Immunotherapy for Infectious Diseases

Cytokines, Cytokine Antagonists, and Growth Factors 123
The number and arrangement of these conserved cysteines allow them to be classified
into three groups: C, CC, or CXC (19). Both the CXC and CC families of
chemokines have four conserved cysteines; the C chemokines have two conserved cysteines.
The CXC and CC groups differ by the presence (CC) or absence (CXC) of an
intervening amino acid between the first two cysteines. Both the CXC and CC groups
have numerous members, whereas the only known members of the C groups include
human and mouse lymphotactin and activation-induced, T-cell-derived and chemokinerelated
molecule (ATAC). Genes encoding members of each group appear to cluster on
the same chromosomes, i.e., genes for CXC chemokines are found on chromosome 4,
those for CC are on chromosome 17, and those for C are on chromosome 1.
Many CXC chemokines have the tripeptide motif glutamic acid-leucine-arginine
(ELR) near the N terminus just prior to the CXC motif, e.g., IL-8, nucleosome assembly
protein-2 (NAP-2), growth related oncogene-� (GRO-�), GRO-�, epithelial allderived
neutrophil activating peptide-78 (ENA-78), and granulocyte chemotactic
protein-2 (GCP-2). All these chemokines can bind the shared IL-8 receptor type II and
are potent mediators of neutrophil chemotaxis (19, 20). The presence of the ELR motif
appears to be associated with chemoattractant properties since CXC chemokines that
lack the ELR motif, e.g., PF-4, inflammatory protein-10 (IP-10), and monokine
inducible by IFN-� (MIG), do not chemoattract neutrophils nor do they bind the shared
IL-8 type II receptor. Although only CC chemokines were initially thought to be able
to induce migration of monocytes and macrophages, some CXC chemokines have been
found to have monocyte attraction activity. Similarly, only the ERL� CXC chemokines
were thought to induce neutrophil migration. However, several CC chemokines, including
macrophage inflammatory protein-1� (MIP-1�) and monocyte chemotactic protein-3
(MCP-3), have been shown to induce migration of neutrophils. In addition to
monocytes and macrophages, some CC chemokines have been shown to induce the
migration of eosinophils, basophils, and mast cells. The responsiveness to chemokine
stimulation depends not only on the specific type of leukocytes but also on the conditions
of stimulation, e.g., the migration of mast cells activated by IgE, and specific antigen
is enhanced in response to MCP-1 and RANTES compared with nonactivated cells.
In addition to their importance in the recruitment and activation of various leukocytes,
chemokines are active on other cell types, including endothelial cells, muscle
cells, melanocytes, and hepatocytes. Data suggest that chemokines have a role in several
other processes, including angiogenesis, tissue development, and fibrosis.
Chemokine Receptors
Chemokines bind to a distinct class of receptors whose structure is similar to that of
rhodopsin. The receptor polypeptide has seven hydrophobic domains passing through
the membrane as �-helices with an extracellular aminoterminus and an intracellular
carboxy terminus (21). Receptor binding can be restricted to a specific chemokine or
shared among several chemokines, e.g., CC CKR1, CC CKR4, and CC CKR5 are
selective for MIP-1� and RANTES but also bind a third chemokine that is not shared
by the other receptors (MCP-3 for CKR1, MCP-1 for CKR4, and MIP-1� for CKR5).
Humans have one chemokine receptor that is promiscuous since it binds to numerous
chemokines. This receptor, the Duffy blood group antigen, was first identified on
red blood cells but is also expressed by several nonerythroid cells, e.g., spleen, lung,