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chemokines

Tuesday 18 November 2003

Chemokines are small peptides involved in the chemotaxis and activation of leukocytes in response to inflammation, tissue damage, or infection. Chemokine receptors belong to the superfamily of G protein-coupled receptors.

Chemokines are chemotactic cytokines that mediate inflammation. Chemokine is a short name for chemotactic cytokines. They include over 50 small molecular weight proteins consisting of 70-130 amino acids secreted by the blood cells to maintain critical functioning of these cells. All chemokines work through surface receptors known as 7 trans-membrane G-protein family of receptors.

Chemokines are a group of small (approximately 8 to 14 kD), mostly basic, structurally related molecules that regulate cell trafficking of various types of leukocytes through interactions with a subset of 7-transmembrane, G protein-coupled receptors.

The chemokines are structurally related proteins that act as chemoattractants and activators of lymphocytes and phagocytes.

Taxonomy

Chemokines are a family of small (8 to 10 kD) proteins that act primarily as chemoattractants for specific types of leukocytes. About 40 different chemokines and 20 different receptors for chemokines have been identified.

They are classified into four major groups, according to the arrangement of the conserved cysteine (C) residues in the mature proteins. Chemokines are divided into 2 major subfamilies, CXCLs and CCLs, based on the arrangement of the first 2 of the 4 conserved cysteine residues; the 2 cysteines are separated by a single amino acid in CXCLs chemokines and are adjacent in CCLs chemokines.

CXCLs chemokines are further subdivided into ELR and non-ELR types based on the presence or absence of a glu-leu-arg sequence adjacent and N terminal to the CXC motif. ELR types are chemotactic for neutrophils, while non-ELR types are chemotactic for lymphocytes.

CXCLs

The majority of the alpha chemokines (CXCLs), which includes IL8 (MIM.146930), target neutrophils, while the beta family members (CCLs) act largely upon monocytes.

- C-X-C chemokines (also called α chemokines) have one amino acid residue separating the first two conserved cysteine residues. The C-X-C chemokines act primarily on neutrophils. IL8 is typical of this group. It is secreted by activated macrophages, endothelial cells, and other cell types and causes activation and chemotaxis of neutrophils, with limited activity on monocytes and eosinophils. Its most important inducers are microbial products and other cytokines, mainly IL1 and TNF.

- C-C chemokines (also called β chemokines) have the first two conserved cysteine residues adjacent. The C-C chemokines, which include monocyte chemoattractant protein (MCP-1), eotaxin, macrophage inflammatory protein-1α (MIP-1α), and RANTES (regulated and normal T cell expressed and secreted), generally attract monocytes, eosinophils, basophils, and lymphocytes but not neutrophils. Although most of the chemokines in this class have overlapping properties, eotaxin selectively recruits eosinophils.

- C chemokines (also called γ chemokines) lack two (the first and third) of the four conserved cysteines. The C chemokines (e.g., lymphotactin) are relatively specific for lymphocytes.
CX3C chemokines contain three amino acids between the two cysteines. The only known member of this class is called fractalkine. This chemokine exists in two forms: the cell surface-bound protein can be induced on endothelial cells by inflammatory cytokines and promotes strong adhesion of monocytes and T cells, and a soluble form, derived by proteolysis of the membrane-bound protein, has potent chemoattractant activity for the same cells.

Chemokines receptors

Chemokines mediate their activities by binding to seven transmembrane G-protein-coupled receptors. These receptors (called CXCR or CCR, for C-X-C or C-C chemokine receptors) usually exhibit overlapping ligand specificities, and leukocytes generally express more than one receptor type.

Certain chemokine receptors (CXCR-4, CCR-5) act as coreceptors for a viral envelope glycoprotein of human immunodeficiency virus (HIV-1) and are thus involved in binding and entry of the virus into cells.

Functions

Chemokines play fundamental roles in the development, homeostasis, and function of the immune system, and they have effects on cells of the central nervous system as well as on endothelial cells involved in angiogenesis or angiostasis.

Chemokines stimulate leukocyte recruitment in inflammation and control the normal migration of cells through various tissues. Some chemokines are produced transiently in response to inflammatory stimuli and promote the recruitment of leukocytes to the sites of inflammation. Other chemokines are produced constitutively in tissues and function in organogenesis to organize different cell types in different anatomic regions of the tissues. In both situations, chemokines may be displayed at high concentrations attached to proteoglycans on the surface of endothelial cells and in the extracellular matrix.

Members

CXCLs CCLs CCRs

See also:

- chemokine receptors

References

- Charo IF, Ransohoff RM. The many roles of chemokines and chemokine receptors in inflammation. N Engl J Med. 2006 Feb 9;354(6):610-21. PMID: 16467548

- Guerau-de-Arellano M, Huber BT. Chemokines and Toll-like receptors in Lyme disease pathogenesis. Trends Mol Med. 2005 Mar;11(3):114-20. PMID: 15760769

- Balkwill F. Cancer and the chemokine network. Nat Rev Cancer. 2004 Jul;4(7):540-50. PMID: 15229479

- Dong VM, McDermott DH, Abdi R. Chemokines and diseases. Eur J Dermatol. 2003 May-Jun;13(3):224-30. PMID: 12804978

- Segerer S, Alpers CE. Chemokines and chemokine receptors in renal pathology. Curr Opin Nephrol Hypertens. 2003 May;12(3):243-9. PMID: 12698061

- Filippatos G, Parissis JT, Adamopoulos S, Kardaras F. Chemokines in cardiovascular remodeling: clinical and therapeutic implications. Curr Mol Med. 2003 Mar;3(2):139-47. PMID: 12630560