Chemokine Signaling

The chemokines are a family of proinflammatory cytokines that act through cell surface receptors to regulate numerous cellular processes. Chemokines exert their effects through G protein-coupled receptors (GPCRs) which are relatively non-selective in their ligand binding. As a result of this promiscuity, many chemokine receptors bind more than one chemokine with high affinity. Chemokines are classified into four subfamilies according to the pattern of conserved cysteines in their amino acid sequences. They include CC chemokines, CXC chemokines, C chemokines and CX3C chemokines. The nomenclature of the chemokine receptors follows the notation used for the chemokine subfamilies.Intracellular signaling by chemokine receptors depends on coupling to heterotrimeric G-proteins. During ligand binding, chemokine receptors associate with G-proteins, facilitating the exchange of guanosine diphosphate (GDP) for guanosine triphosphate (GTP). Activation of CXCR4 and CCR5 receptors for e.g. couple and activate Gq proteins. In the active state, G-proteins dissociate into Gα and Gβsubunits; the latter are able to activate the membrane-associated enzyme phospholipase Cβ2 which in turn results in the production of phosphatidylinositol 1, 4, 5-triphosphate (IP3) and diacyl-glycerol (DAG)). IP3 mobilizes calcium from intracellular stores, whereas DAG acts in conjunction with calcium to activate various isoforms of protein kinase C (PKC). The activation of PKC and of various calcium-sensitive protein kinases e.g. calmodulin kinase (CAMK)catalyze protein phosphorylation which triggers a series of signaling events that eventually leads to cellular responses. One such example is the PKC mediated activation of the focal adhesion kinase PYK2, which in turn triggers the mitogen activated protein kinase (MAPK) pathway, resulting in the further production of chemokines.The chemokine receptor CCR3 is activated by several ligands e.g. eotaxin, monocyte chemotactic peptide 3 (MCP-3), MCP-4, and Regulated on activation normal T cell expressed and secreted (RANTES). The ligand Eotaxin plays an important role in the inflammatory response of eosinophils involving intracellular calcium release, production of reactive oxygen species and changes in actin polymerization through pathway involving Gi proteins. The activation of PLCγ by Gi α results in the production of IP3 and DAG, which trigger RHO kinase and PKC respectively. RHO and its downstream kinase- Rho-associated coiled-coil forming protein kinase (ROCK) regulate actin stress fiber formation and are required for eosinophil chemotaxis. Activated PKC on the other hand is responsible for ROS production in eosinophils. Following CCR3 activation, extracellular signal regulated kinase (ERK) is regulated through the phosphatidylinositol 3 kinase-gamma-(PI3Kγ)/RAS/RAF-1 pathway resulting in ROS production.This pathway highlights some important molecular events involved in chemokine receptor signaling.