Current Drug Targets - Volume 7, Issue 1, 2006

In 1987, three different groups described a novel tissue derived polypeptide capable of inducing migration of neutrophils, which was then named interleukin 8. A few years later, its receptor, which belongs to the seventransmembrane domain G protein-coupled (GPC) receptor family, was identified and cloned. These were the starting points leading to the identification of at least 47 components of a new structurally related superfamily of chemotactic cytokines named chemokines, and their 18 cognate receptors. Chemokines consist of 70 to 130 amino acids with four conserved cysteines. The cysteines form two disulphide bonds which confer to the chemokines their characteristic three-dimensional folding. The disulphides keep two amino-terminal regions together that are essential for receptor recognition and biological activity. Two main subfamilies are distinguished according to the position of the first two cysteines. CXC chemokines comprise 16 molecules, characterized by two cysteines separated by one aminoacid. CXC chemokines can be subdivided in two subfamilies, i.e. those containing the glutamic acid-leucine-arginine (ELR) sequence and those that do not. In particular, CXC-ELR+ chemokines are considered the main activators of neutrophil recruitment to sites of inflammation. CC chemokines include 28 ligands characterized by adjacent cysteines. Mononuclear cells and eosinophils are the preferential targets for CC chemokines, which in turn are generally inactive on neutrophils. Two variants of the chemokine structure paradigm have been described. Lymphotactins (α and β) with only two conserved cysteines (XC), and fractalkine, a membrane-bound mucin bearing three amino acids between the first two cysteines (CX3C). To date, six CXC receptors (CXCR1-6), ten CC receptors (CCR1-10), one CX3C receptor (CX3CR1) and one C receptor (XCR1) have been described. It is now clear that cells involved in the immune response are specifically and selectively recruited at site of inflammation also by means of their chemokine receptor expression, which is determined by the activation state of the cell, and by the pattern of the tissue chemokine expression. Originally identified for their chemoattractant properties, it is becoming increasingly apparent that chemokines exhibit critical functions in many diverse developmental and immunological operations ranging from the regulation of hematopoiesis and angiogenesis to the regulation of tissue architecture and organogenesis. More strikingly, several recent reports suggest that the chemokine-chemokine receptor system is deeply involved in HIV infection regulation, in a number of systemic and organ-specific autoimmune inflammatory diseases, in atherosclerosis as well as in allergic responses, in the development and dissemination of cancer as well as the host response to the neoplastic disease. GPC receptors, including chemokine receptors, are one of the most fruitful targets for pharmacological manipulation. Thus, interfering with the chemokine-chemokine receptor system seems to be a promising therapeutic strategy for a wide spectrum of pathological states in which this system is involved. Indeed, selective antagonists have been identified for the major chemokine receptors useful for the development of drug programs, and clinical trials. In this issue, researchers involved in the study of different diseases report the most recent advances on the pathophysiology of the chemokine-chemokine receptor system as a possible rationale target for an anti-chemokine-based therapeutic approach to the disease.

In the human, chemokines represent a structurally related family of more than forty cytokines which act on distinct subsets of leukocytes via specific G protein-coupled receptors expressed on the cell surface. The induction of select repertoires of chemokines following exposure to allergen provides a biological basis for the selective leukocyte recruitment, observed both clinically and experimentally. The chemokine receptor CCR3 is expressed on the cell surface of eosinophils, Th2 lymphocytes, basophils and mast cells and binds the Eotaxin family of chemokines (CCL11, CCL24 and CCL26), whose production is upregulated following allergen challenge. Once recruited, eosinophils are a source of growth factors associated with tissue repair and remodelling and also have the ability to induce tissue damage, a capacity that extends from their traditional role in protecting the host against parasitic worms. Thus, impairment of their recruitment by selective blockade of the CCR3:eotaxin axis represents an attractive target for the therapeutic treatment of asthma. In this review, we will examine recent developments in the field and highlight the roles of other chemokine:chemokine receptor axes implicated in leukocyte recruitment during allergic inflammation.

