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* The Terry Fox Laboratory, British Columbia Cancer Agency, Vancouver, British Columbia, Canada;
Department of Immunology and Parasitology, University of Occupational and Environmental Health, School of Medicine, Kitakyushu, Japan;
Fachbereich Biologie, Chemie, Pharmazie, Takustr, Freie Universität-Berlin, Berlin, Germany;
Department of Hematopathology, University of Toronto, Toronto, Ontario, Canada;
¶ Department of Immunobiology, Yale University, School of Medicine, New Haven, CT, and the Howard Hughes Medical Institute, Chevy Chase, MD 20815; and
|| Department of Pediatrics, Division of Gastroenterology, BC Children’s Hospital & University of British Columbia, Vancouver, British Columbia, Canada
There is a great deal of interest in determining what regulates the generation of classically activated (M1) vs alternatively activated (M2) macrophages (M
s) because of the opposing effects that these two M subsets have on tumor progression. We show herein that IL-3 and, to a lesser extent, GM-CSF skew murine M progenitors toward an M2 phenotype, especially in the absence of SHIP. Specifically, the addition of these cytokines, with or without M-CSF, to adherence- or lineage-depleted (Lin–) SHIP–/– bone marrow (BM) cells induces high levels of the M2 markers, arginase I, and Ym1 in the resulting mature Ms. These in vitro-derived mature Ms also display other M2 characteristics, including an inability to enhance anti-CD3-stimulated splenic T cell secretion of IFN-
and low IL-12 and high IL-10 production in response to LPS. Not surprisingly, given that IL-3 and GM-CSF utilize STAT5 to trigger many downstream signaling pathways, this M2 phenotype is suppressed when STAT5–/– BM cells are used. Unexpectedly, however, this M2 phenotype is also suppressed when STAT6–/– BM cells are used, suggesting that IL-4- or IL-13-induced signaling might be involved. Consistent with this, we found that IL-3 and GM-CSF stimulate the production of IL-4, especially from SHIP–/– Lin– BM cells, and that neutralizing anti-IL-4 Abs block IL-3-induced M2 skewing. Moreover, we found that basophil progenitors within the Lin– BM are responsible for this IL-3- and GM-CSF-induced IL-4 production, and that SHIP represses M2 skewing not by preventing skewing within Ms themselves but by inhibiting IL-4 production from basophils.
The costs of publication of this article were defrayed in part by the payment of page charges. This article must therefore be hereby marked advertisement in accordance with 18 U.S.C. Section 1734 solely to indicate this fact.
1 This work was supported by the Terry Fox Foundation and the Canadian Cancer Society, with core support from the BC Cancer Foundation and the BC Cancer Agency. R.A.F. is an Investigator of the Howard Hughes Medical Institute.
2 L.M.S. and G.K. co-supervised first author.
3 Address correspondence and reprint requests to Dr. Gerald Krystal, The Terry Fox Laboratory, BC Cancer Research Centre, 675 West 10th Avenue, Vancouver, B.C. V5Z 1L3, Canada. E-mail address: gkrystal{at}bccrc.ca
4 Abbreviations used in this paper: M, macrophage; Arg I, arginase I; BM, bone marrow; Lin–, lineage depleted; TAM, tumor-associated macrophage; WT, wild type.
5 The online version of this article contains supplemental material.
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