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Granulocyte-Macrophage Colony-Stimulating Factor (CSF) and Macrophage CSF-Dependent Macrophage Phenotypes Display Differences in Cytokine Profiles and Transcription Factor Activities: Implications for CSF Blockade in Inflammation¹

Andrew J. Fleetwood^2,*, Toby Lawrence, John A. Hamilton^* and Andrew D. Cook^*

^* Department of Medicine and Cooperative Research Centre for Chronic Inflammatory Diseases, University of Melbourne, Royal Melbourne Hospital, Parkville, Victoria, Australia; and Kennedy Institute of Rheumatology Division, Imperial College London, Hammersmith, London, United Kingdom

GM-CSF and M-CSF (CSF-1) can enhance macrophage lineage numbers as well as modulate their differentiation and function. Of recent potential significance for the therapy of inflammatory/autoimmune diseases, their blockade in relevant animal models leads to a reduction in disease activity. What the critical actions are of these CSFs on macrophages during inflammatory reactions are unknown. To address this issue, adherent macrophages (GM-BMM and BMM) were first derived from murine bone marrow precursors by GM-CSF and M-CSF, respectively, and stimulated in vitro with LPS to measure secreted cytokine production, as well as NF-B and AP-1 activities. GM-BMM preferentially produced TNF-, IL-6, IL-12p70, and IL-23 whereas, conversely, BMM generated more IL-10 and CCL2; strikingly the latter population could not produce detectable IL-12p70 and IL-23. Following LPS stimulation, GM-BMM displayed rapid IB degradation, RelA nuclear translocation, and NF-B DNA binding relative to BMM, as well as a faster and enhanced AP-1 activation. Each macrophage population was also pretreated with the other CSF before LPS stimulation and found to adopt the phenotype of the other population to some extent as judged by cytokine production and NF-B activity. Thus, GM-CSF and M-CSF demonstrate, at the level of macrophage cytokine production, different and even competing responses with implications for their respective roles in inflammation, including a possible dampening or suppressive role for M-CSF in certain circumstances.

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 a grant and a Senior Principal Research Fellowship (to J.A.H.) from the National Health and Medical Research Council of Australia.

² Address correspondence and reprint requests to Dr. Andrew J. Fleetwood, Department of Medicine and Cooperative Research Centre for Chronic Inflammatory Diseases, University of Melbourne, Royal Melbourne Hospital, Parkville, Victoria, Australia 3050. E-mail address: ajfleetwood{at}pgrad.unimelb.edu.au

³ Abbreviations used in this paper: DC, dendritic cell; BMM, M-CSF-dependent murine bone marrow-derived macrophage; GM-BMM, GM-CSF-dependent murine bone marrow-derived macrophage; M-1, proinflammatory type-1 human monocyte-derived subset; M-2, anti-inflammatory type-2 human monocyte-derived macrophage subset; Q-PCR, quantitative PCR.

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