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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.
| Disease States | Site | Chemokine |
| 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 |
| Osteoarthritis | Synovial Fluid | MIP-1B |
| 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 |
| Immune Complex
Glomerulonephritis |
Tissue | IL-8, MCP-1 |
| Uveoretinitis | Tissue | IL-8, IP-10, MCP-1, Rantes, MIP-1A/B |
| Tuberculoid Leprosy | Tissue | IP-10 |
| Post-Major Surgery | Plasma | IL-8 |
| Wound Healing Site | Tissue | MCP-1 and IP-10 |
| Cytomegalovirus
Encephalomyelitis |
Cerebrospinal Fluid | MCP-1 |
| 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.
REFERENCES:
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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