In inflammatory diseases, the inflammatory stimuli that induce chemokine expression can vary widely and include viral and bacterial pathogens and toxic chemicals. Chemokines that are released by resident tissue cells and cells of the vessel wall are responsible for inducing the strong adhesive, integrin-mediated interactions between marginating leukocytes and the endothelium. Adherent leukocytes will migrate through the endothelial cell layer, and will be attracted to the inflammatory site by a chemokine gradient which has been established within the inflammed tissue. Initially, this process is a protective one, causing only minimal damage in the interests of clearing up the infection or irritant. However, this immune response can become an overwhelming attack on healthy tissue, contributing to the damage that is seen in a wide range of inflammatory diseases.

The chemokines that is expressed in diseased tissue will dictate the type of inflammatory infiltrate that characterizes a specific inflammatory disease. Most evidence for this has been from indirect experiments that document chemokine overexpression in affected tissues. More recently, however, scientists have begun using genetically-altered animal models to determine if chemokine expression is actually directly responsible for any of the manifestations of inflammatory diseases.

Chronic Inflammatory Disease

The ability of the chemokines to attract specific leukocyte subsets to sites of disease may contribute to the nature and chronicity of the response. For example, in many acute diseases such as bacterial pneumonia and viral or bacterial meningitis, there is a characteristic early, massive influx of neutrophils into the affected host tissue. This event correlates with a sharp increase in the CXC chemokines IL-8 , MIP-2, and GROα, in the bronchoalveolar fluid and cerebrospinal fluid, respectively. Alternatively, tissue infiltration by lymphocytes and macrophages occurs more frequently in many chronic diseases, and is usually associated with an increase in CC chemokine expression. For example, MCP-1 expression is increased in human atheromatous plaques which are primarily composed of lipid-laden macrophages. Similarly, CC chemokines are implicated in the establishment of chronic inflammation in several autoimmune diseases, such as rheumatoid arthritis and glomerulonephritis. Additionally, some CC chemokines such as eotaxin and MCP-4 are potent activators of eosinophils and mast cells, which are important components of allergic inflammation, such as that seen in asthma. Finally, some inflammatory diseases, including ulcerative colitis and Crohn’s disease, are traditionally characterized by a chronic inflammation typically associated with MCP-1 production, but have periodic acute inflammatory exacerbations associated with increased IL-8 and ENA-78 production.

Infectious Disease

Chemokines and chemokine receptors probably evolved as antimicrobial factors due to their ability to incite an inflammatory reaction that ultimately eradicates pathogens from infected tissues. However, there are two other known situations where chemokines and chemokine receptors are involved in infectious disease. First, intracellular pathogenic agents exploit chemokine receptors for cell entry in order to gain access to the cytoplasm and nucleus of cells. Secondly, certain DNA viruses are known to encode chemokine and/or chemokine receptor-like molecules that are used in an effort to evade host antiviral attacks.

At present, there are at least two known examples of chemokine receptors used as pathogen receptors for host cell entry. The malarial parasite, Plasmodium vivax, binds to DARC to gain entry into human erythrocytes, and interestingly, the existence of an inactivating mutation in DARC confers a high level of resistance to malaria. Likewise, HIV-1 binds to several chemokine receptors, in addition to CD4, to gain entry into T-cells and macrophages, and it has been shown that individuals who display polymorphic variants of certain chemokine receptors are somewhat resistant to HIV-1 infection. The link between pathogenesis of HIV-1 and chemokine receptors was made in 1995, when it was discovered that chemokine receptors are the sole factors that determine HIV-1 tropism. Although some clinical isolates are dual-trophic, in general, CXCR4 is a coreceptor for T- cell-trophic strains of HIV-1, and CCR5 is a coreceptor for HTV-1 isolates that infect macrophages as well as activated T-cells later in the course of infection. RANTES, MIP-lα , and MIP-1β, which are CCR5 ligands, and SDF-1, a CXCR4 ligand, block the entry of HTV-1 into macrophages and T-cells, respectively. Similar to the relationship between DARC and P. vivax,there is a mutant allele in the CCR5 gene that confers resistance to macrophage-trophic HIV-1 infection. This mutation in CCR5 is a 32-base-pair deletion in the ORF, which encodes a truncated, inactive receptor. Persons who are homozygous for this CCR5 mutation are not found in HIV-1 positive cohorts, even among those who are considered at high-risk for HIV-1 infection. Furthermore, individuals who are heterozygous for the above-mentioned CCR5 mutation have a mean two-year delay in the rate of progression to AIDS.

