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Anti-Inflammatory
& Anti-Allergy Agents in Medicinal Chemistry
ISSN: 1871-5230
Anti-Inflammatory & Anti-Allergy
Agents in Medicinal Chemistry
Volume 8, Number 4, December 2009
Contents
Innate Immunity Molecules S100A8/A9 Involved
in Stress Response and Cancer Biology
Guest Editors: Claus Kerkhoff and Saeid Ghavami
Editorial Pp. 279-281
How Important are S100A8/S100A9 Calcium Binding Proteins
for the Activation of Phagocyte NADPH Oxidase, Nox2
Pp. 282-284
S. Berthier, A. Baillet, M.-H. Paclet, P. Gaudin and
F. Morel
[Abstract] [Full
text article]
Anti-Infective Protective Properties of S100/Calgranulins
Pp. 285-305
K. Hsu, C. Champaiboon, B.D. Guenther, B.S. Sorenson, A. Khammanivong,
K.F. Ross, C.L. Geczy and M.C. Herzberg
[Abstract] [Full
text article]
S100A8/A9 as a Pro-inflammatory Cytokine in Obstructive
Airway Disease Via the Multi-Ligand Receptor, RAGE
Pp. 306-317
A.J. Halayko and P. Sharma
[Abstract] [Full
text article]
Apoptosis-Inducing Activity of the S100A8/A9 Heterodimer
Pp. 318-328
M. Hashemi, S. Chitayat, S.R. Ande and W.J. Chazin
[Abstract] [Full
text article]
Dual Role of S100A8 and
S100A9 in Inflammation-Associated Cancer Pp.
329-336
J. Németh, P. Angel and J. Hess
[Abstract] [Full
text article]
A Concept of Homeostatic Inflammation Provided
by Endogenous TLR4 Agonists that Function Before and After
Danger Signal for Metastasis Pp. 337-347
Y. Maru
[Abstract] [Full
text article]
S100A8/A9 Proteins in Diseases of the Exocrine
Pancreas Pp. 348-356
R. Ossig and J. Schnekenburger
[Abstract] [Full
text article]
General Articles
Recent Advances in Improving Sub-Unit Vaccine Efficacy
Using Cytokines as more Specific Immune Inducing Adjuvants
Pp. 357-365
S.D. Cesare, D. Abourbih, R.N. Belfort, L.A. Petruccelli and M.N. Burnier Jr.
[Abstract] [Full
text article]
Hapten Recognition by T Cells: A Functional and Molecular
View Pp. 366-376
A. Franco
[Abstract] [Full
text article]
Inflammation Induces Glucocorticoid
Resistance in Patients with Bronchial Asthma
Pp. 377-386
Yasuhiro Matsumura
[Abstract] [Full
text article]
Abstracts
[Back to top]
Editorial: Innate Immunity Molecules S100A8/A9 Involved in
Stress Response and Cancer Biology
Members of the S100 protein family comprise
a multigenic group of non-ubiquitous cytoplasmic Ca2+-binding
proteins of the EF-hand type, differentially expressed in
a wide variety of cell types. They are small acidic proteins
(10–12 kDa) that are found exclusively in vertebrates,
and have been implicated in the regulation of many diverse
processes such as signal transduction, cell growth and motility,
cell-cycle regulation, transcription, differentiation, and
cell survival.
A large number of different human diseases have been associated
with the variety of S100 proteins and their defective functions,
e.g., cancer, inflammation, cardiomyopathies, neurodegenerative
diseases, and allergies. Most S100 genes are located in a
gene cluster near a region on human chromosome 1q21, which
is responsible for a number of chromosomal abnormalities and
has been frequently rearranged in human cancer. In addition,
the S100 gene cluster is close to the epidermal differentiation
complex as well as to a psoriasis susceptibility region, the
PSORS4 locus. These data are important indications for the
involvement of S100 genes in inflammatory as well as neoplastic
disorders. The rearrangements may result in a deregulated
expression of S100 genes associated with neoplasia. Furthermore,
there is also an extensive interest in researching the possibility
of using S100 proteins/specific antibodies in clinical diagnosis.
It is worth mentioning that the first link between S100 family
members and a specific disease was made for S100A8 and S100A9.
It was speculated for considerable time that these two proteins
could represent the proteins responsible for cystic fi-brosis,
a speculation now superseded by the cloning of the gene encoding
the membrane protein cystic fibrosis conductance regulator.
