Chemokines belong to a family of pro-inflammatory activation-inducible cytokines previously referred to as members of SIS family of cytokines, SIG family of cytokines, SCY family of cytokines, Platelet factor-4 superfamily or Intercrines These proteins are mainly chemotactic for different cell types.
Chemokines molecular weight ranges from 8 kDa to10 kDa and show 20%-50 % sequence homology among each other at the protein level. Chemokines share common gene & tertiary structure. Chemokines possess a number of conserved cysteine residues involved in intramolecular disulfide bond formation.
2 different subfamilies of chemokines are distinguished according to their chromosomal location. The Alpha-Chemokines are referred to also as the 4q chemokine family because the genes encoding members of this family map to human chromosome 4q12-21. The first 2 cysteine residues of this family are separated by 1 amino acids therefore, called CXC-Chemokines [Cysteine- Amino Acid-Cysteine-Chemokines]. The new sytematic nomenclature of this group is called SCY family. Some human CXC-Chemokines are defined by the conserved ELR sequence motif (glutamic acid-leucine-arginine) after the first cysteine residue near the amino-terminal end. Chemokines with an ELR sequence chemoattract & activate primarily neutrophils. Chemokines without the ELR sequence chemoattract and activate monocytes, dendritic cells, T-cells, NK-cells, B-lymphocytes, basophils, and eosinophils.
The Beta-Chemokines or 17q chemokine family map to human chromosome 17q11-32 (mouse chromosome11). The first 2 cysteine residues are adjacent and, therefore, these proteins are called also CC-Chemokines [Cysteine-Cysteine-Chemokines]. The new sytematic nomenclature of this group is called SCY family of cytokines. Several of the Beta-Chemokines contain two additional conserved cysteine residues and sometimes the term C6-beta-Chemokines is used for this subgroup.
C-Chemokines also named Gamma-Chemokines differ from other chemokines by the absence of a one cysteine residue. Chemokines members having a CXXXC cysteine signature are referred to as Delta-Chemokines or CX3C-Chemokines or CXXXC-Chemokines. Gamma & Delta Chemokines are type 1 transmembrane glycoproteins with the chemokine domain resting on top of an extended mucin-like stalk. A soluble form of the chemokine moiety can be released from its transmembrane anchor by extracellular cleavage.
The defined subgroups of chemokines on the basis of structural and functional properties illustrates the importance of chemoattractant diversity in the regulation of the movement of leukocytes through the body. Chemokines have direct microbicidal activities characterized by a structural motif and have been classified as kinocidins.
Biological activity of chemokines is mediated by receptors with overlapping ligand specificities that bind several proteins, which belong either to the CC-Chemokines or the group of CXC-Chemokines. Lymphocytes require stimulation to become responsive to most known chemokines, and this process is linked closely to chemokine receptor expression. Chemokine receptors belong to the large group of G-protein-coupled seven transmembrane domain receptors that contain 7 hydrophobic alpha-helical segments that transverse the membrane. These receptors form a structurally related group within the G-protein-coupled receptor superfamily, which mediate signaling via heterotrimeric G-proteins.
The receptors that bind CXC-Chemokines are designated CXCR such as CXCR1, CXCR2, CXCR3, CXCR4, CXCR5 & CXCR6 while receptors binding CC-Chemokines are designated CCR, examples are: CCR1, CCR2, CCR3, CCR4, CCR5, CCR6, CCR7, CCR8, CCR9, CCR10, CCR10A, CCR10B & CCR11. The "R" nomenclature is used for receptors that bind chemokines and elicit intracellular signaling in response to binding of a ligand.
Examples of viral chemokine receptor homologs are ECRF-3, EBI-1 (EBV induced gene-1) and US28. Examples of viral chemokine activity inhibitors are vCCI, vCKBP. Chemokines have been shown to be capable of binding to heparin moieties of the extracellular matrix. Binding to heparan sulfate or heparin enhances responses of neutrophils to IL8.
Chemokines are essential mediators for trafficking of leukocytes and their role is not only restricted to cell attraction. Chemokines are multipotent cytokines that localize and enhance inflammation by inducing chemotaxis and cell activation of different types of inflammatory cells typically present at inflammatory sites. Chemokines are induced and released into the circulation during acute infection but high concentrations of some chemokines are observed also in normal plasma. Arrest chemokines are a subset of immobilized chemokines expressed by endothelial cells under physiologic or pathologic conditions. Chemokines rapidly activate leukocyte integrin adhesiveness under shear flow.
Chemokines exert their effects on distinct subsets of cells. An example is CXC-Chemokines which attract neutrophils but not macrophages, while CC-Chemokines preferentially induce migration of macrophages. Chemokines have been shown to induce selective migration of subsets of leukocytes.
Chemokines along with other mediators are responsible for the cellular composition at inflammatory sites and also directly cause cell activation. Some chemokines activate granulocytes and/or monocytes and cause respiratory bursts, degranulation, and the release of lysosomal enzymes. Chemokines prime immune cells to respond to sub-optimal amounts of other inflammatory mediators, though other chemokines are potent histamine releasing factors for basophils. Erythrocytes play an important role through their promiscuous chemokine receptor in regulating the chemokine network. Chemokines bound to the receptor on erythrocytes are inaccessible to their normal target cells which provides a sink for superfluous chemokines and may serve to limit the systemic effects of these mediators without disrupting localized processes taking place at the site of inflammation.
During the course of pathophysiological processes many genes encoding chemokines are strongly expressed including autoimmune diseases, cancer, atherosclerosis, and chronic inflammatory diseases.
Specific CC-Chemokines exhibit biological activities other than mere chemotaxis. Chemokines are capable of inducing the proliferation and activation of killer cells known as CHAK (CC-Chemokine-activated killer), which are similar to cells activated by IL2. Chemokines have important developmental functions also apart from inducing Chemotaxis such as the SDF family group. Chemokines also modulate growth of hematopoietic progenitors thus have functions in hematopoiesis, for example: BFU-E, CFU-GM, CFU-GEMM and may play a role in trafficking of hematopoietic progenitor cells in and out of the bone marrow in inflammatory conditions. Chemokines that have suppressive activity against immature subsets of myeloid progenitors stimulated to proliferate by multiple growth factors include: MCP-4, MIP-4, I-309, TECK, GCP-2, Mig, and lymphotactin. Chemokines found to be lacking suppressive activity include: MCP-2, MCP-3, eotaxin-1, MCIF, TARC, MDC, MPIF-2 (eotaxin-2), SDF-1 and fractalkine (neurotactin).
Additional functions of chemokines such as angiogenesis, wound healing, tumor growth, metastasis, development, and genesis, homeostasis and function of the immune system have been reported also.
Chemokines and their receptors are especially important in the control of viral infection and replication as well as interference with viral propagation by enhancing the cytotoxic activity of infected cells or by recruiting activated leukocytes to foci of infection to aid viral clearance. Chemokines suppress infection by HIV-1 and that chemokine receptors serve, along with CD4, as obligate coreceptors for HIV-1 entry, which is an important medical discovery. Many viruses encode a viral homolog of chemokines or chemokine binding proteins, termed virokine and viroceptor, respectively.
For a strategy allowing manipulation of the cell surface expression of chemokine receptors that are involved in the pathogenesis of HIV virus infections (CCR5 and CXCR4) and thus also allowing a modification of cell susceptibility see also: intrakine.