A number of viruses have actually copied host chemokine and chemokine receptor genes into their genome in order to subvert host defenses and to allow for easy replication in host cells. Several viral chemokine receptor genes have been discovered including: US-27, US-28, and UL-33, all encoded by human cytomegalovirus; ECRF3, encoded by the squirrel monkey Herpesvirus saimiri; ORF-74, encoded by Kaposi's sarcoma herpesvirus (KSHV); and K2R ORF of the swinepox virus. These virally encoded receptors often exhibit superior binding and signaling properties compared to the human receptor analogs. It is believed that by expression of these viral chemokine receptor-like molecules, modifies the internal environment of the host cell by increasing binding of chemokines by causing increased activation of signal transduction pathways which can prevent apoptosis and allow for continued replication of the virus. Additionally, these receptors may act as a decoy, binding the chemokines that are being produced locally by the infected cell. This process can inhibit the inflammatory process by delaying recruitment of T cells and other leukocytes. There are also a number of known virally encoded chemokine homologues, including vMIP-l and vMIP-II, from KSHV, and MCI48 from the poxvirus Molluscum contagiosum. These viral chemokines can act as potent chemokine antagonists that are able to block lymphocyte activation and migration in vitro.

Atherosclerosis

Atherosclerosis is a complex, multifactorial disease of large and medium-sized elastic and muscular arteries that can lead to a variety of clinical manifestations, including: peripheral vascular disease, coronary artery disease, and stroke. Throughout this century, cardiovascular disease has been the leading killer in the United States every year but 1918, and currently it is responsible for approximately 42% of all deaths annually. By age 60,1 in 3 men and 1 in 10 women can expect to develop some major form of cardiovascular disease. Additionally, cardiovascular disease is the principal cause of death in both Europe and Asia. Many factors can clearly impact the progression of atherosclerosis and cardiovascular disease, including smoking, hypertension, physical inactivity, hypercholesterolemia, obesity, and diabetes. Many current treatments are aimed at the primary and secondary prevention of cardiovascular disease by control of these associated, independent risk factors.

The role of the chemokines in atherosclerosis has been the focus of research for many laboratories. This interest was initiated because of the ability of the chemokines to selectively recruit mononuclear leukocytes of the type that have traditionally characterized the chronic inflammatory lesions of atherosclerosis. This interest has continued and the paradigm has been expanded more recently due to the ability of the chemokines to stimulate the migration, growth, and activation of multiple cell types present within the atherosclerotic lesion, including endothelial cells, vascular smooth muscle cells, and fibroblasts. The mechanism of chemokine involvement in atherosclerosis begins with the minimal oxidation of plasma LDL that has been trapped in the subendothelial arterial space. This minimally oxidized LDL (mm-LDL) can then induce the production of MCP-1, IL-8 and possibly other chemokines by the overlying endothelial cells and the underlying smooth muscle cells. Proinflammatory cytokines, such as IL-1, IL-13 and TNFα can also induce MCP-1 and IL-8 production by endothelial cells and smooth muscle cells of the vessel wall. The locally produced chemokines are then able to induce leukocyte integrin expression, while other cytokines simultaneously induce expression of the complementary adhesion proteins on the endothelial cells, both of which events are required for the subsequent adhesion and transendothelial migration of peripheral blood monocytes. Once inside the intimal space of the vessel wall, the monocytes differentiate to macrophages, and release reactive oxygen intermediates and aldehydes that will further oxidize the LDL to a highly modified form which can be recognized by macrophage scavenger receptors. This process ultimately results in the collection of lipid-laden macrophages, or foam cells, and the formation of an initial fatty streak. The presence of high levels of HDL or antioxidants can prevent the formation of the biologically active minimally modified-LDL, which significantly reduces the resultant inflammatory reaction. Chemokines such as IL-8 and GROα may further contribute to the process of atherogenesis in later stages of atheroma formation by stimulating the proliferation of endothelial cells, and by promoting chemotaxis of smooth muscle cells and certain T- lymphocyte subsets (CD8+).