Nevertheless, it has been shown that S100A8- and S100A9-expressing
cells belong to the early infiltrating cells and dominate
acute inflammatory lesions. Phagocytes expressing S100A8 and
S100A9 are found in a variety of inflammatory conditions,
including rheumatoid arthritis, allograft rejections, and
inflammatory bowel and lung diseases. Inflammatory disorders
such as chronic bronchitis, cystic fibrosis, and rheumatoid
arthritis are associated with elevated plasma levels of S100A8/A9.
There are high correlations between S100A8/A9 plasma concentrations
and clinical and laboratory markers of inflammation, as well
as the rapid normalization following clinical improvement
suggesting that these proteins track disease activity. Therefore,
S100A8 and S100A9 are widely used as marker proteins for activated
or recruited phagocytes as well as a diagnostic marker for
disease activity. However, over the last decade they have
gained increasing interest in many files of medicine due to
their deregulated epidermal expression as a response to stress
and in association with neoplastic disorders.
S100A8 and S100A9 are predominantly expressed in myeloid cells.
Except for inflammatory conditions, the expression of S100A8
and S100A9 is restricted to a specific stage of myeloid differentiation
since both proteins are expressed in circulating neutrophils
and monocytes but are absent in normal tissue macrophages
and lymphocytes. Under chronic inflammatory conditions, such
as psoriasis and malignant disorders, they are also expressed
in the epidermis.
S100A8 and S100A9 show a strong tendency to form heteromeric
protein complexes. This preference for the formation of the
heterodimeric protein complexes over S100A8 and S100A9 homodimers
in both the apo- and holo-states has been demonstrated by
several biochemical, biophysical and structural methods. Complex
formation is not calcium-dependent as shown in various studies.
However, the binding of calcium results in structural changes
leading to the exposure of hydrophobic surfaces upon calcium
binding. These conformational changes are proposed to provide
for specific interaction with target proteins. Previous studies
have reported that S100A8 and S100A9 are frequently co-expressed
and their expression appears to be coordinately regulated.
Vice versa, it has been demonstrated that either gene knock-out
or gene silencing of one S100 gene caused the absence of the
other at protein level. Therefore, it is nowadays widely accepted
that heteromeric protein complexes are the most functionally
relevant form to study.
Despite a number of distinct functions have been attributed
to the S100 proteins, their biological functions still remain
unclear. The present AIAAMC Hot Topic Issue
is therefore dedicated to the role of the two S100 proteins
in innate immunity; their stress response induced expression
as well as their association with tumor development, cancer
invasion or metastasis. This specific issue brings together
a set of reviews and new articles that reflect the range of
molecular investigations that are current in the field of
S100A8/A9 biology, and provides insight into the common and
unifying themes that are emerging.
In phagocytes, the heteromeric complex of S100A8 and S100A9
has been shown to represent the entire arachidonic acid-binding
capacity. Arachidonic acid is an essential factor for NADPH
oxidase due to its binding to gp91phox
that induces structural changes in cytochrome b558. S100A8/A9
participates in phagocyte NADPH oxidase activation by transferring
arachidonic acid to membrane-bound Nox2 (gp91phox)
during interactions with cytosolic oxidase activation factors.
The functional relevance of S100A8/A9 in the phagocyte NADPH
oxidase activation has been demonstrated by the impairment
of NADPH oxidase activity in neutrophil-like NB4 cells, after
specifically blocking S100A9 expression, and employing bone
marrow-derived PMNs from S100A9 deficient mice. The article
of Berthier et al. (pages 282 –
289) investigates the molecular mechanisms by which S100A8/A9
promotes NADPH oxidase activation. The authors highlight the
importance of the interaction of S100A8/A9 with cytosolic
phox proteins in the allosteric regulation of NADPH
oxidase activity. S100A8 and S100A9 potentiate oxidase activation
by mediating enhancement of p67phox affinity
for cytochrome b558 in synergy, in vivo, with p47phox,
p40phox and Rac1/2. Respective function
of S100A8 and S100A9 has to be determined; while S100A8 is
strategic, efficiency of NADPH oxidase regulation depends
on the presence of both S100A8 and S100A9 proteins.
