THEMES
Microbes and Microbial Toxins: Paradigms for Microbial-Mucosal Interactions
IV. Helicobacter
pylori strain-specific activation of signal transduction cascades
related to gastric inflammation
Richard M.
Peek Jr.
Division of Gastroenterology, Vanderbilt University School
of Medicine, Nashville 37232; and Department of Veterans Affairs
Medical Center, Nashville, Tennessee 37212
 |
ABSTRACT |
Helicobacter pylori strains that
possess the cag pathogenicity island induce more severe
gastritis and augment the risk of developing peptic ulcer disease and
distal gastric cancer. A specific mechanism by which
cag+ strains may enhance gastritis is
strain-selective regulation of interleukin (IL)-8 production. On
contact with gastric epithelial cells, H. pylori activates
multiple signal transduction cascades that regulate IL-8 secretion,
including nuclear factor-
B and mitogen-activated protein kinases,
and these events are dependent on genes within the cag
island. An independent effect of cag-mediated cellular
contact is translocation and phosphorylation of H. pylori proteins within the host epithelial cell. The redundancy of
intracellular signaling cascades activated by H. pylori and
the divergent epithelial cell responses induced by components of the
cag island may contribute to the ability of this organism to
persist for decades within the gastric niche.
interleukin-8; nuclear factor-
B; mitogen-activated protein
kinases
 |
INTRODUCTION |
THE GASTROINTESTINAL TRACT represents
an important barrier between human hosts and microbial populations. One
potential consequence of host-microbial interactions is the development
of mucosal inflammation. Regardless of the initiating event, if
allowed to become persistent, inflammatory states may lead to
clinically apparent disease. A paradigm for such chronic host-microbial
relationships is carriage of Helicobacter pylori,
Gram-negative bacteria that colonize the stomachs of humans and
primates. H. pylori colonization induces chronic gastritis
in essentially all hosts, a process that increases the risk of
developing peptic ulceration, distal gastric adenocarcinoma, and
gastric mucosal lymphoproliferative disease (Fig.
1). However, only a small percentage of
persons carrying H. pylori develop clinical sequelae;
enhanced risk may be related to differences in expression of specific
bacterial products, to variations in the host inflammatory response to
the bacteria, or to specific interactions between host and microbe. The
recent demonstration that a subset of H. pylori strains are
associated with a reduced risk of developing esophageal adenocarcinoma
(28) further underscores the importance of identifying
mechanisms that predispose colonized individuals toward disease.

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Fig. 1.
Variable disease outcomes that develop within the context
of Helicobacter pylori-induced gastric inflammation. OR,
odds ratio.
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|
Certain H. pylori components such as urease and porins
are ubiquitous and necessary for colonization and survival, and
variation in clinical outcome is unlikely to develop as a result of
these highly conserved traits. Genes that are heterogeneously
represented among H. pylori strains, however, may encode
candidate virulence factors that influence the pathological course. One
specific phenotype shown to differ among H. pylori isolates
is production of an immunodominant protein encoded by the gene
cagA (3), which is present in ~60% of US
strains. Persons colonized with cagA+ strains
are at increased risk of developing more severe gastritis, peptic ulcer
disease, and distal gastric cancer compared with persons harboring
cagA
strains. cagA is a component
of and a marker for a 40-kb region of chromosomal DNA acquired by
horizontal transfer called the cag pathogenicity island,
which is inserted at the 3'-terminus of the glutamate racemase gene
(3). Several cag island genes possess homology
to components of a type IV secretion system that, in other prokaryotic
species, functions as a conduit for export of multimeric proteins and
nucleoproteins across both the inner and outer bacterial membrane.
The H. pylori cag island is required for both
translocation of bacterial proteins into host cells (2, 20,
26) and induction of proinflammatory cytokine release (3). Thus cagA+ strains are
disproportionately represented among persons who develop serious
sequelae of H. pylori infection, and genes within the
cag island are necessary for induction of epithelial cell responses relevant to pathogenesis.
