The molecular basis of leukocytosis
Section snippets
Induction of leukocytosis
Leukocytosis is a response to several changing parameters: production and immigration from the marrow into the blood, demargination from blood vessel walls (e.g. after extreme exercise), and prevention of emigration into tissues. Leukocytosis is often associated with infection; other common causes are hemorrhage, trauma (including surgery), myocardial infarction, malignancies (sarcoma, carcinoma, leukemia, myelosclerosis), poisoning and metabolic disturbances (drugs, chemicals, venoms, tubular
Interleukin 1
When the first preparations of lipopolysaccharide (LPS)-free pure natural interleukin 1β (IL-1β) were injected intravenously, an immediate leukopenia was observed: granulocytes disappeared within 30 min and returned to normal levels by 5 h (Refs 12, 13). The degree and duration of the leukocytosis was dependent on the dose of IL-1β injected. In contrast to granulocytes, the changes in lymphocyte numbers were more protracted, being reduced to minimal levels after 6–8 h and returning to normal by 24
The role of proteases in leukocytosis
Although there are ample reasons to associate protease activity with leukocytosis, experimental evidence is emerging only now. A major drawback for this association has been the fact that many proteases act in cascades. Thus, although individual enzymes from such a chain might be available in a purified form for in vivo testing, homeostatic mechanisms (e.g. natural inhibitors) might prevent visualization of their effect on leukocytosis.
The proteases that act on extracellular matrices (bone
Cell adherence in the bone marrow
Alterations in the adherence of hematopoietic cells within the bone marrow matrix are based on weak but multivalent carbohydrate–protein interactions and on stronger protein–protein associations. This, in turn, is determined by the expression of selectins and mucin-like glycoproteins, and of leukocytic and endothelial integrins or adhesion molecules of the immunoglobulin family. It is evident that changes in these types of cell–cell and cell–matrix interactions might contribute to leukocytosis.
The flux model of leukocytosis
The flux of leukocytes at certain anatomical sites and the cellular interactions involved have been reviewed elsewhere54, 55. Leukocytosis is dependent on the production of cells in the bone marrow, detachment from the marrow microenvironment and immigration into the blood, followed by adherence to the endothelium and emigration into inflamed tissues. Many factors act cooperatively to influence each of these individual steps, as described below and in Fig. 1.
Conclusions and perspectives
Recent research at the molecular level has broadened our insights into the (patho)physiological mechanisms that govern white blood cell homeostasis and leukocytosis. In most cases, leukocytosis is a component of a host defense mechanism in the fight against infections. The molecules and mechanisms of leukocytosis are summarized in Appendix C. The net number of circulating blood leukocytes is at any moment the result of the concert of these interactions, and can be dramatically altered by
Acknowledgements
These studies are supported by the General Savings and Retirement Fund (A.S.L.K.), the Fund for Scientific Research (FWO-Vlaanderen), the `Geconcerteerde OnderzoeksActies, GOA', the `InterUniversitaire AttractiePolen, IUAP' and the Dutch Cancer Society (N.K.B.). The illustration was made by René Conings.
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