Recent investigations suggest that S100A8 and S100A9 (as well
as the functional homolog S100A12) are involved in the first
line of defense against infection and inflammation. The S100/calgranulin
proteins are expressed in those cells that form physical barriers
to keep pathogens from entering. S100A8 and S100A9 are expressed
in squamous mucosal keratinocytes and innate immune cells
present at mucosal surfaces. The S100/calgranulin proteins
are abundant in myeloid cells whereas their expression is
induced in epidermal keratinocytes, gastrointestinal epithelial
cells and fibroblasts during inflammation. Hsu
et al. (pages 290 – 305)
decipher the protective anti-infective and anti-inflammatory
functions of the S100/calgranulins for the mammalian host.
The proteins may serve as leukocyte chemoattractants and display
protective functions including oxidant scavenging, antimicrobial
activity, and chemokine-like activities. Each function may
reflect the concentration of the S100/calgranulins, post-transcriptional
modifications, oligomeric forms, and the proximal intracellular
or extracellular environments. The authors conclude that S100/calgranulins
play important roles in resistance of the host to infection
and protection against adverse affects of inflammation.
Neutrophils abundantly expressing S100A8 and S100A9 are engaged
to the lung during acute asthma exacerbation and could be
detected very rapidly in bronchial biopsies and sputum. Airway
neutrophil inflammation after withdrawal of inhaled corticosteroid
is a prediction of un-controlled asthma exacerbation. On the
other hand, the receptor of advanced glycation endproducts
(RAGE) is a putative receptor for S100A8/A9, and is highly
expressed in lung tissue. There are also some recent reports
indicating the importance of RAGE in airway remodeling during
bleomycin-induced lung injury. To date there has been little
focus on the possible role S100A8/A9 and its consequences
in allergic asthma, which could be of particular relevance
in neurtrophilic-dependent severe asthma. Halayko
and Sharma (pages 306 – 317) therefore have
investigated the possible role of S100A8/A9 in two murine
models of allergic airway inflammation with differential neutrophilia.
Preliminary data indicate that S100A8/A9 levels were enhanced
in the bronchoalveolar lavage fluid of acute ovalbumin and
chronic house dust mite challenged BALB/c mice. Flow cytometry
analysis revealed specific binding of S100A8/A9 on primary
cultured human airway smooth muscle cells which highly expressed
RAGE as measured by RT-PCR and Western blot analysis. These
cells treated with S100A8/A9 showed both enhanced cell growth
and increased synthesis and secretion of eotaxin-1 and IL-8
compared to control, indicative for the importance of S100A8/A9
in allergic airways inflammation. In their current review
they dicuss the possible cellular pathways that might be involved
in S100A8/A9 effect in airway remodeling during asthma.
The demonstrations that S100A8/A9 exerts apoptotic/cytotoxic
effects against various tumor cells, and S100A8- and S100A9-positive
cells, macrophages and polymorphonuclear leukocytes, accumulate
along the invasive margin of carcinoma has prompted several
investigators to study the possible participation of S100A8/A9
in carcinoma regression. Hashemi et al.
(pages 318 – 328) summarize in their review the current
knowledge about the molecular mechanisms by which S100A8/A9
performs its role as a novel apoptotic agent. In the past
the apoptosis-inducing activity of S100A8/A9 was proposed
to be due to the ability to bind divalent metal ions including
Zn2+, Mn2+ and Cu2+ at sites
that are distinct from Ca2+-binding sites. However,
recent reports now indicate that S100A8/A9 exerts its activity
by two different mechanisms a) chelation of trace metal ions
such as Zn2+ and b) cell surface receptor mediated
pathways. Although a number of receptors have been shown to
bind S100A8/A9, the nature of the receptor involved in S100A8/A9-induced
cell death remains to be elucidated. Experiments with certain
cell lines either deficient for or over expressing components
of the death signaling machinery as well as RAGE gene silencing
and blocking RAGE-specific antibody approaches excluded both
RAGE and the classical death receptor to be involved in S100A8/A9-induced
cell death, even though S100A8/A9 can specifically bind to
cancer cells and RAGE mediates the growth-promoting activity
obvious at low micromolar concentrations of S100A8/A9. Clearly,
investigations to identify the receptor involved in S100A8/A9-induced
cell death are critical.
