Chemokines

Definition
Chemokines are a family of small cytokines that have the ability to induce chemotaxis in nearby responsive cells1. Proteins are classified as chemokines according to shared structural characteristics such as small size (approximately 8-10 kDa), and the presence of four cysteine residues in conserved locations that are key to forming their 3-dimensional shape1.

Discovery
Platelet Factor 4 was the first chemokine to be identified in 19742. It was first identified in serum from clotted monkey blood which had the ability of promoting growth of arterial smooth muscles in culture2.

Classification
Chemokine family is classified into four groups: CC, CXC, C and CX3C chemokines. The classification is based on differences in their structural characteristics3.

Structural Characteristics
The CC chemokines have 3-4 cysteines with 2 adjacent cysteines situated near their N terminus3. CXC chemokines also have two cysteines at their N terminus but they are separated by an amino acid3. C chemokines have only one cysteine at their N terminus, the other one being present downstream in their sequence3. The last family of chemokines, CX3C has three amino acids between the N terminal cysteines3.

Mode of action
Chemokines bind to chemokine receptors that activate G proteins which in turn activate the enzyme, Phospholipase C (PLC) 4. PLC cleaves a molecule called phosphatidylinositol (4,5)-bisphosphate into two second messenger molecules known as Inositol triphosphate (IP3) and diacylglycerol (DAG) that trigger intracellular signaling events; DAG activates another enzyme called protein kinase C (PKC), and IP3 triggers the release of calcium from intracellular stores4. These events promote many signaling cascades (such as the MAP kinase pathway) that generate responses like chemotaxis, degranulation, release of superoxide anions and changes in the avidity of cell adhesion molecules called integrins within the cell harbouring the chemokine receptor5.

Functions
Chemokines act as a chemoattractant to guide the migration of cells such as directing lymphocytes to the lymph nodes so they can screen for invasion of pathogens by interacting with antigen-presenting cells residing in these tissues. Chemokines also promote angiogenesis or guide cells to tissues that provide specific signals critical for cellular maturation6. Other chemokines are inflammatory and are released from a wide variety of cells in response to bacterial infection, viruses and agents that cause physical damage such as silica or the urate crystals that occur in gout3. Their release is often stimulated by pro-inflammatory cytokines such as interleukin1. Inflammatory chemokines function mainly as chemoattractants for leukocytes, recruiting monocytes, neutrophils and other effector cells from the blood to sites of infection or tissue damage7. Certain inflammatory chemokines activate cells to initiate an immune response or promote wound healing. They are released by many different cell types and serve to guide cells of both innate immune system and adaptive immune system7. Inappropraite activation of chemokine network is associated with several diseases such as cardiovascular disease, allergic inflammatory disease, transplantation, neuroinflammation, cancer and HIV-associated disease8.

References
1.Laing K, Secombes C (2004). Chemokines. Dev Comp Immunol., 28 (5), 443–60.
2.Ross R, Glomset J, Kariya B, Harker L (1974). A platelet-dependent serum factor that stimulates the proliferation of arterial smooth muscle cells in vitro. Proc Natl Acad Sci U S A, 71(4), 1207-10.
3.Fernandez E, Lolis E (2002). Structure, function, and inhibition of chemokines. Annu Rev Pharmacol Toxicol., 42, 469–99.
4.Lodowski DT, Palczewski K (2009). Chemokine receptors and other G protein-coupled receptors. Curr Opin HIV AIDS, 4(2):88-95.
5.Craig Murdoch and Adam Finn (2000). Chemokine receptors and the role in inflammation and infectious disease. Journal of the American Society of Hematology, 95 (10), 3032–3043.
6.Vindrieux D, Escobar P, Lazennec G (2009). Emerging roles of chemokines in prostate cancer. Endocr Relat Cancer, [Epub ahead of print].
7.Bajetto A, Bonavia R, Barbero S, Florio T, Schettini G (2001). Chemokines and their receptors in the central nervous system. Front Neuroendocrinol, 22(3):147-84.
8.Gerard C & Rollins BJ (2001). Chemokines and disease. Nature Immunology, 2, 108 – 115.