Chemokine biological functions

Chemokine Receptors. Figure 1 Biological functions of chemokine receptors as exemplified by the chemokine receptor CXCR4. 

This review will describe the biological functions and regulation of the recently identified cytokines—interleukins, chemokines, and peptide growth factors—their intracellular signal transduction and role in certain diseases, and different cytokine assay methods and their clinical applications. 

We thank all our colleagues in Geneva and elsewhere who have worked with us to help us understand the biological function of chemokines, but especially Christine Power and Amanda Proudfoot. 

Numerous and diverse biological functions are regulated by chemokines. In addition to the well characterized proinflammatory activities such as integrin activation, chemotaxis, lipid mediator biosynthesis, superoxide radical production, and granule enzyme release (reviewed in refs. 1-4), chemokines have been shown to suppress and stimulate angiogenesis (5-7), suppress hematopoiesis (8-10), suppress apoptosis (11), control viral infection (12,13), and effect leukocyte differentiation (14). Among the proinflammatory activities, chemotaxis in particular has received considerable attention as a target for novel antiinflammatory therapeutics (reviewed in ref. 15). 

As the number of chemokines and receptors continue to expand so too does the list of ascribed biological functions. Beyond their characterized roles in leukocyte trafficking and inflammation, chemokines have been shown to effect angiogenesis (24-26), hematopoiesis (27-29), T-cell differentiation (30), apoptosis (31), and viral infection (32,33), although the biological significance of these effects as well as the mechanism of action remain to be determined in many cases. Furthermore, chemokine receptor expression has been reported on nonlymphoid cell types in brain and vasculature (34,35). Antibodies will no doubt prove to be useful in determining the function of these receptors in other systems. 

The identity of the biologically functional form of the chemokines is quite controversial. 

Several lines of evidence favor the monomer as the functional form of the chemokine. Structural analysis conditions require very high concentrations of protein - levels 10- to 1000-fold greater than the protein concentrations needed for biological function, which may not occur in vivo. Also, mutational changes can be made in the primary structure that prevent multimerization and do not significantly affect function (Rajarathnam et al., 1994). Finally, the primary structure of vMIP-II, a virally encoded (human herpesvirus 8 or HHV8) chemokine, resembles that of MIP-la however, vMIP-II fails to dimerize regardless of the pH or protein concentration (personal communication from Barry L. Schweitzer). 

Chemokines constitute a large family of about 50 proteins that interact with about 20 different receptors. Cbemokines play a crucial biological role in inflammation, immunity and viral infection. In spite of certain degree of redundancy, the chemokine system presents several levels of specificity in terms of receptor interaction, target cells and biological functions. The relevance of certain chemokines in specific immune responses is also suggested by the expression of selected chemokine-like proteins or chemokine-receptors by viruses as way to escape host response. 

Another related group of molecules are the chemokines. Chemokines are small peptide molecules that, hke cytokines, were originally associated with the immune system, but which now are recognized as being produced by almost all cells of the body and involved in a multitude of biological functions. Chemokines play many roles, including modulation of the Thl/Th2 balance associated with autoimmunity and hypersensitivity (Montovani et al., 1998), as mediators of allergic inflammation (Bacon and Schall, 1996), and modulation of the function of leukocytes in disease states such as rheumatoid arthritis and asthma. 

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