Atherosclerosis is a chronic disease with high morbidity and mortality around the globe. It is characterized by chronic inflammation of the vessel wall, which is perpetuated by the continuous migration of cells to and within the atherosclerotic lesion. Chemokines (CK) and chemokine receptors (CKR) together with other chemoattractants and adhesion molecules are major mediators facilitating this process. Many CK/CKR (CC, CX3C and CXC) and other chemoattractants (e.g. leukotrienes) have been implicated in atherogenesis, but only a few have been validated as pathogenic by in vitro assays, in vivo experiments using gene-targeted animal models and genetic studies. Promising attempts are currently made to inhibit CK-dependent cell recruitment to lesion by using neutralizing antibodies, mutant proteins, viral and synthetic inhibitors or receptor antagonists. Some of the therapeutics have already entered clinical trials for other conditions and are about to be tested in human atherosclerosis. However, our limited understanding of the complex CK system and the functional specialization of individual CK/CKR, translatability of animal research into human population, limitations of current imaging techniques and surrogate markers for evaluation of the benefits of potential anti-CK compounds are still hampering therapeutic exploitation of the CK system in atherosclerosis. Hopefully we will be able to solve many of these issues in the near future and use this approach to control atherosclerotic disease in man.

Almost a decade ago, it was discovered that the human deficiency virus (HIV) makes use of chemokine receptors to infect blood cells. This appreciation of the clinical relevance of specific chemokine receptors has initiated a considerable boost in the field of chemokine research. It is clear today that chemokine signaling orchestrates the immune system and is widely involved in both physiological and pathophysiological processes. Since the chemokine system offers various targets through which pathology could be influenced, most pharmaceutical companies have chosen this system as a therapeutic target for a variety of diseases. Here recent developments concerning the role of chemokines in diseases of the central nervous system (CNS) as well as their possible therapeutic relevance are discussed.

The intestine is constantly challenged by food antigens and pathogens and is therefore in need of a good working innate and adaptive immune response. Chemokines are important modulators as they assure the directed movement of immune cells within the body. In addition, chemokines play an important role in hematopoiesis, angiogenesis and tumor metastasis. This review focuses on chemokines and gastrointestinal disorders, more particularly on inflammatory bowel diseases and gastrointestinal tumors. In a first part, the current knowledge on chemokine expression in inflammatory bowel diseases is summarized. Idiopathic inflammatory bowel diseases are characterized by an uncontrolled immune response. The resulting chronic inflammation of the intestine involves massive infiltration of immune cells, causing intestinal damage by the release of cytokines and proteolytic enzymes. Chemokines are believed to be key mediators in this process of aberrant leukocyte recruitment. Chemokine expression in inflammatory bowel disease strongly correlates with the grade of disease activity. The potential therapeutic use of chemokines in gastrointestinal tumors by the use of gene therapy is also reviewed. Chemokines have therapeutic potential in anti-tumor therapy by their angiostatic effect. On the other hand, chemokines can augment the cell-mediated adaptive immune response and thereby exert anti-tumor activity. However, chemokines can passively favor escape of tumor cells by stimulating the release of tissue degrading matrix metalloproteinases and can actively promote metastasis of chemokine receptor-expressing tumor cells.

Infiltrating inflammatory cells into the kidney mediate the initiation and progression of damage by direct cytotoxicity, the secretion of soluble factors such as cytokines and proteases, or by the subsequent induction of further immune response. Before leukocytes can exert their effects on renal damage or repair, they have to reach the site of injury. It has become clear in recent years that a group of small proteins called chemokines are the chemotactic cytokines considered to be the main regulators of directional leukocyte trafficking under homeostatic and inflammatory conditions. In this review, we summarize available in vivo studies on the neutralization of chemokines and chemokine receptors in renal inflammatory disease, and especially focus on the potential therapeutic effects of chemokine blockade in glomerulonephritis and renal transplantation. Although interference with chemokine expression holds great promises for the treatment of inflammatory renal diseases, it has been shown that such an approach may actually worsen in diseases under certain circumstances. This suggests that inhibition of chemokine expression and action must be time and compartment specific to provide therapeutic benefit for renal structure and function.

