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M-CSF

[macrophage colony stimulating factor; monocyte colony stimulating factor]


ALTERNATIVE NAMES

CSA (colony stimulating activity);
CSF (colony stimulating factor without any further designation; especially in the older literature);
CSF-1 (colony stimulating factor-1);
CSF-HU (Urinary colony stimulating factor)

KPB-M15-CSA (KPB-M15 derived colony stimulating activity)
Lanimostim (in some databanks)

L-cell CSF (L-cell colony stimulating factor);
LSF (leukemogenic stromal factor);
MAF-J6-1;
MGF (macrophage growth factor);
MGI-1M (macrophage-granulocyte inducer);
XS cell growth factor.
See also: individual entries for further information.


SOURCES

M-CSF is produced by monocytes, granulocytes, endothelial cells, and fibroblasts. After cell activation, B-cells and T-cells and also a number of tumor cell lines are capable also of synthesizing this factor. M-CSF has been found to be synthesized by uterine epithelial cells in vivo. The factor is found also in human urine.

The synthesis of M-CSF can be induced by IL1, TNF-alpha, IFN-gamma, GM-CSF and PDGF. Prostaglandins, glucocorticoids, TGF-beta and substances that raise intracellular levels of cAMP inhibit the synthesis of M-CSF.

The murine op allele (see: op/op mice) is caused by a mutation of the M-CSF gene. These mice are characterized by a complete absence of this factor.


PROTEIN CHARACTERISTICS

M-CSF is a homodimeric glycoprotein the subunits of which are linked by disulfide bonds. The sugar moiety is not required for the full spectrum of biological activities. Different molecular forms of M-CSF with lengths of 256 (M-CSF-alpha), 554 (M-CSF-beta) and 438 (M-CSF-gamma) amino acids have been described. They arise by translation of alternatively spliced mRNAs. Another splice variant is called CSF-4. For deletion variants see: LSF (leukemogenic stromal factor).

M-CSF-beta is a secreted protein that does not occur in a membrane-bound form. M-CSF-alpha is expressed as an integral membrane protein that is slowly released by proteolytic cleavage. The membrane-bound form of M-CSF can interact with receptors on near-by cells and therefore mediates specific cell-to-cell contacts (see: juxtacrine). Some high-molecular weight forms of murine M-CSF have been described. These forms are complexed with proteoglycan (see: PG-M-CSF).

A comparison of the primary sequence of M-CSF with those of the other human colony stimulating factors (GM-CSF, G-CSF) reveals that the three factors are not related to each other.


GENE STRUCTURE

The human M-CSF has a length of approximately 20 kb and contains ten exons. The gene was originally thought to be located to human chromosome 5q33 in close proximity to genes encoding other Hematopoietic growth factors GM-CSF, IL3, IL4 and IL5. The gene has now been reassigned to chromosome 1p13-p212 in the vicinity to the amylase genes. The murine M-CSF gene has been shown to be the site of the mutation in a form of osteopetrosis (see: op/op). The rat gene tl (toothless), likewise, causes osteopetrosis, and is due to a mutation in the M-CSF gene.


RECEPTORS

The biological activities of M-CSF are mediated by a receptor of 165 kDa encoded by a gene mapping to human chromosome 5q33. 3 (see also: 5q minus syndrome). The M-CSF receptor is identical with the proto-oncogene fms. It has been renamed CD115. The gene is approximately 800 bp from the PDGF receptor gene. The expression of both receptor genes is probably controlled by common regulatory sequences since the M-CSF receptor gene does not possess regulatory regions of its own.

The receptor is a transmembrane protein with an extracellular ligand-binding domain of 512 amino acids, an intramembrane domain of 25 amino acids, and a cytoplasmic domain of 435 amino acids encoding a bipartite tyrosine kinase interrupted by a so-called kinase insert (see also: PTK, protein tyrosine kinase).

