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Chemokines: BACKGROUND INFORMATION
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During the late 1960's and 1970's, supernatants from cultures of stimulated leukocytes were shown to contain chemoattractants for monocytes and granulocytes. Over the past twelve years, many of these chemoattractants and their receptors have been purified and/or molecularly clones (as reviewed in 1-3). This has revealed an expanding family of homologous chemotactic cytokines now known as chemokines. The chemokines are 8-16 kDa soluble proteins produced and released by a wide variety of cell types during the initial phase of host response to injury, allergens, antigens, or invading microorganisms. They selectively attract leukocytes to inflammatory foci, inducing both cell migration and activation. Based upon the positioning of their cysteine residues, the chemokines have been classified into the ALPHA (C-X-C), the Beta (C-C), and the GAMMA (C) subgroups. The a chemokines have a single amino acid inserted between the first and second of their four cysteine residues, whereas these cysteines are not separated in the B group. The gamma (C)chemokines have only one pair of cysteines.
The mechanism of chemokine action involves initial binding to specific seven transmembrane spanning G protein-linked receptors on target cells. To date, four different such receptors have been identified for the a chemokines (CXCR1-4) and five for the B chemokines (CCR1-5). The interaction of chemokines with these G protein-linked receptors causes a rapid reconfiguration of adhesion proteins, such as B integrins, on the surface of the respond-ng cells, facilitating their adhesion to endothelial cells (EC) lining blood vessel walls. This adhesion is followed by leukocyte transmigration between the EC into the tissues. Once there, the inflammatory leukocytes migrate along a gradient of increasing concentration of the chemokine to the site of origin. In response to the higher chemokine concentration at the site of injury or microbial invasion, the leukocytes are activated to perform effector functions such as release of their granule contents and increased production of cytokines.
The central role of chemokines in inflammatory reactions has been demonstrated by numerous studies. Local administration of a chemokines, e.g., IL-8, by subcutaneous injection results in acute inflammatory reactions which are dominated by neutrophil infiltration. A more delayed mononuclear cell infiltration occurs in response to B chemokines, such as MCP-1, RANTES, and MIP-1a. On the other hand, suppression of chemokines by treatment with neutralizing antibodies has been shown to reduce inflammatory responses. Neutralizing antibodies to IL-8 suppress acute inflammatory reactions due to reperfusion injury, endotoxin-induced arthritis, endotoxin-provoked subcutaneous inflammation, and acute glomerulonephritis (4). Anti-IL-8 also has been shown to reduced delayed -type hypersensitivity reactions (5). Antibodies to MIP-1a reduce the severity of experimental autoimmune encephalomyelitis (EAE) in mice. Additionally, deletion of the MIP-1a gene in mice reduces the severity of post-Coxsackie-induced myocarditis, but also decreases the resistance of such mice to influenza infection (6), implying that MIP-1a may promote antiviral host defenses.
Chemokines have been detected in local tissues or bodily fluids by immunohistochemical or enzyme-linked immunoassay techniques, respectively, in a wide variety of inflammatory conditions, as shown in Table A.
|Cystic Fibrosis||Lavage Fluid||IL-8, ENA-78, MCP-1|
|Acute Pulmonary Diseases||Tissue||IL-8, ENA-78, MCP-1, Rantes|
|Asthmatic Reactions||Lavage Fluid||MCP-1, MIP-1A, Rantes|
|Endotoxemia and Sepsis||Plasma||IL-8, MIP-1A, MCP-1, Rantes|
|Rheumatoid Arthritis||Synovial Fluid||IL-8, ENA-78, MCP-1, MIP1 alpha|
|Psoriatic Scale||Tissue Extract||IL-8, GROa,B,G, MCP-1, IP-10, ENA-78|
|Gastrointestinal Inflammation||Tissue||IL-8, MCP-1, MIP1A/B, Rantes, IP-10|
|Arteriosclerosis||Tissue||MCP-1, MIP1A/B, Rantes, IL-8, GROB|
|Uveoretinitis||Tissue||IL-8, IP-10, MCP-1, Rantes, MIP-1A/B|
|Wound Healing Site||Tissue||MCP-1 and IP-10|
|Atopic and Contact Dermatitis||Tissue||Rantes, Eotaxin, IL-8, MCP-1, IP-10|
In addition to being proinflammatory messengers, chemokines have other vital biological effects. For example, IL-8 has been shown to stimulate the proliferation of endothelial cells and promote vascularization, whereas IP-10, MIG, and PF-4 are angiostatic (7) suggesting that chemokines contribute to tissue remodeling and wound healing. Tumors transfected with RANTES and iP-10 have been shown to regress with the subsequent development of tumor immunity. A number of B chemokines have beem shown to have immunoenhancing effects by acting as co-stimulants of lymphocyte cytolysis, proliferation, and cytokine production (8). They also have been shown to be chemotactic for antigen-presenting dendritic cells and to increase their capacity to activate T cells.
Recently, it has been reported that a cocktail of the B chemokines MIP-1a, MIP-1B, and RANTES increases the resistance of cultured CD4+T lymphocytes to infection by HIV-1 (9). Conversely, antibodies to these chemokines promote the in vitro spread and replication of HIV-1.
Receptors for some of the chemokines, namely CCR5 and fusin (CX-CR3), and to a lesser extent CCR3 and CCR2B, have been reported to act as coreceptors along with CD4 for the entry of HIV-1 into human T cells and monocytes (10,11). The chemokines are thought to competitively block entry of HIV-1 in a passive manner by binding to the chemokine receptor. This view is supported by experiments showing that pertussis toxin, which blocks signal transduction by such receptors, does not interfere with the inhibitory effect of the chemokines. Consequently, chemokines, by displacing HIV-1, interfere with the cell-to-cell spread of the virus and provide potential therapeutics for AIDS patients. It is also reasonable to propose that chemokine antagonists that do not initiate signal transduction may competitively inhibit the spread of HIV-
1. Administration of such antagonists would avoid the potentially toxic side effects of chemokines. All in all, the field of chemokine research is deservedly flourishing. Scientists from an everincreasing number of disciplines have been attracted by this family of molecules. More chemokines and receptors are still in the pipeline and more discoveries are yet to be made.
1. Baggiolini, M. et al., Adv. Immunol. 55,97-179 (1994).
2. Ben-Baruch, A. et al., J. Biol.Chem. 270, 11703-11706 (1995).
3. Murphy, P.M., Cytokine and Growth Factor Reviews 7, 47-64,(1996).
4. Harrada, A. et al., J. Leuk. Biol. 56,559-564 (1994).
5. Larsen, C.G., et al., J.Immunol. 155,2141-2157 (1995).
6. Cook, D.N.,J. Leuk. Biol. 59, 61-67 (1996).
7. Streiter,R.M. et al., J. Leuk.Biol. 58, 752-763 (1995).
8. Taub, D.D. et al., J. Leuk. Biol. 59,81-90 (1996).
9. Cocchi,F. et al., Science 270, 1811-1815 (1995).
10. Feng, Y. et al., Science 272,872-877 (1996).
11. Liu, R. et al., Cell 86, 367-377 (1996).2-
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