Macrophage colony stimulating factor: Not just for macrophages anymore! A gateway into complex biologies

Biology Department, California State University Long Beach, 1250 Bellflower Blvd, Long Beach CA 90840, United States.
International Immunopharmacology (Impact Factor: 2.47). 11/2008; 8(10):1354-76. DOI: 10.1016/j.intimp.2008.04.016
Source: PubMed


Macrophage colony stimulating factor (M-CSF, also called colony stimulating factor-1) has traditionally been viewed as a growth/differentiation factor for monocytes, macrophages, and some female-specific tumors. As a result of alternative mRNA splicing and post-translational processing, several forms of M-CSF protein are produced: a secreted glycoprotein, a longer secreted form containing proteoglycan, and a short membrane-bound isoform. These different forms of M-CSF all initiate cell signaling in cells bearing the M-CSF receptor, called c-fms. Here we review the biology of M-CSF, which has important roles in bone physiology, the intestinal tract, cancer metastases to the bone, macrophage-mediated tumor cell killing and tumor immunity. Although this review concentrates mostly on the membrane form of human M-CSF (mM-CSF), the biology of the soluble forms and the M-CSF receptor will also be discussed for comparative purposes. The mechanisms of the biological effects of the membrane-bound M-CSF reveal that this cytokine is unexpectedly involved in many complex molecular events. Recent experiments suggest that a tumor vaccine based on membrane-bound M-CSF-transduced tumor cells, combined with anti-angiogenic therapy, should be evaluated further for use in clinical trials.