Chronic inflammation increases the risk for the expansion
of transformed cells and aggravates the development of many
recognized malignancies in as much as inflammation promotes
angiogenesis, induces the expression of tumor growth-promoting
cytokines and anti-apoptotic genes, and feeds forward signaling
in tumor cells through cell surface receptors such as RAGE.
Several lines of evidence identified an enhanced expression
of S100A8 and S100A9 in pathological conditions of chronic
inflammation and inflammation-associated carcinogenesis. Genetically
modified mouse models and cell lines derived thereof have
provided important new insights into the regulation and molecular
function of S100A8 and S100A9 in vivo and in
vitro. Nemeth et al. (pages
329 – 336) present a review of the current knowledge
on S100A8 and S100A9 regulation and function on tumor cell
signaling and survival, as well as the establishment of an
inflammatory, pro-tumorigenic microenvironment. These findings
provide a strong rationale to interfere with S100A8/A9-mediated
signaling as a novel therapeutic option for treatment of inflammatory
diseases as well as cancer.
Pancreatitis is inflammation of the pancreas that may occur
as an acute, painful attack, or may be a chronic condition
developing gradually over time. It is caused when pancreatic
enzyme secretions build up and begin to digest the organ itself.
Another term for this condition is auto digestion, which occurs
when, for some unknown reason, the pancreas' powerful enzymes
are activated in the pancreas itself rather than in the duodenum.
It is believed that trypsin sets off a domino effect, activating
other enzymes to speed the auto digestive process thereby
inducing an inflammatory cascade. The progression of this
inflammatory cascade depends on the rapid infiltration of
leukocytes into pancreatic tissue, and consequently, inhibition
of leukocyte infiltration was shown to reduce the severity
of acute pancreatitis. Ossig and Schnekenburger
(pages 348 – 356) report that S100A9 deficient mice
display less severity of acute experimental pancreatitis compared
to wild-type mice as analyzed by measuring serum amylase and
lipase activities, intrapancreatic trypsin activation, and
pancreatic morphology. Interestingly, leukocyte infiltration
in pancreas and lungs was strongly reduced in S100A9 deficient
mice suggesting a crucial function of infiltrating leukocytes
not only for the progression of acute pancreatitis towards
systemic inflammation but also in the initiation of the intra-acinar
cell zymogen activation cascade. Furthermore, these authors
discuss the recent postulate of a pathway from chronic pancreatic
inflammation to pancreas tumor development, in view of the
recent finding that S100A8/A9 proteins were found in myeloid
cells within tumor-associated stroma.
Metastasis is thought to be a multistep process requiring
the concerted actions of multiple genes. Specific genes allow
tumor cells to shed from the primary tumor and these cells
travel through the blood vessels to secondary sites, attach
to endothelial cells, invade through proteolysis of the extracellular
matrix and finally cause macrometastases at distant organs.
Tumor-associated cells, such as macrophages and hematopoietic
bone-marrow progenitors enhance metastasis because they prepare
the environment for invasion in potential premetastatic organs.
In a previous study, Maru and colleagues searched for genes
related to the premetastatic phase, and found that S100A8/A9
attracts Mac-1+ myeloid cells to the lung tissue.
Recruited Mac-1+ myeloid cells in lung in turn
produce S100A8/A9 in response to primary malignant cells in
a so called “premetastatic phase”. This phase
shows the general characteristics of an inflammation state
which facilitates the micro-environmental changes required
for the migration and implantation of primary tumor cells
to lung tissue. After preparation of the target tissue for
accepting the malignant cells, tumor cells mimic Mac-1+
myeloid cells in response to S100A8/A9 chemotactic signaling
and migrate to lung. Maru (pages 337 –
347) continues this issue by presenting a novel so-called
“homeostatic inflammation” concept that extends
the concept of danger signals. This concept includes the toll-like
receptor 4 (TLR4) and its endogenous ligands S100A8 and serum
amyloid A3 (SAA3) that signals a pseudo-alarm before destruction
actually takes place such as those in pre-metastatic microenvironment
and possibly even in physiological conditions. This concept
suggests the endogenous TLR4 ligands S100A8 and SAA as attractive
targets for the development of strategies counteracting tumor
metastasizing to certain organs.