Chemokines are low molecular weight cytokines specialized in leukocyte recruitment. Recent studies have shown that tumor cells of hematopoietic and non hematopoietic origin express different chemokine receptors that may be involved in neoplastic cell growth, metastasis and angiogenesis. Human lymphoproliferative disorders arise from the malignant transformation of normal lymphoid cells frozen at discrete maturational stages. Studies performed with acute or chronic lymphoproliferative disorders have shown that CXCR4, the unique receptor for CXCL12, is up-regulated in many B and T cells malignancies and may be involved in metastatic localization of the neoplastic elements. Additional chemokine receptors are expressed in the individual lymphoproliferative disorders, but some of these are often non functional. Here we shall review the state of the art on chemokine receptor expression and function in human lymphoproliferative disorders, stressing the potential value of chemokines receptors as novel therapeutic targets. In this respect, small antagonistic peptides are being produced by pharmaceutical companies and hold great promise for clinical application.

Chemotactic cytokines, termed chemokines, mediate the ingress of leukocytes into the inflamed synovium. In this review, authors discuss the role of the most relevant chemokines and chemokine receptors involved in chronic inflammatory rheumatic diseases. Rheumatoid arthritis was chosen as a prototype to discuss these issues, as the majority of studies on the role of chemokines in inflammatory diseases were carried out in arthritis. However, other rheumatic diseases including systemic lupus erythematosus, systemic sclerosis, Sjogren's syndrome, mixed connective tissue disease, polymyositis/dermatomyositis, antiphospholipid syndrome and systemic vasculitides are also discussed in this context. Apart from discussing the pathogenic role of chemokines and their receptors, authors also review the regulation of chemokine production by other inflammatory mediators, as well as the important relevance of chemokines for antirheumatic therapies.

Viral infections depend on an intimate relationship between the infectious agent and the host cells. Viruses need the host cells for replication, while the innate- and adaptive- immunesystem of the host is fighting to kill the infected cell in order to clear out the pathogen and survive the infection. However, since both virus and host exist, the organisms struggle must reach an ecological equilibrium. Among the best-studied interactions between viruses and the host immune system are those between herpesviruses and their hosts. Herpesviruses are known to devote a significant part of their large genomes on immuno-modulatory genes, some encoding chemokines or chemokine receptors. These genes, which may be dispensable for viral replication in vitro, are highly important for viral growth in vivo, for viral dissemination and disease progression. Indeed, all β- and γ-herpesviruses have acquired homologs of both chemokines and chemokine receptors belonging to the 7 transmembrane (7TM) spanning, G protein-coupled receptor family. 7TM receptors are very efficient drug targets and are currently the most popular class of investigational drug targets. A notable trait for the virus encoded chemokine receptors seems to be their constitutive activity. The biological function of the constitutive activity is still unclear, but it has become clear that the receptors are involved in important parts of the viral lifecycle in vivo, and that the receptor signaling is involved in γ-herpesvirus mediated cell transformation. Therefore, blocking the signaling of these receptors will provide an efficient and highly specific way to inhibit viral replication in vivo and disease progression in the hosts.

Bacterial sepsis causes a high mortality rate when it occurs in patients with compromised host defenses. Severely burned patients, typical immunocompromised hosts, are extremely susceptible to infections from various pathogens, and a local wound infection frequently escalates into sepsis. In these patients, Staphylococcus aureus, Enterococcus faecalis and Pseudomonas aeruginosa are familiar pathogens that cause opportunistic infections. Also, polymicrobial sepsis frequently occurs in these patients. In this review, therefore, the roles of chemokines in thermally injured patients infected with these 3 pathogens and polymicrobial sepsis will be discussed. These infections in thermally injured patients may be controlled immunologically, because immunocompetent hosts are resistant to infections with these pathogens. Classically activated macrophages (M1M) are major effector cells for host innate immune responses against these infections. However, M1M are not generated in thermally injured patients whose alternatively activated macrophages (M2M) predominate. M2M appear in patients early after severe burn injuries. M2M inhibit M1M generation through the secretion of CCL17 and IL-10. As a modulator of M, two different subsets of neutrophils (PMN-I, PMN-II) are described. PMN-I direct the polarization of resident M into M1M through the production of CCL3. M2M are induced from resident M by CCL2 released from PMN-II. Therefore, as an inhibitor of CCL2, glycyrrhizin protects individuals infected with S. aureus. Sepsis stemming from P. aeruginosa wound infection is also influenced by CCL2 released from immature myeloid cells. A large number of immature myeloid cells appear in association with burn injuries. Host resistance to S. aureus, E. faecalis, P. aeruginosa or polymicrobial infections may be improved in thermally injured patients through the induction of M1M, elimination of CCL2 and/or depletion of M2M induced by CCL2.