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Current
Drug Targets
ISSN: 1389-4501
Current Drug Targets
Volume 7, Number 1, January 2006
Contents
The Chemokine Network as Therapeutic Target
in Human Diseases
Guest Editor: Luciano Ottonello
Editorial Pp.
1
Asthma, Allergy and Chemokines Pp. 3-12
J.E. Pease
[Abstract]
Chemokines as Potential Therapeutic Targets in Atherosclerosis
Pp. 13-27
Y.A. Sheikine and G.K. Hansson
[Abstract]
Chemokines and Their Receptors in Central Nervous
System Disease Pp. 29-46
K. Biber, E.K. de Jong, H.R.J. van Weering and H.W.G.M.
Boddeke
[Abstract]
Chemokines in Gastrointestinal Disorders
Pp. 47-64
K. Gijsbers, K. Geboes and J. Van Damme
[Abstract]
Kidney Diseases and Chemokines Pp. 65-80
U. Panzer, O.M. Steinmetz, R.A.K. Stahl and G. Wolf
[Abstract]
Lymphoproliferative Disorders and Chemokines Pp.
81-90
V. Pistoia, A. Corcione, F. Dallegri and L. Ottonello
[Abstract]
Chemokines in Rheumatic Diseases Pp. 91-102
Z. Szekanecz, G. Szücs, S. Szántó and
A.E. Koch
[Abstract]
Targeting Herpesvirus Reliance of the Chemokine System
Pp. 103-118
M.M. Rosenkilde and T.N. Kledal
[Abstract]
Bacterial Sepsis and Chemokines Pp. 119-134
M. Kobayashi, Y. Tsuda, T. Yoshida, D. Takeuchi, T. Utsunomiya,
H. Takahashi and F. Suzuki
[Abstract]
Abstracts
[Back to top]
Editorial
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 seven-transmembrane 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.
Dr. Luciano Ottonello
Laboratory of Phagocyte Physiopathology
and Inflammation
Department of Internal Medicine
and Medical Specialties
University of Genoa Medical School
16132 Genoa,
Italy
[Back to top]
Asthma, Allergy and Chemokines
J.E. Pease
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 re-cruitment,
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 capac-ity that extends from their
traditional role in protecting the host against parasitic
worms. Thus, impairment of their re-cruitment 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.
[Back to top]
Chemokines and Their Receptors in Central
Nervous System Disease
K. Biber, E.K. de Jong, H.R.J. van Weering and H.W.G.M.
Boddeke
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 ad-hesion 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 patho-genic 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 com-plex 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.
[Back to top]
Chemokines and Their Receptors in Central Nervous
System Disease
K. Biber, E.K. de Jong, H.R.J. van Weering and H.W.G.M.
Boddeke
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.
[Back to top]
Chemokines in Gastrointestinal Disorders
K. Gijsbers, K. Geboes and J. Van Damme
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.
[Back to top]
Kidney Diseases and Chemokines
U. Panzer, O.M. Steinmetz, R.A.K. Stahl and G. Wolf
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 glomeru-lonephritis 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 un-der certain circumstances. This suggests
that inhibition of chemokine expression and action must be
time and compart-ment specific to provide therapeutic benefit
for renal structure and function.
[Back to top]
Lymphoproliferative Disorders and Chemokines
V. Pistoia, A. Corcione, F. Dallegri and L. Ottonello
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.
[Back to top]
Chemokines in Rheumatic Diseases
Z. Szekanecz, G. Szücs, S. Szántó and
A.E. Koch
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 in-flammatory 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, Sjögren’s
syndrome, mixed connective tissue dis-ease, polymyositis/dermatomyositis,
antiphospholipid syndrome and systemic vasculitides are also
discussed in this con-text. 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 antirheu-matic therapies.
[Back to top]
Targeting Herpesvirus Reliance of the Chemokine System
M.M. Rosenkilde and T.N. Kledal
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 dis-semination 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 constitu-tive 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.
[Back to top]
Bacterial Sepsis and Chemokines
M. Kobayashi, Y. Tsuda, T. Yoshida, D. Takeuchi, T. Utsunomiya,
H. Takahashi and F. Suzuki
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 (M1MΦ)
are major effector cells for host innate immune responses
against these infections. However, M1MΦ
are not generated in thermally injured patients whose alternatively
activated macro-phages (M2MΦ)
predominate. M2MΦ
appear in patients early after severe burn injuries. M2MΦ
inhibit M1MΦ
generation through the secretion of CCL17 and IL-10. As a
modulator of MΦ,
two different subsets of neutrophils (PMN-I, PMN-II) are described.
PMN-I direct the polarization of resident MΦ
into M1MΦ
through the production of CCL3. M2MΦ
are induced from resident MΦ
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 M1MΦ,
elimination of CCL2 and/or depletion of M2MΦ
induced by CCL2.
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