The present AIAAMC Hot Topic Issue on “Innate
Immunity Molecules S100A8/A9 involved in Stress Response and
Cancer Biology” demonstrates the diverse intracellular
and extracellular functions of S100A8 and S100A9 in normal
and pathophysiological conditions. Intra- as well as extracellular
roles has been proposed. Intracellular S100A8/A9 promotes
NADPH oxidase subsequently followed by NF-κB
activation. The secreted form has chemotactic as well as cytokine-like
properties, and the binding to cell surface receptor(s) induces
the expression of cytokine(s). S100A8/A9 is released from
activated phagocytes and has been shown to induce apoptosis
in various cancer cells. This cellular response could be important
for the antitumor response of PMNs. On the other hand, it
has been shown that cancer cells utilize S100A8 and S100A9
as guidance for the adhesion and invasion of disseminating
malignant cells. Moreover, S100A8/A9-mediated NF-κB
(and Akt) activation could also function as a reversible signal
for cellular proliferation with relevance for tumorgenesis.
The promiscuity of the two S100 proteins is provocative, however,
also implying a range of potential effects on human health.
Therefore, further investigations are necessary to discover
the biological function of S100A8/A9 in the immune response
and its relationship to inflammation-associated cancerogenesis.
Claus Kerkhoff
Guest Editor
Anti-Inflammatory & Anti-Allergy Agents in Medicinal Chemistry
Institute of Immunology
Roentgenstr. 21, 48149 Muenster
Germany
Tel: +49 251 8352942
Fax: +49 251 8356549
E-mail: kerkhoc@uni-muenster.de
Saeid Ghavami
Guest Editor
Anti-Inflammatory & Anti-Allergy Agents in Medicinal Chemistry
Department of Physiology
University of Manitoba
730 William Avenue
(Basic Science Building)
Winnipeg, MB Canada R3E 3J7
Canada
E-mail: ghavami@cc.umanitoba.ca
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[Full
text article]
How Important are S100A8/S100A9 Calcium Binding
Proteins for the Activation of Phagocyte NADPH Oxidase, Nox2
Sylvie Berthier, Athan Baillet, Marie-Hélène
Paclet, Philippe Gaudin and Françoise Morel
S100A8 and S100A9 are two soluble calcium-binding proteins
highly expressed in myeloid cells, mainly neutrophils (45%
of cytosolic proteins) or monocytes (1-5%) and also early
differentiated macrophages. In neutrophils, they are believed
to be expressed as a 1/1 non covalent heterodimer; the process
of dimer and mainly tetramer formation is calcium dependent.
The S100A8/S100A9 calcium loaded complex binds arachidonic
acid and shuttles between cytosol and plasma membrane upon
neutrophil stimulation.
Neutrophils display, upon stimulation, a respiratory burst
in which the cells catalyze NADPH oxidase activity through
a redox membrane hemoprotein, cytochrome b558,
which is constituted of 2 subunits: gp91-phox, the redox core
and p22-phox the stabilizing partner. In neutrophils, this
activity is transitory: to be active, regulatory cytosolic
factors, p67-phox, p47-phox, p40-phox and Rac1/2 assemble
with membrane cytochrome b558.
Both S100A8 and S100A9 were recently introduced as partners
for NADPH oxidase activation and associate with the cytosolic
activating factors especially p67-phox and Rac1/2. Moreover,
S100A8/S100A9 potentiates NADPH oxidase activity. This was
observed ex vivo after co-transfection of genes encoding
both S100A8 and S100A9 in B lymphocytes that express all the
components of the phagocyte oxidase, but display a very low
NADPH oxidase activity (in these cells, S100A8 and S100A9
are not present endogenously). In the biological function
of S100A8/S100A9, S100A8 is a strategic protein that needs
to be active in vivo as in vitro, its specific
partner S100A9. New data introduce S100A8 and S100A9 as positive
effectors in allosteric regulation of phagocyte NADPH oxidase
activity.
