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Year XVI -Issue 06 - 2000
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monocytes that are in the vicinity. The actual factors eliciting release of mature cells from the bone marrow and attracting them to the infection site are chemotaxins, of which IL8 appears at present to be the most active. Injected CSFs elicit a relatively slow rise in blood granulocyte and monocyte levels based eventually on increased cell production in the marrow and spleen. The key to a successful response to a local infection is how rapidly adequate, if initially relatively small, numbers of neutrophils and monocytes can reach the infection site. The reason why prior injection of CSFs is superior is because time has been permitted for the CSFs to amplify cell production in the marrow with the generation of large numbers of mature cells available for rapid release by the chemokines (39). CSF injections therefore play two quite distinct roles in the control of infections - activation of the functional activity of locally available mature cells and the eventual generation of greatly increased numbers of mature cells. The usual manner in which CSFs are used clinically does not allow either function of the CSFs to be properly exhibited. CSF treatment after irradiation or extensive chemotherapy has little prospect of activating mature cells because the numbers of such cells have been drastically reduced. Furthermore, it is during this initial leukopenic period that infections are likely to become established. Finally, the CSFs are not at first particularly effective in stimulating the increased formation of mature cells if most progenitor cells in the marrow have been destroyed by pretreatment. As a consequence, the clinical impact of CSF use on the occurrence and severity of infections, although measurable, is far lower than that achievable in experimental models. There is a need for clinical reappraisal of the manner in which CSFs are used in the hope of reducing infections in cancer patients. Similarly, in patients of other types at risk of infections, earlier rather than later use of the CSFs would clearly be preferable. There are indeed many situations in which prophylactic use of CSFs should be possible for example, in cases of severe burns or in patients with trauma or about to undergo complex abdominal surgery. In all these situations, infections are likely, so there is a strong argument for preempting possible future problems by initiating immediate CSF treatment. CSF Membrane Receptors All actions of the CSFs and other hematopoietic regulators on responding cells are mediated by high-affinity binding of the regulators to their specific membrane receptors. Receptor numbers for the CSFs are surprisingly low on most hematopoietic cells and typically number only a few hundred, with only a fraction of these needing to be occupied to elicit responses in the cells (4). Signaling from receptors occurs following low-affinity binding to one receptor chain followed by binding to a second, often different, receptor chain. This cross-linking of receptor chains results in activation by phosphorylation of various regions of the cytoplasmic domain of the receptor chain. Hematopoietic regulator receptors are of multiple types, typified by the CSF receptors. The receptor for MCSF is a classical transmembrane homodimer with cytoplasmic tyrosine kinase domains that become autophosphorylated following MCSF binding (40). Receptors for the other CSFs fall into the large group of hemopoietin receptors characterized by lack of a cytoplasmic tyrosine kinase domain, a common WSXWS motif in the extracellular domain and one or more hemopoietin domains. The receptor for GCSF is a homodimer of two similar chains (41) but the receptors for GMCSF (42) and MultiCSF (43) are heterodimers with a specific alfachain and a signaling betachain which, in man, is shared by the alfachains for GMCSF, MultiCSF and IL5 (43, 44). Sharing of common betachains is a common feature in receptors for hematopoietic regulators and not only indicates a common ancestral origin of such receptors but provides the physical basis for observed competition for binding between the regulators concerned as they compete for access to limiting numbers of betachains. While the ligand-receptor complexes exhibit very high binding affinity and slow offrate kinetics, activated receptors are promptly internalized and remain capable of signaling only until degradation of the complex occurs by proteasomal degradation. For
each CSF, only one type of membrane receptor exists. The polyfunctionality
exhibited by CSFs requires changes in gene activation of multiple types
and actions in differing locations in the cell. This is achieved by
the presence of distinct functional regions in the cytoplasmic domains
of signaling receptors (45, 46). In most cases signals for cell proliferation
are initiated by a region close to the membrane. In contrast, signals
for differentiation commitment and for maturation initiation originate
from a more Cterminal region - the exact location of this region differing
slightly in different cell types. In most receptors, the extreme Cterminus
of the receptor initiates negative signals dampening down responses
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