The mucosal inflammatory infiltrate that develops in response to
H. pylori consists of neutrophils, lymphocytes, plasma
cells, and macrophages. The presence of both acute and chronic
inflammatory components within colonized mucosa suggests that soluble
mediators capable of attracting cells derived from varying lineages may be key regulators in the development of gastritis. Interleukin (IL)-8
is a potent neutrophil- and lymphocyte-activating chemotactic cytokine
(chemokine), and gastrointestinal epithelial cells secrete biologically
activated IL-8 in response to infection with pathogenic bacteria
(7). Chemokines produced by activated enterocytes bind to
the extracellular matrix, thereby establishing a chemotactic gradient
that directs inflammatory cell migration toward the epithelial cell
surface. IL-8 expression is enhanced within H. pylori-colonized mucosa (6, 21), and increased IL-8
protein is primarily localized to gastric epithelial cells
(6). Carriage of cagA+ strains
further augments mucosal IL-8 expression, and such increases are
directly related to the more severe inflammatory response induced by
these strains (21). In vitro H. pylori
stimulates IL-8 expression in gastric epithelial cells, and these
events require an active interplay between live bacteria and host cells (25). Similar to findings within gastric tissue,
cagA+ strains induce significantly higher levels
of IL-8 in vitro than cagA
strains
(4). Thus a paradigm for H. pylori-induced
gastric inflammation is that contact between bacteria and epithelial
cells stimulates IL-8 secretion that then regulates neutrophilic and monocytic infiltration into the gastric mucosa. Because cytokine production and severity of gastric inflammation are enhanced by cagA+ strains, this themes article will focus on
strain-specific activation of molecular signaling events that regulate
IL-8 expression as a mechanistic model for H. pylori-induced gastritis.
 |
H. PYLORI-INDUCED IL-8 EXPRESSION IS MEDIATED BY
ACTIVATION OF NUCLEAR FACTOR- B |
The human IL-8 gene contains several binding sites within its
promoter region (Fig. 2). A nuclear
factor (NF)-
B binding motif is located at nucleotides (nt)
80 to
70, and a NF-IL-6 site lies immediately adjacent to this motif (nt
94 to
81). In addition to these loci, a binding site for
c-fos and c-jun, which together comprise the
transcription factor AP-1, is present at nt
126 to
120 (Fig. 2).

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Fig. 2.
Binding motifs for transcription factors within the human
interleukin (IL)-8 gene promoter. NF, nuclear factor.
|
|
NF-
B is a transcription factor sequestered in the cytoplasm, whose
activation and regulation are tightly controlled by a class of
inhibitory proteins termed I
Bs (I
B
, I
B
, and I
B
). Through noncovalent association, I
B proteins mask the nuclear localization signals of NF-
B, thereby preventing movement of NF-
B
to the nucleus. On stimulation with signaling molecules such as tumor
necrosis factor (TNF)-
, phosphorylation of I
B
and I
B
leads to the ubiquitination and 26S proteosome-mediated degradation of
phospho-I
B
, thereby liberating NF-
B to enter the nucleus,
where it regulates transcription of a variety of genes including those
involved in inflammation (Fig. 3). Two
cytokine-inducible kinases, I
B kinase-
(IKK-
) and -
(IKK-
), have recently been characterized, and these enzymes
phosphorylate I
B
in response to proinflammatory cytokines
(16). An upstream mediator of these events is
NF-
B-inducing kinase (NIK), a novel member of the mitogen-activated protein kinase/extracellular signal-regulated kinase kinase (MEKK) family, which has been shown to activate both IKK-
and IKK-
through interaction with adaptor proteins associated with receptors for
TNF-
and IL-1 (15). The adaptor proteins TRAF2
and TRAF6 belong to the TNF receptor-associated factor (TRAF) family
and act as effectors for activated TNF-
and IL-1 receptors,
respectively (Fig. 3) (14).

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Fig. 3.
Schematic presentation of signaling events leading to
NF- B activation induced by stimuli such as cytokines and H. pylori. TRAF, tumor necrosis factor (TNF) receptor-associated
factor; NIK, NF- B-inducing kinase; IKK, I B kinase; P,
phosphorylated; Ub, ubiquitnated.
|
|
Stimulation of NF-
B does not require protein synthesis, thereby
allowing efficient activation of target genes such as IL-8. This system
is particularly utilized in immune, inflammatory, and acute phase
responses, where rapid activation of defense genes after exposure to
pathogens is critical for survival of an organism. Several studies
demonstrated that contact between H. pylori and gastric
epithelial cells results in brisk activation of NF-
B that is
followed by increased IL-8 mRNA and protein expression (11,
24). The ability of H. pylori to activate NF-
B in
vitro has been corroborated in vivo because activated NF-
B is
present within gastric epithelial cells of infected but not uninfected patients (11), and this site of localization mirrors the
pattern of increased IL-8 protein levels within colonized mucosa.
