Biological Responses to Chemokine Superfamily Members

In the immune system, leukocytes are directed to sites of inflammation under the influence of a concentration gradient of soluble chemotactic molecules, a process known as chemotaxis. Upon encountering a chemotactic molecule, a responding leukocyte begins to directionally migrate from regions of low ligand concentrations toward the sites of chemoattractant production. A number of endogenous compounds have been shown to mediate leukocyte migration, including activated serum components; platelet activating factor (PAF); eicosanoids; cytokines such as interleukin 1 (IL-1), tumor necrosis factor a (TNFa), and interferon y (IFNy); and neuroendocrine hormones (Shimizu et al., 1992; Taub, 1996; Baggiolini et al., 1997). While many of these factors are believed to play some role in inflammation, their relevance to leukocyte locomotion in various pathological disease states and in normal homing processes has been brought into question.

During the 1990s, more than 50 unique human and rodent cytokines have been identified as members of a superfamily of chemoattractants called chemokines. Chemokines have been shown to induce the directional migration of selected cell types including neutro-phils, monocytes, macrophages, dendritic cells, lymphocytes, basophils, eosinophils, and fibroblasts. Based on the presence or absence of certain conserved cysteine residues within the primary sequence, the chemokine superfamily can be separated into four distinct subfamilies called the CXC (or a), the CC (or P), the C (or y), and the CXXXC (or 5) subfamilies (Baggiolini et al., 1997; Luster, 1998; Mantovani, 1999). Besides being highly basic in nature and being able to bind heparin through heparin-binding domains, many chemokines exhibit a significant level of homology at the amino acid level (24% to 80%).

Historically, the chemokine subfamilies were biologically distinguished from one another by their apparent leukocyte specificity in mediating cell migration. The early rule was that CXC chemokines (in particular, those containing an ELR motif in their amino-ter-minal sequences) induce neutrophil but not monocyte migration, whereas CC chemokines predominantly act on monocytes and macrophages but have no activity on neutrophils. However, with the examination of additional leukocyte subsets and the discovery of additional chemokine subfamily members, distinguishing chemokine subfamilies based on leukocyte motility and specificity has become invalid. Today, both CXC and CC family members are known to act on a number of cell types besides neutrophils and monocytes, including basophils, eosinophils, lymphocytes, endothelial cells, epithelial cells, melano-cytes, smooth muscle cells, keratinocytes, and hepatocytes. All of the CC, C, and CXXXC chemokines, as well as several CXC chemokines, have been shown to induce human lymphocyte migration both in vitro and in vivo (Taub, 1996; Baggiolini et al., 1997; Luster, 1998; Berger et al., 1999; Horuk, 1999). Furthermore, contrary to the early rule, several CC chemokines, including macrophage inflammatory protein 1a (MIP-1a) and macrophage chemotactic protein 3 (MCP-3), are capable of stimulating neutrophil migration and activation, whereas CXC chemokines like interferon-inducible protein 10 (IP-10) and monokine induced by y-interferon (MIG) are modest monocyte chemoattractants.

Besides chemotaxis, chemokines have also been shown to mediate a number of other biological effects including respiratory burst, enzyme release, degranulation, intracellular free Ca2+ mobilization, cellular polarization, shape changes, actin polymerization, integrin expression alterations, and an increase in adherence of leukocytes to endothelium and matrix proteins. In in vitro assays, redundancy in the activities of the chemokines is common, although it remains to be seen whether the various chemokines have unique roles in vivo. A detailed summary of all of the chemokine subfamily members including alternative names, receptor-ligand pairs, receptor cellular distribution, and leukocyte responsiveness can be found in Tables 6.12.1 and 6.12.2.

unit 6.12

Cytokines and Their Cellular Receptors

Contributed by Dennis D. Taub and Eric Schaffer

Current Protocols in Immunology (2000) 6.12.1-6.12.32 Copyright © 2000 by John Wiley & Sons, Inc.

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