SHIP represses the generation of IL-3-induced M2 macrophages by inhibiting IL-4 production from basophils.

Full Abstract

There is a great deal of interest in determining what regulates the generation of classically activated (M1) vs alternatively activated (M2) macrophages (Mphis) because of the opposing effects that these two Mphi subsets have on tumor progression. We show herein that IL-3 and, to a lesser extent, GM-CSF skew murine Mphi 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 Mphis. These in vitro-derived mature Mphis also display other M2 characteristics, including an inability to enhance anti-CD3-stimulated splenic T cell secretion of IFN-gamma 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 Mphis themselves but by inhibiting IL-4 production from basophils.

Author information

Author/s: Kuroda, Etsushi (E); Ho, Victor (V); Ruschmann, Jens (J); Antignano, Frann (F); Hamilton, Melisa (M); Rauh, Michael J (MJ); Antov, Andrey (A); Flavell, Richard A (RA); Sly, Laura M (LM); Krystal, Gerald (G);

Affiliation: Terry Fox Laboratory, British Columbia Cancer Agency, Vancouver, British Columbia, Canada.

Grants: (Agency:Howard Hughes Medical Institute)

Journal and publication information

Publication Type: Journal Article; Research Support, Non-U.S. Gov't

Journal: Journal of immunology (Baltimore, Md. : 1950) (J Immunol), published in United States. (Language: eng)

Reference: 2009-Sep; vol 183 (issue 6) : pp 3652-60

Dates: Created 2009/09/03; Completed 2009/09/23;

PMID: 19710468, status: MEDLINE (last retrieval date: 9/23/2009, IMS Date: )

Sourced from the National Library of Medicine. Abstract text and other information may be subject to copyright.

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MeSH headings (categories)

This article was linked to the MESH Headings shown below.

Animals
Basophils - metabolism
Cell Differentiation - immunology
Granulocyte-Macrophage Colony-Stimulating Factor - pharmacology
Interleukin-3 - pharmacology
Interleukin-4 - biosynthesis

Interleukin-4 - biosynthesis
Macrophage Activation
Macrophages - cytology
Mice
Phosphoric Monoester Hydrolases - physiology
Stem Cells - cytology

Associated Chemicals: Interleukin-3 (0) ; Interleukin-4 (207137-56-2) ; Granulocyte-Macrophage Colony-Stimulating Factor (83869-56-1) ; Phosphoric Monoester Hydrolases (EC 3.1.3.-) ; inositol-1,4,5-trisphosphate 5-phosphatase (EC 3.1.3.56)

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