Recently, Maeda et al. (14) identified upstream mediators
that regulate H. pylori-induced NF-
B-dependent IL-8
production. Using in vitro transfections, these investigators
demonstrated that H. pylori-mediated NF-
B activation is
inhibited by IKK-
and IKK-
kinase-deficient mutants, indicating
that I
B
is degraded via activation of IKK-
and IKK-
during
H. pylori coculture (14). Kinase-deficient NIK
as well as dominant-negative mutants of the upstream adaptor proteins
TRAF2 or TRAF6 also inhibit the ability of H. pylori to
activate NF-
B (14). These results have established a
hierarchical series of events culminating in NF-
B activation in
which H. pylori activates NIK via TRAF2 and TRAF6, which, in
turn, phosphorylates and activates IKK-
and IKK-
. The activated
IKKs then phosphorylate I
B
, leading to its proteosome-mediated
degradation, with subsequent release and nuclear translocation of
NF-
B and induction of IL-8 (Fig. 3).
 |
REGULATION OF H. PYLORI-INDUCED IL-8 PRODUCTION BY
MITOGEN-ACTIVATED PROTEIN KINASE CASCADES |
Although the studies described have identified intracellular
intermediaries through which H. pylori activates NF-
B and
induces IL-8, recent investigations implicated mitogen-activated
protein kinases (MAPK) as additional mediators of H. pylori-dependent NF-
B activation and IL-8 expression. MAPK
cascades are signal transduction networks that target transcription
factors and thus participate in a diverse array of cellular functions
including cytokine production. MAPK cascades are organized in
three-kinase tiers consisting of a MAPK, a MAPK kinase (MKK), and a MKK
kinase (MKKK). Transmission of signals occurs by sequential
phosphorylation and activation of the components specific to a
respective cascade. In mammalian systems, five MAPK modules have been
identified and characterized to date; these include extracellular
signal-regulated kinase 1 and 2 (ERK 1/2), p38, and c-Jun
NH2-terminal kinase (JNK) (Fig.
4). In addition to regulating NF-
B,
MAPK can activate other transcription factors, such as AP-1, that
regulate cytokine gene expression. Because MAPK can activate both
NF-
B and AP-1, and the IL-8 gene promoter contains motifs for both
of these DNA binding proteins (Fig. 2), a fundamental extension of
previous studies focused on intracellular signaling has been to
determine whether MAPK activation is also required for H. pylori-mediated IL-8 production.

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Fig. 4.
Hypothetical model by which H. pylori
strain-specific components activate multiple signal transduction
cascades in gastric epithelial cells. N-WASP, neural Wiskott-Aldrich
syndrome protein; MKK, mitogen-activated protein kinase kinase; ERK,
extracellular signal-related kinase; PAK, p21-activated kinases; JNK,
c-Jun NH2-terminal kinase; ARP2/3, ARP2/3 actin nucleator;
MEK, mitogen-activated protein kinase/ERK kinase.
|
|
Using gastric epithelial cells, Keates et al. (12)
demonstrated that H. pylori rapidly induced a dose-dependent
activation of ERK, p38, and JNK MAPK, and, similar to NF-
B
activation, these effects were dependent on the presence of live
bacteria. Preincubation with ERK- and p38-specific inhibitors
completely blocked the ability of H. pylori to induce IL-8
but did not affect I
B
degradation or NF-
B activation. A recent
report from the Max Planck Institute extended these observations by
focusing on H. pylori-stimulated JNK activation
(18). JNK is activated by MKK4 and MKK7 and targets the
transcription factors c-fos and c-jun, which are
components of AP-1. Upstream kinases within the JNK cascade include
p21-activated kinases (PAK), which were the first kinases identified as
being direct effectors for the low-molecular-weight Rho-GTPases Rac1 and Cdc42. Naumann et al. (18) have now shown that
H. pylori directly activates Rho-GTPases that subsequently
stimulate PAK. PAK then activates MKK4 through an as yet unidentified
intermediary MKKK, which activates JNK (18).
Phosphorylated JNK then activates AP-1, possibly by activating
Elk-1 (which drives expression of c-fos) and
c-jun (Fig. 4).
An important question raised by these studies is whether H. pylori-induced IL-8 production is dependent on activation of
NF-
B, MAPK, or both. In vitro experiments utilizing IL-8 reporter
constructs revealed that H. pylori-induced IL-8 gene
expression is dependent on activation of both NF-
B and AP-1
(1), and cross-talk between NF-
B and MAPK pathways has
been previously demonstrated. For example, MEKK1 and NIK each can
directly activate the I
B kinase signalsome, resulting in I
B
phosphorylation and release of activated NF-
B (15, 16).
However, although inhibition of ERK and p38 MAPK attenuates H. pylori-induced IL-8 secretion, this does not affect NF-
B
activation (12), raising the possibility that synergistic interactions between AP-1 and NF-
B within the IL-8 promoter are required for maximal H. pylori-induced IL-8 production.