[Back to top] [Full
text article]
Anti-Infective Protective Properties of S100 Calgranulins
Kenneth Hsu1, Chantrakorn Champaiboon, Brian D. Guenther,
Brent S. Sorenson, Ali Khammanivong, Karen F. Ross, Carolyn
L. Geczy1 and Mark C. Herzberg
The calgranulins are a subgroup of proteins in the S100
family (calgranulin A, S100A8; calgranulin B, S100A9 and calgranu-lin
C, S100A12) that provide protective anti-infective and anti-inflammatory
functions for the mammalian host. In this review, we discuss
the structure-function relationships whereby S100A8 and S100A9,
and for comparison, S100A12, provide intra- and extracellular
protection during the complex interplay between infection
and inflammation and how the calgranulins are regulated to
optimally protect the host. Ideally located to support epithelial
barrier function, calprotectin, a complex of S100A8/S100A9,
is expressed in squamous mucosal keratinocytes and innate
immune cells present at mucosal surfaces. The calgranulins
are also abundantly produced in neutrophils and monocytes,
whereas expression is induced in epidermal keratinocytes,
gastrointestinal epithelial cells and fibroblasts during inflammation.
The calgranulins show species-specific expression and function.
For example, S100A8 is chemotactic in rodents but not in humans.
In humans, S100A12 appears to serve as a functional chemotactic
homolog to murine S100A8. Transition metal-binding and oxidation
sites within calgranulins are able to create structural changes
that may orchestrate new protective functions or binding targets.
The cal-granulins thus appear to adopt a variety of roles
to protect the host. In addition to serving as a leukocyte
chemoattractant, protective functions include oxidant scavenging,
antimicrobial activity, and chemokine-like activities. Each
function may reflect the concentration of the calgranulin,
post-transcriptional modifications, oligomeric forms, and
the proximal intracellular or extracellular environments.
Calprotectin and the calgranulins are remarkable as multifunctional
proteins dedicated to protecting the intra- and extracellular
environments during infection and inflammation.
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[Full
text article]
S100A8/A9 as a Pro-inflammatory Cytokine in Obstructive
Airway Disease Via the Multi-Ligand Receptor, RAGE
Andrew J. Halayko and Pawan Sharma
Asthma and chronic obstructive pulmonary disease (COPD)
are persistent inflammatory conditions that have exhibited
significantly increased prevalence in the past two decades.
Though many current medications relieve the symptoms of obstructive
airway disease, morbidity can still increase over time in
individual patients. With particular respect to asthma, despite
satisfactory control of symptoms in most patients with inhaled
steroids, a sub-phenotype of subjects, representing ~15%
of all asthmatics, do not respond to steroids – these
patients can exhibit severe asthma, which accounts for ~50%
of asthma health care costs. Moreover, inhaled steroids are
not recommended as a sole therapy for COPD, and there is limited
evidence for their effectiveness in preventing disease pathogenesis.
Thus, it is important to better understand mechanisms for
severe asthma and COPD and identify mediators released by
cells, such as neutrophils, that are unresponsive to steroid
therapy. This review focuses on the probable role of one the
most abundant neutrophil proteins, called S100A8/A9, in asthma.
S100A8/A9 is released in abundance in rheumatoid arthritis,
inflammatory bowel disease and cancer, but there are no definitive
studies on its role in obstructive airways disease. A primary
receptor for S100A8/A9, which is uniquely expressed in high
abundance in the lung, is the multi-ligand receptor
for advanced glycated end-products (RAGE)
of the immunoglobin-like receptor family. RAGE participates
in mediating fibroproliferative lung remodeling in idiopathic
pulmonary fibrosis, and in bleomycin-exposed animal models.
This review provides an overview of the S100A8/A9-RAGE axis,
and discusses its potential in mediating chronic airway inflammation
and tissue remodeling in asthma and COPD.
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[Full
text article]
Apoptosis-Inducing Activity of the S100A8/A9 Heterodimer
Mohammad Hashemi, Seth Chitayat, Sudharsana Rao Ande
and Walter J. Chazin
The S100A8/S100A9 heterodimer, commonly referred to as
calprotectin (CP), is a member of the S100 sub-family of EF-hand
calcium binding proteins that is largely expressed in activated
monocytes and macrophages and has well-defined functions in
acute and chronic inflammation. Indeed, certain S100 proteins
including S100A8/A9 are exported from cells by an as-yet unknown
mechanism. Once outside the cell, S100A8/A9 activates cell
surface receptors such as the receptor for advanced glycation
end products (RAGE) and has also been shown to inhibit the
growth of pathogenic bacteria through the chelation of trace
metal ions such as zinc (Zn2+) and manganese (Mn2+).