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    • "M-CSF is constitutively produced at detectable, but low levels, and it exists in multiple isoforms. The glycoprotein and the proteoglycan isoforms can be secreted and thus circulate throughout the body while the cell-surface protein isoform acts locally (Douglass et al. 2008). M-CSF is associated with increased defences against a number of fungal, bacterial and viral agents including Candida albicans , Mycobacterium avium and Leishmania major (Chitu & Stanley 2006). "
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    ABSTRACT: The field of eco-immunology seeks to address the causes and consequences of natural variation in immune responses. Recently, the development of more immunological resources for non-model systems along with the growing availability of genomic data, has made it feasible to explore more complex immunological differences in non-model systems. Cytokines are small molecular weight proteins that are the major signaling molecules of the immune system. Studies in mice and humans have demonstrated the importance of tightly regulated cytokine signaling, and thus cytokines may play a major, unexplored role in explaining natural variation in immune responses. In this review, we highlight cytokines that are likely to be important for eco-immunology studies and what is currently known about their presence or absence in the major vertebrate groups. We also explore what types of questions an eco-immunologist might ask involving cytokines and discuss potential ways to measure cytokines in non-model systems. Inclusion of cytokines in eco-immunology will advance the field as it will help us to better understand mechanisms behind both natural variation in immune responses and how different taxa respond to immune challenges. This article is protected by copyright. All rights reserved.
    Preview · Article · Mar 2014 · Functional Ecology
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    • "Macrophage colony stimulating factor (MCSF), also referred to as colony stimulating factor-1(CSF-1), is a growth factor responsible for survival, proliferation and differentiation of cells of hematopoietic lineages [1]. Outside the hematopoietic system, MCSF has an important role in the development and regulation of placenta, mammary gland, brain and bone physiology [2]–[4]. MCSF is encoded by a unique gene, however, through alternative mRNA splicing and differential post-translational modification, three different forms of MCSF, such as, a secreted glycoprotein, a secreted proteoglycan and a short membrane bound isoform are found [1]. "
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    ABSTRACT: Macrophage colony stimulating factor (MCSF) regulates growth, proliferation and differentiation of haematopoietic cell lineages. Many cancers are known to secrete high level of MCSF, which recruit macrophages into the tumour micro-environment, supporting tumour growth. Herein, we report the cloning of MCSF and subsequent generation of U87MG expressing MCSF stable cell line (U87-MCSF). Cytotoxicity of anti-cancer drug 5-fluorouracil (5-FU) was evaluated on both U87MG and U87-MCSF cells. Interestingly, the proliferation of U87-MCSF cells was less (p<0.001) than that of U87MG cells alone, after treatment with 5-FU. Significant decrease in expression levels of cyclin E and A2 quantified by real time PCR analysis corroborated the reduced proliferation of 5-FU treated U87-MCSF cells. However, JC-1 staining did not reveal any apoptosis upon 5-FU treatment. Notch-1 upregulation induced a possible epithelial-mesenchymal transition in U87-MCSF cells, which accounted for an increase in the proportion of CD24(high)/CD44(less) cancer stem cells in U87-MCSF cells after 5-FU treatment. The elevated resistance of U87-MCSF cells towards 5-FU was due to the increase in the expressions (10.2 and 6 fold) of ABCB1 and mdm2, respectively. Furthermore, increase in expressions of ABCG1, mdm2 and CD24 was also observed in U87MG cells after prolonged incubation with 5-FU. Our studies provided mechanistic insights into drug resistance of U87MG cells and also described the pivotal role played by MCSF in augmenting the resistance of U87MG cells to 5-FU.
    Full-text · Article · Dec 2013 · PLoS ONE
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    • "CSF-1 is the primary regulator of macrophage differentiation, survival and proliferation, and during development it plays an essential and non-redundant role in regulating organogenic macrophage functions [17,18,33,34]. Administration of CSF-1 to neonatal mice was shown to increase the number and proportion of developmental macrophages within the lung at P5. Flow cytometric analysis was performed on whole lungs, with populations of Csf1r-EGFP+ leukocytes (Figure 5C) further gated on F4/80 expression to investigate macrophages (Figure 5D&E). "
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    ABSTRACT: Background: Macrophages are traditionally associated with inflammation and host defence, however a greater understanding of macrophage heterogeneity is revealing their essential roles in non-immune functions such as development, homeostasis and regeneration. In organs including the brain, kidney, mammary gland and pancreas, macrophages reside in large numbers and provide essential regulatory functions that shape organ development and maturation. However, the role of macrophages in lung development and the potential implications of macrophage modulation in the promotion of lung maturation have not yet been ascertained. Methods: Embryonic day (E)12.5 mouse lungs were cultured as explants and macrophages associated with branching morphogenesis were visualised by wholemount immunofluorescence microscopy. Postnatal lung development and the correlation with macrophage number and phenotype were examined using Colony-stimulating factor-1 receptor-enhanced green fluorescent protein (Csf1r-EGFP) reporter mice. Structural histological examination was complemented with whole-body plethysmography assessment of postnatal lung functional maturation over time.Flow cytometry, real-time (q)PCR and immunofluorescence microscopy were performed to characterise macrophage number, phenotype and localisation in the lung during postnatal development. To assess the impact of developmental macrophage modulation, CSF-1 was administered to neonatal mice at postnatal day (P)1, 2 and 3, and lung macrophage number and phenotype were assessed at P5. EGFP transgene expression and in situ hybridisation was performed to assess CSF-1R location in the developing lung. Results: Macrophages in embryonic lungs were abundant and densely located within branch points during branching morphogenesis. During postnatal development, structural and functional maturation of the lung was associated with an increase in lung macrophage number. In particular, the period of alveolarisation from P14-21 was associated with increased number of Csf1r-EGFP+ macrophages and upregulated expression of Arginase 1 (Arg1), Mannose receptor 1 (Mrc1) and Chemokine C-C motif ligand 17 (Ccl17), indicative of an M2 or tissue remodelling macrophage phenotype. Administration of CSF-1 to neonatal mice increased trophic macrophages during development and was associated with increased expression of the M2-associated gene Found in inflammatory zone (Fizz)1 and the growth regulator Insulin-like growth factor (Igf)1. The effects of CSF-1 were identified as macrophage-mediated, as the CSF-1R was found to be exclusively expressed on interstitial myeloid cells. Conclusions: This study identifies the presence of CSF-1R+ M2-polarised macrophages localising to sites of branching morphogenesis and increasing in number during the alveolarisation stage of normal lung development. Improved understanding of the role of macrophages in lung developmental regulation has clinical relevance for addressing neonatal inflammatory perturbation of development and highlights macrophage modulation as a potential intervention to promote lung development.
    Full-text · Article · Apr 2013 · Respiratory research
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