The chemokine and chemokine receptor superfamilies and their molecular evolution

The human chemokine superfamily currently includes at least 46 ligands, which bind to 18 functionally signaling G-protein-coupled receptors and two decoy or scavenger receptors. The chemokine ligands probably comprise one of the first completely known molecular superfamilies. The genomic organization of the chemokine ligand genes and a comparison of their sequences between species shows that tandem gene duplication has taken place independently in the mouse and human lineages of some chemokine families. This means that care needs to be taken when extrapolating experimental results on some chemokines from mouse to human.     

The chemokine and chemokine receptor superfamilies and their molecular evolution

The human chemokine superfamily currently includes at least 46 ligands, which bind to 18 functionally signaling G-protein-coupled receptors and two decoy or scavenger receptors. The chemokine ligands probably comprise one of the first completely known molecular superfamilies. The genomic organization of the chemokine ligand genes and a comparison of their sequences between species shows that tandem gene duplication has taken place independently in the mouse and human lineages of some chemokine families. This means that care needs to be taken when extrapolating experimental results on some chemokines from mouse to human.     

Sequence evolution of the CCR5 chemokine receptor gene in primates.

The chemokine receptor CCR5 can serve as a coreceptor for M-tropic HIV-1 infection and both M-tropic and T-tropic SIV infection. We sequenced the entire CCR5 gene from 10 nonhuman primates: Pongo pygmaeus, Hylobates leucogenys, Trachypithecus francoisi, Trachypithecus phayrei, Pygathrix nemaeus, Rhinopithecus roxellanae, Rhinopithecus bieti, Rhinopithecus avunculus, Macaca assamensis, and Macaca arctoides. When compared with CCR5 sequences from humans and other primates, our results demonstrate that: (1) nucleotide and amino acid sequences of CCR5 among primates are highly homologous, with variations slightly concentrated on the amino and carboxyl termini; and (2) site Asp13, which is critical for CD4-independent binding of SIV gp120 to Macaca mulatta CCR5, was also present in all other nonhuman primates tested here, suggesting that those nonhuman primate CCR5s might also bind SIV gp120 without the presence of CD4. The topologies of CCR5 gene trees constructed here conflict with the putative opinion that the snub-nosed langurs compose a monophyletic group, suggesting that the CCR5 gene may not be a good genetic marker for low-level phylogenetic analysis. The evolutionary rate of CCR5 was calculated, and our results suggest a slowdown in primates after they diverged from rodents. The synonymous mutation rate of CCR5 in primates is constant, about 1.1 x 10(-9) synonymous mutations per site per year. Comparisons of Ka and Ks suggest that the CCR5 genes have undergone negative or purifying selection. Ka/Ks ratios from cercopithecines and colobines are significantly different, implying that selective pressures have played different roles in the two lineages.     

Cattle and chemokines: evidence for species-specific evolution of the bovine chemokine system

The chemokine system comprises a family of small chemoattractant molecules that have roles in both the healthy and diseased organism. Chemokines act by binding specific receptors on the target cell surface and inducing chemotaxis. The human chemokine system is well characterized, with approximately fifty chemokines identified that fall into four families. The chemokines and their receptors are promiscuous in that one chemokine can often bind several receptors, and vice versa. Study of the bovine chemokine system has been restricted to date to a handful of chemokines, and the identification of bovine chemokines is largely based on the closest human homologue. This method of identification is prone to error and may result in the misassumption of function of a particular chemokine. Here, we review current knowledge of bovine chemokines and reassess the bovine chemokine system based on phylogenetic and syntenic approaches. The bovine chemokine system, for the most part, shows high similarity to the chemokine system of other mammals such as humans; however, differences have been identified. Cattle possess fewer chemokines than humans, yet also possess chemokines that have no obvious homologue in the human system. These 'missing' and 'novel' chemokines may represent functional differences between the bovine and human chemokine systems that may affect the way in which these species are able to respond to specific pathogen repertoires.     