Monocyte-derived macrophages constitute the predominant cells of the initial fatty streak lesions of atherosclerosis, and appear to be essential for atherogenesis. The macrophage is the only cell type that is present and active in atherosclerotic lesions at all stages of lesion development. While many CC chemokines could potentially mediate this monocyte/macrophage recruitment and activation, most published evidence to date supports the notion that atherogenic macrophage movement is mediated by MCP-1. In 1991, Navab et al.demonstrated that incubation of human vascular smooth muscle cells with aortic endothelial cells in the presence of LDL results in increases in MCP-1 mRNA, MCP-1 protein levels, and a seven-fold increase in the transmigration of monocytes to the subendothelial space of the coculture. They further showed that the addition of HDL to the coculture system reduced the monocyte transmigration by 91%, Others have shown more recently that the receptor for MCP-1, CCR2, is also upregulated in human monocyte cultures containing LDL. In addition to LDL, pro-atherogenic cytokines, such as TNF-α, can also increase MCP-1 mRNA expression by cells of the vessel wall in culture. In vivo, MCP-1 has been detected in macrophage-rich areas of human, rabbit, and primate atherosclerotic lesions by RT-PCR, Northern blot, Western blot, immunohistochemical analysis, and in situ hybridization techniques. In addition, monocyte CCR2 gene expression is dramatically increased in hypercholesterolemic patients when compared to normocholesterolemic patients.

Chemokines and Influenza A

The hallmark of pulmonary inflammation following influenza A infection is the recruitment, migration and activation of leukocytes. This cell-mediated immunity involves natural killer cells, dendritic cells, activated macrophages and various populations of T-lymphocytes. While the importance of proinflammatory cytokines, such as TNFα, IL-l, IL-6 and IFNγ, has been well established, little attention has focused until recently on the role of chemotactic cytokines, or chemokines, in the mononuclear leukocyte response to influenza infection. CC chemokines preferentially attract monocytes/macrophages and distinct populations of T lymphocytes, and in turn, these cells become biologically relevant sources of chemokines. Therefore, chemokines are likely the molecules that are responsible for the selective tissue recruitment of leukocytes that occurs after influenza infection. Further, chemokines are also likely responsible for the trafficking of T-lymphocytes into regional lymph nodes that occurs during the immune response to influenza infection.

The first evidence confirming the importance of chemokines in influenza infection was provided by Cook et al.in 1995. In these experiments, MIP-1α deficient mice infected with the influenza A virus developed significantly less pulmonary edema and a significantly reduced mononuclear cell infiltration at necropsy than did infected age-matched control mice. Furthermore, the MIP-1α deficient mice had increases in viral titers altogether suggesting that MIP-1α may be responsible for the recruitment of T-lymphocytes into infected lungs, which is required for viral clearance. More recently, a number of in vitro experiments have identified other CC chemokines that may be important in the cellular response to influenza virus infection. In culture, influenza A virus infection of human monocytes results in rapid and marked increases in both mRNA and protein levels of CC chemokines MCP-1, MIP-1α, MIP-1β, RANTES and IP-10, and suppression of other CXC chemokines. Additionally, RANTES protein and mRNA was detected in the media of cultured human bronchial epithelial cells infected with influenza A virus.

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