The binding of these metal ions by S100A8/A9 has also been
shown to induce apoptosis in various tumor cell lines. However,
several lines of evidence have suggested that S100A8/A9-dependent
apoptosis is not solely due to its ability to sequester Zn2+
from cells. Rather, it appears that trace metal binding to
S100A8/A9 triggers a novel conformational switch in the protein,
which promotes binding to specific sites on the surface of
cells or through interaction with yet unidentified cell surface
receptors. This review summarizes what is currently known
regarding the molecular mechanisms by which S100A8/A9 performs
its role as a novel apoptotic agent.
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[Full
text article]
Dual Role of S100A8 and S100A9 in Inflammation-Associated
Cancer
Julia Németh, Peter Angel and Jochen
Hess
Human cancer is a chronic disease that originates from
transformed tumor cells harboring genetic as well as epigenetic
altera-tions. It develops via a multi-step process that can
be divided both operationally and mechanistically into three
phases: initiation, promotion and progression. However, cancer
is not merely an autonomous mass of mutant cells, but is composed
of multiple cell types, such as fibroblasts and epithelial
cells, innate and adaptive immune cells, and cells forming
blood vessels and lymphatic vasculature. A striking feature
of many cancers is an underlying persistent and unresolved
inflammation, which often orchestrates a tumor supporting
microenvironment. Several lines of evidence identified an
enhanced expression of S100A8 and S100A9 proteins in pathological
conditions of chronic inflammation and inflammation-associated
carcinogenesis in patient specimens as well as cell culture
and experimental animal models. More recently, the analysis
of genetically modified mouse models and cell lines derived
thereof has provided important new insights into the regulation
and molecular function of S100A8 and S100A9 proteins in
vivo and in vitro. In this review, we will summarize
our current knowledge on S100A8 and S100A9 regulation and
function on tumor cell signaling and survival, as well as
the establishment of an inflammatory, pro-tumorigenic microenvironment.
Based on this knowledge, this review will discuss potential
strategies to interfere with S100A8 and S100A9 function as
a novel option to develop innovative strategies for cancer
prevention or therapy.
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[Full
text article]
A Concept of Homeostatic Inflammation Provided by
Endogenous TLR4 Agonists that Function Before and After Danger
Signal for Metastasis
Yoshiro Maru
Provoked by the discovery of metastasis-inducing endogenous
ligands of TLR4 that has been recognized as a sensor for extrinsic
pathogens, I propose an extended concept for danger signal
that originally meant sentinels over tissue destruction by
cancer. The so-called “homeostatic inflammation”
concept includes signals before destruction actually takes
place such as those in pre-metastatic microenvironment and
possibly even in physiological conditions. It is orchestrated
by tight cross-talks between growth factor and chemokine signaling.
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[Full
text article]
S100A8/A9 Proteins in Diseases of the Exocrine Pancreas
Rainer Ossig and Jürgen Schnekenburger
The function of the exocrine pancreas is the production
and secretion of digestive enzymes. Major pathologies of the
exocrine pancreas are pancreatitis, a sterile inflammation,
and pancreatic adenocarcinoma, a highly lethal tumor. Both
diseases involve cells of the immune system and calcium binding
proteins of the S100 family. Here, we review the known function
of these proteins in pancreatitis and pancreas cancer.
Few S100 proteins were detected during pancreatitis and only
for the S100A8/A9 complex data are available that elucidate
a presumable function. In a rodent model of caerulein-induced
acute pancreatitis, pancreatic S100A8/A9 expression was exclusively
detected in infiltrating leukocytes. S100A9 knockout animals
developed less pancreatic tissue damage, no significant edema
formation, and the intrapancreatic infiltration of leukocytes
was inhibited. Purified S100A8/A9 dissociated calcium-dependent
cell-cell contacts between pancreatic acinar cells in
vitro and in vivo. These results indicate that
the dissociation of epithelial cell-cell contacts mediated
by secreted S100A8/A9 is crucial for the infiltration of leukocytes
into the pancreas.
Several studies revealed an expression of S100 proteins in
pancreatic cancers. Especially S100A8/A9 proteins were found
in myeloid cells within tumor-associated stroma. Whether these
proteins contribute to a recruitment of specific immune cells
to tumors or to other steps of pancreatic tumor progression
is not clear. None of the S100 proteins has been clearly confirmed
as a pancrea tumor marker.
Taken together, S100A8/A9 proteins are essential for the inflammation
induced infiltration of leukocytes in murine pancreatic tissue
a mechanism which may also support tumor progression and metastasis.
