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fully elucidated. Leukocyte trafficking to sites of inflammation involves
interactions between hematopoietic and activated endothelial cells that is
facilitated by adhesion molecules, chemoattractants, and their receptors
[4]
. Chemokines are an important subset of the regulatory proteins that
contribute to leukocyte migration; substantial evidence suggests that the
accumulation of immune cells within inflamed tissue is regulated in large
part by the expression of chemokines and their receptors. Chemokines (a
hybrid of “chemotactic cytokines”) are a large family of predominantly 8- to
10-kDa polypeptide molecules that regulate many aspects of the immune
response. Chemokines have well-defined roles in orchestrating the move-
ments of immune cells both directly via their chemoattractant properties
(i.e., by providing “directional clues”) and indirectly via integrin activation
[5]
. Comparable to cytokines, a chemokine response may be elicited by
nearly any stimulus that disrupts immunologic homeostasis and can result
in a robust recruitment of inflammatory cells. When that stimulus is potent
and long lasting, an injurious rather than protective/reparative chemokine
response may ensue and foster progressive, leukocyte-mediated tissue
damage and organ dysfunction.
Although originally defined by their ability to control leukocyte chemo-
taxis
[5,12]
, chemokines can also regulate the activation and differentia-
tion of effector lymphocyte (Th1, Th2, Th17) myeloid cell subsets
[13]
. In
each scenario, chemokines can have inductive and repressive effects.
Thus, migrational responsiveness to chemoattractant signals can be tightly
coupled to signals that regulate cell activation or differentiation
[5,12]
.
Fifty-plus chemokines (
Table 17.1
) have been identified to date and are
classified structurally into four main groups according to the configuration
of cysteine residues near the N terminus (CC, CXC, C, and CX
3
C). The CC or
“α chemokines” and CXC or “β chemokines” are the two largest subsets
[5]
,
and members of each are the primary focus of this chapter. CC chemokines
have either four or six cysteines in highly conserved positions in which the
first two cysteines are juxtaposed, whereas the CXC chemokines are charac-
terized by four cysteine residues at the N terminus, the first two of which are
separated by a nonconserved amino acid
[12]
. CXC chemokines are classi-
fied further by the presence or the absence of the amino acid sequence glu-
tamic acid-leucine-arginine (the ELR motif ), which immediately precedes
the CXC sequence. ELR+ chemokines have been shown to promote angio-
genesis, whereas ELR− chemokines inhibit it
[14]
. Nearly all of the known
ELR− CXC chemokines also promote neutrophil chemotaxis
[14]
.
397
Actions of chemokines are mediated through a large family of seven-
transmembrane-spanning, serpentine, G-protein-coupled receptors. Over
20 chemokine receptors have been identified to date (
Table 17.1
). Each
receptor has a restricted expression on subclasses of leukocytes and ligand
specificity. However, ligand binding can overlap; some chemokines bind
to several receptors, and some receptors bind multiple ligands
[15]
. Che-
mokines and their receptors have been functionally divided into two broad
categories but this distinction is not absolute
[16]
. “Inducible” or “inflam-
matory” chemokines are
[1]
regulated by proinflammatory stimuli,
[2]
help orchestrate innate and adaptive immunity, and
[3]
recruit leukocytes
to sites of inflammation in response to physiologic stress. Inflammatory
chemokines, produced by a variety of cell types, classically include CCL2
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