Primate origins and the evolution of angiosperms

Traditionally, the morphological traits of primates were assumed to be adaptations to an arboreal way of life. However, Cartmill [1972] pointed out that a number of morphological traits characteristic of primates are not found in many other arboreal mammals. He contends that orbital convergence and grasping extremities indicate that the initial divergence of primates involved visual predation on insects in the lower canopy and undergrowth of the tropical forest. However, recent research on nocturnal primates does not support the visually-oriented predation theory. Although insects were most likely important components of the diets of the earliest euprimates, it is argued here that visual predation was not the major impetus for the evolution of the adaptive traits of primates. Recent paleobotanical research has yielded evidence that a major evolutionary event occurred during the Eocene, involving the angiosperms and their dispersal agents. As a result of long-term diffuse coevolutionary interactions with flowering plants, modern primates, bats, and plant-feeding birds all first arose around the Paleocene-Eocene boundary and became the major seed dispersers of modern tropical flora during the Eocene. Thus, it is suggested here that the multitude of resources available on the terminal branches of the newly evolved angiosperm, rain forest trees led to the morphological adaptations of primates of modern aspect.     

Investigating the evolution and structure of chemokine receptors

Chemokine receptors represent a prime target for the development of novel therapeutic strategies in a variety of disease processes, including inflammation, allergy and neoplasia. Here we use maximum likelihood methods and bootstrap methods to investigate both the phylogenetic relationships in a large set of human chemokine receptor sequences and the relationships between chemokine receptors and their nearest neighbors. We found that CCR and CXCR families are not homogeneous. We also provide evidences that angiotensin receptors are the closest neighbors. Other close neighbors include opioid, somatostatin and melanin-concentrating hormone receptors. The phylogenetic analysis suggests ancient paralogous relationships and establishes a link between immune, metabolic and neural systems modulation. We complement our findings with a structural analysis based on wavelet methods of the major branches of chemokine receptors phylogeny. We hypothesize that receptors very close in the tree can form heterodimers. Our analyses reveal different characteristics of amino acid hydrophobicity and volume propensity in the different subfamilies. We also found that the second extra-cytoplasmic loop has higher rates of evolution than the internal loops and transmembrane segments, suggesting that selection, shifting, reassignments and broadening of receptor binding specificities involve mainly this loop.     

Heterophilic chemokine receptor interactions in chemokine signaling and biology

It is generally accepted that G-protein coupled receptors (GPCR), like chemokine receptors, form dimers or higher order oligomers. Such homo- and heterophilic interactions have been identified not only among and between chemokine receptors of CC- or CXC-subfamilies, but also between chemokine receptors and other classes of GPCR, like the opioid receptors. Oligomerization affects different aspects of receptor physiology, like ligand affinity, signal transduction and the mode of internalization, in turn influencing physiologic processes such as cell activation and migration. As particular chemokine receptor pairs exert specific modulating effects on their individual functions, they might play particular roles in various disease types, such as cancer. Hence, chemokine receptor heteromers might represent attractive therapeutic targets. This review highlights the state-of-the-art knowledge on the technical and functional aspects of chemokine receptor multimerization in chemokine signaling and biology.     

Polymorphisms in chemokine and chemokine receptor genes and the development of coal workers' pneumoconiosis

Chemokines and their receptors are key regulators of inflammation and may participate in the lung fibrotic process. Associations of polymorphisms in CCL5 (G-403A) and its receptor CCR5 (Delta32), CCL2 (A-2578G) and CCR2 (V64I), and CX3CR1 V249I and T280M with coal worker's pneumoconiosis (CWP) were investigated in 209 miners examined in 1990, 1994 and 1999. Coal dust exposure was assessed by job history and ambient measures. The main health outcome was lung computed tomography (CT) score in 1990. Internal coherence was assessed by studying CT score in 1994, 4-year change in CT score, and CWP prevalence in 1999. CCR5 Delta32 carriers had significantly higher CT score in 1990 and 1994 (2.15 vs. 1.28, p=0.01; 3.04 vs. 1.80, p=0.04). The CX3CR1 I249 allele was significantly associated with lower 1990 CT score and lower progression in 4-year change in CT score in CCR5 Delta32 carriers only (p for interaction=0.03 and 0.02). CX3CR1 V249I was associated with lower 1999 CWP prevalence (16.7%, 13.2%, 0.0% for VV, VI and II); the effect was most evident in miners with high dust exposure (31.6%, 21.7%, 0.0%). Our findings indicate that chemokine receptors CCR5 and CX3CR1 may be involved in the development of pneumoconiosis.     