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Recent Advances in Improving Sub-Unit Vaccine Efficacy
Using Cytokines as more Specific Immune Inducing Adjuvants
Sebastian Di Cesare, Daniel Abourbih, Rubens
N. Belfort, Luca A. Petruccelli and Miguel N. Burnier
Jr.
Current vaccine research is now heavily focused on improving
the efficacy and potency of sub-unit peptide vaccines. Many
successful vaccines developed in past decades have been able
to sufficiently prime proper immune responses without the
use of any specific adjuvant immune mediators. Due to the
intrinsic nature of more immune-evading pathogens and neoplasms,
novel “tricks” are needed to elucidate a proper
and protective immune response. It is important to note that
without cytokines, proper execution of the immune response
would be completely inhibited. They are responsible for the
recruitment and chemo-tactic movement of most innate cellular
effectors such as polymorphonucleocytes (PMN), macrophages,
and dendritic cells. Most importantly, the entire Th1/Th2
balance is completely dependent on the unique nature and signature
of differential cytokine production. These expression signatures
are crucially needed to tip the scale either way, depending
on which immune reaction is appropriate. This review will
specifically explain the use of Th1 inducing cytokines as
an adjuvant in current vaccine development. This rapidly developing
field aims to produce more powerful and effective Th1 responses
in the hopes of improving the treatment of cancer, intracellular
infectious agents, and autoimmune diseases.
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Hapten Recognition by T Cells: A Functional and
Molecular View
Alessandra Franco
T cells specific for haptens determine immunopathology, as
for the recognition of the β-lactamic
ring by CD4+ T helper cells, responsible for the severe immune
response to Penicillin in allergic patients.
In this review we report studies that address functional and
molecular aspects of hapten recognition by α/β
T cells, enlightening the most relevant examples of hapten-specific
T cells and their role in vivo.
Using Trinitrophenyl as a contact allergen model and tumor
associated carbohydrate antigens (TACA) as antigen models
in cancer, our laboratory extensively studied T cell recognition
by hapten-specific T cells suggesting new, unexplored avenues
for T cell-based immunotherapy.
In fact, the evidence of hapten recognition by “conventional”
α/β
T cells is of a critical importance in designing new immunotherapeutic
approaches to treat allergies, cancer and chronic viral diseases.
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Inflammation Induces Glucocorticoid Resistance in
Patients with Bronchial Asthma
Yasuhiro Matsumura
Glucocorticoids (GCs) represent the cornerstone of treatment
of patients with bronchial asthma; however, inflammation in
bronchial asthma is sometimes incompletely controlled. GCs
switch on the expression of anti-inflammatory genes by binding
to DNA and recruiting transcriptional coactivator molecules.
In contrast, they can switch off activated inflammatory genes
by recruiting transcriptional repressor molecules such as
histone deacetylase (HDAC) 2.
Proinflammatory transcriptional element activator protein-1
(AP-1) and transcription factor nuclear factor kappa B (NF-κB),
and upstream kinase p38 and c-Jun-N-terminal kinase (JNK)
amplify inflammation and resistance to the actions of GCs.
The activity of histoneacetyltransferase (HAT) and HDAC influences
the expression of inflammatory genes. Cytokines, inflammatory
mediators, allergens, viral or bacterial infections, oxidative
stress, smoking, and vitamin D deficiency may all lead to
a worsened clinical outcome by influencing these pathways.
Conventional therapy acts by inhibiting NF-κB,
enhancing glucocorticoid receptor (GR) functions, and restoring
HDAC activity, resulting in helpful add-on therapy. Targeting
kinases such as inhibitor of κB
kinase (IKK)2, mitogen activated protein (MAP) kinase (MAPK)s
and phospho-inositol (PI)3 kinase (PI-3K) should be effective
as therapy. Decoy oligonucleotides for AP-1and NF-κB
are also candidates for the treatment of glucocorticoid-resistant
(GC-R) asthma.
Since various factors affect GC response, the pathogenesis
of GC-R asthma is considered to be heterogeneous. Most GC
nonresponsiveness in these patients is relative and not absolute,
suggesting that resistance is dependent on the intensity of
localized inflammation. A better understanding of the inflammatory
mechanisms of asthma may signal the management of GC-R asthma.
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