro system using hematopoietic progenitors that reproduced the in vivo phenotype of SHIP-/- mice. Lineage-negative marrow (Lin-) cells isolated from wild-type mice failed to differentiate into B cells when cocultured with those of SHIP-/- mice. Furthermore, culture supernatants of SHIP-/- Lin- cells suppressed the B lineage expansion of wild-type lineage-negative cells, suggesting the presence of a suppressive cytokine. SHIP-/- Lin- cells contained more IL-6 transcripts than wild-type Lin- cells, and neutralizing anti–IL-6 antibody rescued the B lineage expansion suppressed by the supernatants of SHIP-/- Lin- cells. Finally, we found that addition of recombinant IL-6 to cultures of wild-type Lin- bone marrow cells reproduced the phenotype of SHIP-/- bone marrow cultures: suppression of B cell development and expansion of myeloid cells. The results identify IL-6 as an important regulatory cytokine that can suppress B lineage differentiation and drive excessive myeloid development in bone marrow.

Key Words: lymphopoiesis • inflammation • SHIP • interleukin 6

Abbreviations used in this paper: Fc{gamma}RII, Fc{gamma} receptor II; NOD, nonobese diabetic; PI-3K, phosphatidylinositol 3-kinase; PIP3, phosphatidylinositol 3,4,5-trisphosphate; SH, src homology; SHIP, SH2-containing 5-inositol phosphatase.


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