Differential recognition and scavenging of native and truncated macrophage-derived chemokine (macrophage-derived chemokine/CC chemokine ligand 22) by the D6 decoy receptor

The promiscuous D6 receptor binds several inflammatory CC chemokines and has been recently proposed to act as a chemokine-scavenging decoy receptor. The present study was designed to better characterize the spectrum of CC chemokines scavenged by D6, focusing in particular on CCR4 ligands and analyzing the influence of NH(2)-terminal processing on recognition by this promiscuous receptor. Using D6 transfectants, it was found that D6 efficiently bound and scavenged most inflammatory CC chemokines (CCR1 through CCR5 agonists). Homeostatic CC chemokines (CCR6 and CCR7 agonists) were not recognized by D6. The CCR4 agonists CC chemokine ligand 17 (CCL17) and CCL22 bound to D6 with high affinity. CCL17 and CCL22 have no agonistic activity for D6 (chemotaxis and calcium fluxes), but were rapidly scavenged, resulting in reduced chemotactic activity on CCR4 transfectants. CD26 mediates NH(2) terminus processing of CCL22, leading to the production of CCL22 (3-69) and CCL22 (5-69) that do not interact with CCR4. These NH(2)-terminal truncated forms of CCL22 were not recognized by D6. The results presented in this study show that D6 recognizes and scavenges a wide spectrum of inflammatory CC chemokines, including the CCR4 agonists CCL22 and CCL17. However, this promiscuous receptor is not engaged by CD26-processed, inactive, CCL22 variants. By recognizing intact CCL22, but not its truncated variants, D6 expressed on lymphatic endothelial cells may regulate the traffic of CCR4-expressing cells, such as dendritic cells.     

Molecular evolution and modern human origins

While molecular evolutionists may be fascinated by the features and history of a particular gene or DNA segment, evolutionary anthropologists are often more interested in the activities and history of groups of people. We may want to know, for instance, when and where humans have migrated, how much exchange between groups has taken place, and how population sizes have changed. Population genetic theory provides the hope that through analyses of genetic data we will gain insight into the history of populations. Genetic data from extant human populations are now accruing at a remarkable rate. We might, therefore, expect to have answers in hand. There remains, however, a wide gap between the available theory and data; too often we fail to draw firm conclusions because our interpretation of analytic results requires that we make myriad assumptions about our data. In any one instance, these assumptions might include estimates of mutation rate, mutational mechanism, population sizes, the role that natural selection has played, and the rate of migration among groups. Often these assumptions are implicit, invisible to most. How, then, are we to make any progress? © 1998 Wiley-Liss, Inc.     

Radiation-induced pulmonary fibrosis: examination of chemokine and chemokine receptor families

Fibrosis is a common outcome of chronic inflammation or injury. Pulmonary fibrosis may be the result of abnormal repair after an acute inflammatory response. The process of repair initiated by a tissue insult is largely a function of the activation of cells to produce important biological mediators such as cytokines, growth factors and chemokines, which orchestrate most aspects of the inflammatory response. Consequently, altered regulation of the production of inflammatory cell cytokines and chemokines after injury and repair likely contributes to the fibrosis. Our hypothesis is that chronic expression of specific chemokine and chemokine receptors during the fibrotic phase induced by thoracic irradiation may perpetuate the recruitment and activation of lymphocytes and macrophages, which may contribute to the development of fibrosis. Fibrosis-sensitive (C57BL/6) and fibrosis-resistant (C3H/HeJ) mice were irradiated with a single dose of 12.5 Gy to the thorax. Total lung RNA was prepared and hybridized using microarray analysis and RNase protection assays. At 26 weeks postirradiation, messages encoding the chemokines BLC (now known as Scyb13), C10 (now known as Scya6), IP-10 (now known as Scyb10), MCP-1 (now known as Scya2), MCP-3 (now known as Scya7), MIP-1gamma (now known as Scya9), and RANTES (now known as Scya5) and the chemokine receptors Ccr1, Ccr2, Ccr5 and Ccr6 were elevated in fibrosis-sensitive (C57BL/6) mice. In contrast, only the messages encoding SDF-1alpha (now known as Sdf1) and Ccr1 were elevated 26 weeks postirradiation in fibrosis-resistant (C3H/HeJ) mice. Our results point to the CC and CCR family members as the predominant chemokine responders during the development of fibrosis. These studies suggest that monocyte/macrophage and lymphocyte recruitment and activation are key components of radiation-induced fibrosis.