Binding of the ligand leads to the autophosphorylation of the receptor. Ligand/receptor complexes are internalized by the cell and degraded. Effects associated with ligand binding include the stimulation of protein biosynthesis, glucose transport, and Na+/K+-ATPase activity. Intracellular signaling also involves a G-protein. After binding of M-CSF to its receptor the receptor associates with non-receptor protein kinases called fyn and yes, which appear to mediate some of the intracellular signals.

M-CSF circulating in the serum is mainly removed by binding to macrophage receptors and subsequent internalization and degradation. A binding factor for M-CSF has been found in the serum from a patient in remission from lymphma (see: CSF-1 binding factor).

Experiments with a functional M-CSF receptor gene have been used to study the plasticity of B-lymphoid progenitor cells. Murine cells develop into which a cloned receptor gene was introduced can differentiate into macrophages in the presence of M-CSF. Similar results are obtained by introduction of the myc oncogene and the raf oncogene into normal bone marrow cells using a retrovirus vector. This phenomenon is known as lineage switching. The switching process can be inhibited by IL7 in these cells. Approximately 5-10 % of all acute leukemias are biphenotypic and express markers of lymphoid cells and myeloid cells. These leukemias cannot be assigned to a distinct lineage and may be the result of transformation of biphenotypic progenitor cells.


BIOLOGICAL ACTIVITIES

Human M-CSF is active in mouse and rat cells. The murine factor is active in rat cells but inactive in human cells.

M-CSF was isolated initially as a factor stimulating the growth of colonies of macrophages and granulocytes in soft agar cultures (see also: Colony formation assay). M-CSF influences the proliferation and differentiation of hematopoietic stem cells into macrophages but mainly the growth survival and differentiation of monocytes. In combination with another colony stimulating factor, GM-CSF, one observes the phenomenon of synergistic suppression, i.e., the combination of these two factors leads to a partial suppression of the generation of macrophage-containing cell colonies

M-CSF is a specific factor in that the proliferation inducing activity is more or less restricted to the macrophage lineage. M-CSF also is a potent stimulator of functional activities of monocytes.

In normal human macrophages M-CSF induces antibody-dependent cell-mediated cytotoxicity (see: ADCC).

In monocytes and macrophages M-CSF induces the synthesis of IL1, G-CSF, IFN, TNF, plasminogen activator, thromboplastin, prostaglandins and thromboxanes and also oxidative metabolism. M-CSF synergises with IL1, IL3 and IL6 in the stimulation of proliferation and the differentiation of primitive hematopoietic cells into macrophages.

Since M-CSF is synthesized also by uterine epithelial cells it may be involved in the maintenance of normal placental functions, acting on the decidua and trophoblasts.

In experimental animals M-CSF reduces plasma levels of cholesterol.

In humans M-CSF enhances counts of monocytes and leads to an expansion of neutrophilic granulocytes.


DETECTION AND ASSAY METHODS

M-CSF can be assayed in a colony formation assay by the development of colonies containing macrophages. M-CSF is also detected in specific bioassays with cells lines that depend in their growth on the presence of M-CSF or that respond to this factor (see: BAC1.2F5; BaF3; GNFS-60; J774). An alternative and entirely different detection method is RT-PCR quantitation of cytokines. For further information see also subentry "Assays" in the reference section. For further information on assays for cytokines see also: bioassays, cytokine assays.


CLINICAL USE AND SIGNIFICANCE

M-CSF may be clinically relevant in its capacity to reconstitute the hematopoietic system in combination with other hematopoietic factors (see also: hematopoiesis, Hematopoietins).

M-CSF accelerates the recovery of the pool of leukocytes following bone marrow transplantation. In some cases of acute myeloid leukemia M-CSF induces the terminal differentiation of these cells into cell types that do no longer proliferate.

M-CSF may be a tumor marker for ovarian tumors and tumors of the endometrium for which it may act as an autocrine growth modulator. Since M-CSF induces the synthesis of some inflammatory proteins it may be involved in inflammatory reactions, which should then be amenable to manipulation with suitable inhibitors.



 

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