Over the past ten years, numerous chemokines have been identified as attractants of different types of blood leukocytes to sites of infection and inflammation. They are produced locally in the tissues and act on leukocytes through selective receptors. Chemokines are now known to also function as regulatory molecules in leukocyte maturation, traffic and homing of lymphocytes, and the development of lymphoid tissues.
Interleukin 8, the first chemokine to be characterized, was discovered nearly ten years ago. Today, more than 30 human chemokines are known. They are often upregulated in inflammation and act mainly on leukocytes inducing migration and release responses. The present review deals largely with the new developments of the last three years. Several structural studies have shown that most chemokines form dimers. The dimers, however, dissociate upon dilution, and the monomers constitute the biologically active form. Chemokine activities are mediated by seven-transmembrane-domain, G protein coupled receptors, five of which were discovered in the past three years. The primary receptor-binding domain of all chemokines is near the NH2 terminus, and antagonists can be obtained by truncation or substitutions in this region. Major progress has been made in the understanding of chemokine actions on T lymphocytes that respond to several CC chemokines but also to IP10 and Mig, two CXC chemokines that selectively attract T cells via a novel receptor. Effects of chemokines on angiogenesis and tumor growth have been reported, but the data are still contradictory and the mechanisms unknown. Of considerable interest is the recent discovery that some chemokines function as HIV-suppressive factors by interacting with chemokine receptors which, together with CD4, were recognized as the binding sites for HIV-1.
A PIJfATIVE chemokine receptor that we previously cloned and termed LESTR 1 has recently been shown to function as a coreceptor (termed fusin) for lymphocyte-tropic HIV-1 strains 2 • Cells expressing CD4 became permissive to infection with T -cellline-adapted HIV-1 strains of the syncytium-i.nducing phenotype after transfection with LESTR/fusin complementary DNA. We report here the identification of a human chemokine of the CXC type, stromal cell-derived factor 1 (SDF-1), as the naturaJ ligand for LESTR/fusin, and we propose the term CXCR-4 for this receptor, in keeping with the new cbemokine-receptor nomenclature. SDF-1 activates Chinese hamster ovary (CHO) cells transfected with CXCR-4 eDNA as well as blood leukocytes and lymphocytes. In cell lines expressing CXCR-4 and CD4, and in blood lymphocytes, SDF-1 is a powerful inhibitor of infection by lymphocyte-tropic HIV-1 strains, whereas the CC chemokines RANTES, MIP-1a and MIP-1~, which were shown previously to prevent infection with primary, monocyte-tropic viruses 3 , are inactive. In combination with CC chemokines, which block the infection with monocyte/macrophage-tropic viruses, SDF-1 could help to decrease virus load and prevent the emergence of the syncytium-inducing viruses which are characteristic of the late stages of AIDS 4• LESTR (leukocyte-expressed seven-transmembrane-domain receptor) is an orphan receptor with structural similarity to chemokine receptors. Despite extensive testing of a large number of chemokines, the ligand for LESTR remained elusive 1 • Murine SDF-1 was described as a factor that is produced by bonemarrow stromal cells and shown to induce proliferation of B-cell progenitorsM as well as recruitment of T cells 7 • The human homologue, which was cloned subsequently, is virtually identical to murine SDF-1 (see Methods). SDF-1 is a CXCchemokine with the typical four-cysteine motif and the first two cysteines separated by one amino acid 8 • When human SDF-1 was tested on the CH0-1C2 clone which stably expresses LESTR, a transient rise of cytosolic free Ca 2 + ([Ca 2 +];) was observed (Fig. 1a). This response, which is characteristic of the action of chemokines on blood leukocytes, was not observed with parental CHO cells. Other chemokines, including RANTES (for regulation-upon-activation, normal T expressed and secreted) macrophage inflammatory protein (MIP), MIP-1o: and MIP-1~, were not active. Monocytes, neutrophils and phytohaemagglutinin (PHA)-activated peripheral-blood lymphocytes (PBLs) were also stimulated by SDF-1, as shown by [Ca 2 +]; changes and chemotaxis (Fig. 1b, d). Real-time recordings of Ca 2 + mobilization after sequential stimulation are a reliable way to assess receptor usage by chemokines 8 • Stimulation with a chemokine (at saturating concentrations) causes receptor desensitization, and no response is observed when the cells are restimulated within a short time by a chemokine acting on the same receptor. As shown in Fig. lc, monocytes stimulated with SDF-1 remained fully responsive to subsequent stimulation with ...
SummaryA human receptor that is selective for the CXC chemokines IP10 and Mig was cloned and characterized. The receptor cDNA has an open reading frame of 1104-bp encoding a protein of 368 amino acids with a molecular mass of 40,659 dalton. The sequence includes seven putative transmembrane segments characteristic of G-protein coupled receptors. It shares 40.9 and 40.3% identical amino acids with the two IL-8 receptors, and 34.2-36.9% identity with the five known CC chemokine receptors. The IPl0/Mig receptor is highly expressed in IL-2-activated T lymphocytes, but is not detectable in resting T lymphocytes, B lymphocytes, monocytes and granulocytes. It mediates Ca 2+ mobilization and chernotaxis in response to IP10 and Mig, but does not recognize the CXC-chemokines IL-8, GROom, NAP-2, GCP-2, ENA78, PF4, the CC-chemokines MCP-1, MCP-2, MCP-3, MCP-4, MIP-lot, MIP-I[~, RANTES, I309, eotaxin, nor lymphotactin. The exclusive expression in activated T-lymphocytes is of high interest since the receptors for chemokines which have been shown so far to attract lymphocytes, e.g., MCP-1, MCP-2, MCP-3, MIP-lot, MIP-I[3, and R_ANTES, are also found in monocytes and granulocytes. The present observations suggest that the IP10/Mig receptor is involved in the selective recruitment of effector T cells.
The three-dimensional structure of stromal cell-derived factor-1 (SDF-1) was determined by NMR spectroscopy. SDF-1 is a monomer with a disordered N-terminal region (residues 1-8), and differs from other chemokines in the packing of the hydrophobic core and surface charge distribution. Results with analogs showed that the N-terminal eight residues formed an important receptor binding site; however, only Lys-1 and Pro-2 were directly involved in receptor activation. Modification to Lys-1 and/or Pro-2 resulted in loss of activity, but generated potent SDF-1 antagonists. Residues 12-17 of the loop region, which we term the RFFESH motif, unlike the N-terminal region, were well defined in the SDF-1 structure. The RFFESH formed a receptor binding site, which we propose to be an important initial docking site of SDF-1 with its receptor. The ability of the SDF-1 analogs to block HIV-1 entry via CXCR4, which is a HIV-1 coreceptor for the virus in addition to being the receptor for SDF-1, correlated with their affinity for CXCR4. Activation of the receptor is not required for HIV-1 inhibition.
lntcrlcukind (IL-Q belongs to a family of small, structurally related cytokincs similar to platclct factor 4. It is produced by phagocytes and mcsenchymal cells exposed to inflammatory stimuli (e.g. interlcukin-I or tumor necrosis her) and activales ncutrophils inducing chcmotaxis, cxocytosis and the respiratory burst. In vivo, IL-8 elicits a massive neutropbil accumulation at thz site or injection. Five nuutrophil-activating cytokines similar to IL-8 in structure and function have been identified recently. IL-8 and the related cytokincs are produced in several tissues upon infection, inflammation, ischcmia, trauma etc., and are thought to bc the main cause of local ncutrophil accumul;ition.
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