Chemokines.

not been systematically examined. Similar clustering has C been observed among genes encoding chemokine receptors. HEMOKINES have recently become the focus of intense interest and discussion. This has occurred, in One exception to the CC/CXC rule is lymphotactin, a part, because of an enlarging view of what chemokines do. potent attractant for T lymphocytes, but not monocytes. As recently as 2 or 3 years ago a chemokine review would Although it is the right size to be a chemokine and it has have begun with a discussion of the importance of chemotacseveral characteristic sequence signatures common to CC tic factors in controlling leukocyte function and trafficking, chemokines, it has only two cysteines. Nonetheless, these and would have pointed out that specificity for leukocyte cysteines correspond to cysteines 2 and 4 of chemokines, subsets is what sets chemokines apart from other chemoatand it has been suggested that lymphotactin belongs to a tractants. For example, formylated peptides (eg, f-Met-Leuthird chemokine subfamily denoted C, because of the lone Phe), complement fragments (eg, C5a), or arachidonic acid cysteine in the N-terminal domain. Consistent with its new metabolites (eg, LTB4) attract neutrophils and monocytes assignment, lymphotactin’s gene maps to 1q. So far, lymphowith equal potency, whereas some chemokines (eg, interleutactin is the only member of this putative family. kin-8 [IL-8]) attract neutrophils but have no discernible efAnother exception is a CX3C chemokine (also referred to as fects on monocytes. This discrimination has led to the fre‘‘fractalkine’’ or ‘‘neurotactin’’) that is an integral membrane quently espoused proposition that chemokines are involved protein with a chemokine domain at its N-terminus. This in the pathogenesis of diseases having characteristic infildomain differs from other chemokines by the presence of three trates. amino acids intervening between the first two cysteines. ModelHowever, we now know that chemokines and their receping studies suggest that the three-dimensional structure of tors are expressed by a wide variety of nonhematopoietic chemokines (see below) can only accommodate 0, 1, or 3 cells, and that chemokine function extends far beyond leukoamino acids between the first two cysteines, explaining the cyte physiology. Even within the world of leukocytes, the absence of a CX2C chemokine. Like lymphotactin, the gene connections among chemokines, their receptors, and human encoding CX3C chemokine maps to a locus different from other immunodeficiency virus (HIV) infection broadens the prechemokines, and so far it is the sole example of a chemokine viously narrow focus on chemokines as mere chemoattracwith this structural motif. tants. Furthermore, a proliferation of animal models has more precisely defined the functions of chemokines in vivo. CXC CHEMOKINES This review will attempt to describe what is understood Discussions of chemokine function tend to look like a about chemokines in light of recent discoveries. collection of disconnected observations. It is extremely difficult to divine rules, particularly because the dose responses CHEMOKINE FAMILIES for given effects in vitro may not be relevant in vivo. For example, the fact that the ED50 for MCP-1’s ability to attract Based on genomics efforts, it has been estimated that there monocytes is 10-fold lower than MCP-2’s may imply that may be as many as 40 to 50 human chemokines. The determiMCP-1 is a more potent chemoattractant. However, a 10nation that a gene encodes a chemokine depends on structural fold increase in MCP-2 expression in vivo would make it and, to a lesser extent, genetic criteria. Chemokines are physiologically equipotent with MCP-1. Therefore, the folsmall, with molecular weights in the range of 8 to 12 kD, lowing discussion merely catalogs chemokine properties but there are exceptions which involve proteins comprised without necessarily implying their physiologic importance of multiple domains, one of which looks like a chemokine. in vivo. Chemokine domains are defined by the presence of four ELR chemokines. The prototypic CXC chemokine is ILcysteines in highly conserved positions (Fig 1). One major 8, which was purified by several groups as a monocytechemokine subfamily is called ‘‘CXC’’ because the two derived factor that attracts neutrophils, but not monocytes, amino acids nearest the N-termini of these proteins are sepain Boyden chamber assays. Several other CXC chemorated by a single amino acid. This is in contrast to the other kines are also potent neutrophil chemoattractants (see Table major subfamily which is called ‘‘CC’’ because these two 1), and structure/activity analyses show that this property cysteines are adjacent. Many of the genes encoding chemokines have been mapped, and they cluster at specific loci. CC chemokine From the Department of Adult Oncology, Dana-Farber Cancer genes are grouped at 17q11.2-12 and CXC chemokine genes Institute and Harvard Medical School, Boston, MA. at 4q13 (although there are exceptions; see below). This Submitted February 6, 1997; accepted March 19, 1997. suggests that chemokines arose by duplication and diverSupported by a grant from the National Institutes of Health. B.J.R. gence from a primordial chemokine gene, with an early split is a Scholar of The Leukemia Society. into the two loci. Because mice appear to have fewer chemoAddress reprint requests to Barrett J. Rollins, MD, PhD, Danakines than humans (for example, there is no clear-cut murine Farber Cancer Institute, 44 Binney St, Boston, MA 02115. homolog of IL-8), some of this development may have ocq 1997 by The American Society of Hematology. 0006-4971/97/9003-0046$3.00/0 curred relatively recently in evolutionary terms, but this has