Characteristics of chemokines

Over 30 unique human and mouse cytokines have been identified as members of the chemokine super-family (Table 1). Based on the presence or absence of an intervening amino acid residue located between the first two of the four conserved cysteine residues, the chemokine superfamily can be separated into two distinct subfamilies called the a (or C-X-C) and the /3 (or C-C) subfamilies. As the chemokines are secreted molecules, their cDNAs code for a precursor protein which contains a leader sequence (20-25 amino acids), which presumably enables the chemokines to

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be produced, cleaved and secreted to yield a mature form at the cell membrane by a wide variety of cell types. Chemokines share many other similarities, including their high basic nature as well as their ability to bind heparin through heparin-binding domains. At the amino acid level these molecules exhibit between 24-80% homology. Chemokines in

Infection or Injury

Figure 1 Schematic model of leukocyte trafficking into inflammatory tissues. Many of the models describing leukocyte entry Into inflammatory sites depend on at least three distinct molecular interactions: selectln-carbohydrate, chemokine-receptor, and intergrin-CAM. As leukocytes circulate in the blood and lymph (1), they constantly survey the surrounding endothelial barrier for the presence of distress signals alerting them to problem areas. Once alerted, a sequential series of signals is required to mediate leukocyte entry into the extravascular tissues. With the release of d stress mediators such as IL-1, TNF, LPS, or histamine, various selectin ligands are rapidly expressed and mobilized to the membrane of the activated endothelial cells within the tissue environment. The selectlns mediate the initial tethering and rolling of responding leukocytes to the blood vessel wall slowing their transit through the circulation (2). Upon interacting with proadhesive signals (3), most likely provided by heparan proteoglycan- or extracellular matrix-bound chemokines, the integrin molecules on the leukocyte surface are altered from a conformationally inactive complex to a high avidity state permitting leukocyte binding to the expressed cell adhesion molecules (such as ICAM-1, VCAM-1, etc.) present on inflamed endothelial cell surface (3). At this point, leukocyte rolling stops and firm adhesion begins. These adherent leukocytes are then permitted to spread out along the activated endothelial barrier and migrate (with the assistance of various proteinases) through the vascular endothelial barrier and basement membrane into the extravascular tissue space (5). Once through, soluble as well as extracellular matrix- and heparan proteoglycan-bound chemokines derived from the inflammatory lesion form a concentration gradient promoting the directional migration of leukocytes from areas of low chemokine levels toward the areas of chemokine production.

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