What are Chemokines?

Chemokines are chemotactic cytokines which play a crucial role in immune and inflammatory reactions and in viral infection. They are approximately 8 to 11 kilodaltons (kD) in molecular weight and are active over a 1 to 100 ng/ml concentration.

Chemokines are produced by a wide variety of cell types. The production of chemokines is induced by exogenous irritants and endogenous mediators such as IL-1, TNF- a, PDGF, and IFN-a.

Their name chemokines is derived from their ability to induce directed chemotaxis in nearby responsive cells. They attract and activate leukocytes and regulate diverse cellular systems and organs ranging from blood vessels to the central nervous system.

Some chemokines are considered pro-inflammatory and can be induced during an immune response to promote cells of the immune system to a site of infection, while others are considered homeostatic and are involved in controlling the migration of cells during normal processes of tissue maintenance or development.

Chemokines are found in all vertebrates, some viruses and some bacteria, but none have been described for other invertebrates. These proteins exert their biological effects by interacting with G protein-linked transmembrane receptors called chemokine receptors that are selectively found on the surfaces of their target cells.

Interaction between the chemotactic factor and its corresponding receptor triggers a series of coordinated biochemical events which include changes in the cell transmembrane potential, altered cyclic nucleotide levels and ion flow across the cytoplasmic membrane and increased glucose utilization and oxygen consumption.

The composition of membrane phospholipids is altered and arachidonic acid released by phospholipases, is metabolized into a number of biologically active intermediates and products.

Within a few minutes, the leukocyte changes its shape that is oriented along the direction of chemotactic gradient. Reorganization of cytoskeletal contractile elements, particularly actin microfilaments and microtubular structures, contributes to the change in shape.

The amino acids such as cysteines that are important for creating three dimentional tertiary structures are conserved in all chemokines. All the chemokine molecules share 20-50% structural similarities, including four conserved cysteine residues which form disulphide bonds in the tertiary structure of the proteins.

The first two cysteines are situated near the N-terminal end of the mature protein, the third cysteine resides in the centre of the molecule and the fourth is in C-terminal end.

Approximately 50 human chemokines that are known segregate into four families on the basis of differences in structure (especialy on the spacing of their first two cysteine residues) and function. They are as follows:

(1) CC chemokines:

The largest family of chemokines is named as “CC chemokines” due to the presence of first two of the four cysteine residues in adjacent position to each other. About 27 distinct members of this subgroup have been reported in mammals.

A small number of CC chemokines possess six cysteine amino acids instead of four. CC chemokines attract mononuclear cells to the site of chronic inflammation.

The most thoroughly characterized CC chemokine is monocyte chemoattractant protein 1 (MCP-1), termed as “chemokine ligand or CCL2” in the systematic nomenclature. It is a potent agonist for monocytes, dendritic cells, memory T cells, and basophils.

Other CC chemokines include macrophage inflammatory protein-1 alpha (MlP-la) (CCL3), MIP-1-beta (CCL4) and RANTES (CCL5).

(2) CXC chemokines:

The second family CXC chemokines consists of a single amino acid residue between the first two canonical cysteines. The letter “X”represent the amino acid present between the two cysteines. 17 different CXC chemokines have been described in mammals and are subdivided into two categories based on the presence of specific amino acid sequence “glutamic acid- leucine-arginine” or ELR for short before the first cysteine.

ELR-positive CXC chemokines eg. Interleukin-8 (CXCL8) specifically induces neutrophils to leave the bloodstream and enter into the surrounding tissue. Other CXC chemokines that lack the ELR e.g. interleukin-13 (CXCL13) tend to be chemoattractant for lymphocytes.

The prototype CXCL8 also activates monocytes and may direct the recruitment of these cells to vascular lesions.

(3) C chemokines:

The third group of chemokines is known as the C chemokines (or chemokines). Unlike all other chemokines the C (gamma) subfamily lacks the first and third cysteine residues.

Lymphotactin (also known as SCM-1 alpha) and SCM-1 beta are currently the only two family members. Both have chemotactic activity for lymphocytes and NK cells.

(4) CX3C chemokines:

The fourth group of chemokines have three amino acids between the two cysteines hence it is termed as ‘CX3C chemokine” or “d-chemokines”.

The only CX3C chemokine discovered to date is fractalkine or CX3CL1. It is both secreted and tethered to the surface of the cell that expresses it, thereby serving as both a chemoattractant and as an adhesion molecule.

Within the fascinating world of chemokines, C and CX3C chemokines have long been regarded as two minor components, even though they present unique features and show less redundancy than the other chemokine families.

Nevertheless, the body of data on their expression and role in various inflammatory disorders has grown in the past few years.