Chemokines are a family of pro-inflammatory activation-inducible cytokines, or small secreted protein signals. Chemokines induce directed chemotaxis in nearby responsive cells, hence the name chemotactic cytokines. Former names for these proteins include SIS family of cytokines, SIG family of cytokines, SCY family of cytokines, Platelet factor-4 superfamily or Intercrines.
Chemokines 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 gout. They function mainly as chemoattractants for leukocytes, recruiting monocytes, neutrophils and other effector cells from the blood to sites of infection or damage. They can be released by many different cell types and serve to guide cells involved in innate immunity and also the lymphocytes in adaptive immunity. Some chemokines also have roles in the development of lymphocytes, migration and angiogenesis (the growth of new blood vessels.
Members of the chemokine family fall mostly into two broad groups-CC chemokines (or β-chemokines) with two adjacent cysteines near the amino terminus of the protein, and CXC chemokines (or α-chemokines) in which the cysteines are separated by an amino acid. The two groups of chemokines act on different receptors. CC chemokines bind to CC chemokine receptors, of which nine have been discovered to date, designated CCR1-9. CXC chemokines bind to CXC chemokine receptors, of which five have been discovered to date, designated CXCR1-5. These receptors are expressed on the surface of different cell types. CXC chemokines which have a specific amino acid sequence (or motif) of Glutamic acid-Leucine-Arginine (or ELR for short) immediately before the first cysteine induce the migration of neutrophils. An example of this is interleukin-8 (IL-8) which induces neutrophils to leave the bloodstream and enter into the surrounding tissue.
Other CXC chemokines which lack the ELR motif, such as the B-lymphocyte chemokine are chemoattractant for lymphocytes. CC chemokines induce the migration of monocytes and other cell types such as NK cells and dendritic cells. An example of a CC chemokine is monocyte chemoattractant protein-1 (MCP-1) which induces monocytes to leave the bloodstream and enter the surrounding tissue, becoming tissue macrophages. The only known chemokine with only one cysteine is lymphotactin and is thought to attract T cell precursors to the thymus. Its family is known as the C chemokines (or γ-chemokines). A fourth group has also been discovered and members have three amino acids between the two cysteines and is termed CX3C chemokine (or δ-chemokines). The only CX3C chemokine discovered to date is called 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.
The discovery that the β chemokines RANTES, MIP (macrophage inflammatory proteins) 1α and 1β (now known as CCL5, CCL3 and CCL4 respectively) suppress HIV-1 provided the initial connection and indicated that these molecules might control infection as part of immune responses in vivo.() The association of chemokine production with antigen-induced proliferative responses, more favorable clinical status in HIV infection, as well as with an uninfected status in subjects at risk for infection suggests a positive role for these molecules in controlling the natural course of HIV infection. ()
Chemokines and innate immunity
Rev Immunogenet. 2000;2(3):339-58. Matsukawa A, Hogaboam CM, Lukacs NW, Kunkel SL.
- Our environment contains a great variety of infectious microbes that may be potentially destructive and threaten our survival. As soon as microbes try to establish a site of infection, the host launches a complex defense system. Innate immunity is a non-specific response and serves as the first-line of defense where phagocytes, such as neutrophils and macrophages, and NK cells play central roles in neutralizing and clearing microorganisms. Thus, migration of cells into infectious foci and subsequent activation of these cells appear to be a critical step, enabling the host to achieve effective and efficient removal of microbes. Over the past decade, chemokines have been identified as chemotactic cytokines that attract and activate specific types of leukocyte populations in vitro. There is now evidence that the magnitude of chemokines' expression in infectious diseases is strongly associated with the severity of the inflammatory responses. Blocking chemokines or their receptors with neutralizing antibodies or gene targeting technology has allowed us to understand the pathological significance of chemokines in animal models of infectious diseases. Growing evidence suggests that chemokines play an important beneficial role in immune system development, homeostasis and in innate immunity, which may pave the way for new therapeutic strategies for the treatment of infectious diseases.