Chemokines are small cell signalling molecules secreted by certain cells in the presence of infective bodies such as bacteria or viruses. These chemokines induce the migration of immune cells, which target the invasive body through a variety of mechanisms.
The process by which activated immune cells move towards a site of infection is called chemotaxis, that is the movement of cells in response to chemicals in their surrounding environment. Chemokines are therefore chemotactic cytokines.
Chemokines are small molecules with a molecular weight of around 8 to 10 kilodaltons. They also share a similar structure and contain cysteine residues that determine their three dimensional shape.
Chemokines bind to chemokine receptors, which are part of the family of G protein-coupled receptors. These transmembrane (spanning the inside and outside of the membrane) receptors are coupled to the G-protein which lies inside the cell and induces signal transduction pathways when it is activated. The chemokine receptors are predominantly expressed on the surface of white blood cells.
Once various immune cells are stimulated by chemokines, they act in several ways including migrating towards the site of infection, activating integrins, releasing the contents of their granules and generating superoxide anions that can destroy invading microbes.
The chemokines are divided into four subfamilies based on the type of chemokine they bind to. These include:
- CCR - binds to CC chemokines
- CXCR - binds to CXC chemokines
- CX3CR1 - binds to the CX3C chemokine
- XCR1- binds to the XC chemokines, XCL1 and XCL2
Structural similarities and differences between chemokine receptors
Around 19 types of chemokine receptor have been identified to date and they are made up of around 350 amino acids. These amino acids are divided into a short extracellular N-terminus, seven transmembrane helical domains, six hydrophilic loops (three that lie outside the cell and three inside), and an intracellular C-terminus which has serine and threonine residues as phosphorylation sites for activation.
The N-terminus of the receptor is bound specifically by chemokines and the G-protein, which induces cell signalling after binding has occurred, is coupled to the receptor at the C-terminus.
The association of the chemokine receptor with the G-protein leads to a chain of events that results in the activation of an enzyme called phospholipase C (PLC).
PLC then cleaves a molecule called phosphatidylinositol (PIP2) to form two messenger molecules - inositol triphosphate (IP3) and diacylglycerol (DAG). DAG activates protein kinase 3 and IP3 induces the release of calcium from stores within the cell.
Together, these events initiate intracellular signalling pathways that lead to cellular responses such as chemotaxis, degranulation, superoxide anion release and alterations in cell adhesion molecules.