Consistent with this hypothesis, activation of ERK by H. pylori results in Elk-1 phosphorylation and enhanced
c-fos transcription (Fig. 4) (17). However, p38
is not required for H. pylori-induced activation of either
Elk-1 or AP-1 (17, 18). Thus ERK (via activation of Elk-1
and c-fos) may exert regulatory effects on H. pylori-induced IL-8 production that are primarily dependent on
AP-1, whereas p38 MAPK appears to influence IL-8 induction through
mechanisms that are independent of AP-1 or NF-
B (Fig. 4).
Collectively, these findings indicate that there is considerable
redundancy in the intracellular signaling pathways activated by
H. pylori that regulate IL-8 expression.
 |
BACTERIAL COMPONENTS REQUIRED FOR H. PYLORI
STRAIN-SPECIFIC ACTIVATION OF SIGNAL TRANSDUCTION PATHWAYS |
The ability of H. pylori to induce epithelial cell
responses related to pathogenesis is not uniform across strain
populations, and, similar to associations with increased disease
frequency, cagA+ strains are more potent in
stimulating IL-8 production than cagA
strains
(4). One of the first H. pylori strain-specific
constituents identified as being necessary for IL-8 production was
cagE, a component of the cag pathogenicity
island, and inactivation of this gene not only attenuates IL-8
expression but also decreases NF-
B activation in vitro
(27). Since this report, numerous cag island
genes (cagG, cagH, cagI,
cagL, and cagM), but not cagA, have
been demonstrated to be required for NF-
B activation
(10). The identical cag island gene products
responsible for NF-
B activation have now been shown to be necessary
for activation of MAPK and AP-1 (12, 17, 18), confirming
the pivotal role of the cag locus in activating eukaryotic
signal transduction pathways that influence induction of IL-8 (Fig. 4).
Several caveats to this model require discussion. Although
cagA+ strains stimulate higher levels of IL-8
than cagA
strains, there is substantial
heterogeneity among cagA+ isolates in the
ability to induce IL-8 in vitro, and a small proportion of wild-type
cagA
strains can stimulate IL-8 production
(25). Furthermore, certain isogenic mutant strains (i.e.,
cagE
, cagL
) can
induce a limited IL-8 response compared with uninfected control cells
(3). These observations suggest that undetected differences in the genetic composition of the cag island or
genetic loci exogenous to the island may also contribute to the ability of H. pylori to induce IL-8. Censini et al. (3)
reported that considerable differences exist in cag island
gene content among strains that contain the cagA gene (and
hence are classified as cagA+). Yamaoka and
colleagues (29) provided further insights into these
relationships by identifying a H. pylori outer membrane protein (oipA) that is synergistic with cagE in
inducing IL-8 in vitro, supporting the contention that additional as
yet unidentified strain-specific genes may also be required for
induction of IL-8. Identification of such genes using molecular
fingerprinting techniques such as restriction fragment length
polymorphisms or random arbitrarily primed PCR is limited by the
extensive genetic diversity that exists among H. pylori
strains. It is likely, however, that additional H. pylori
components required for stimulation of IL-8 will be identified in the
near future with the development and refinement of whole genome
microarrays (22), which will allow comprehensive genomic
comparisons to be made between isolates that differ in their ability to
induce proinflammatory cytokines.
 |
H. PYLORI CAG-MEDIATED EPITHELIAL CELL RESPONSES THAT
ARE INDEPENDENT OF INFLAMMATION |
One hypothesis generated by the preceding data is that the
cag type IV secretion system translocates a bacterial factor
into the epithelial cell that activates NF-
B and/or MAPK with
subsequent induction of IL-8. Three studies have now demonstrated that
tyrosine phosphorylation of CagA occurs within the host epithelial cell after H. pylori-epithelial cell contact (2, 20,
26). However, disruption of cagA does not affect
NF-
B or MAPK activation or IL-8 release (12, 24, 27),
indicating either that an independent bacterial factor is injected into
the host cell by the cag island or that perturbation of the
eukaryotic membrane per se by the type IV secretion system affects IL-8
expression (Fig. 4). What then might be the biological importance of
CagA translocation and phosphorylation? The significance of
phosphorylated bacterial proteins within host cells is a phenomenon
that is becoming increasingly recognized. For example, the translocated
intimin receptor (Tir) of enteropathogenic Escherichia coli
is injected into and tyrosine phosphorylated within epithelial cells
and serves as a receptor for intimin adhesion (13). Recent
data indicate that phosphorylated CagA induces cytoskeletal changes
including cell elongation, cell spreading, and production of filapodia
and lamellipodia (23). Because CagA tyrosine
phosphorylation triggers host cell morphological changes, pathways that
control organization of the actin cytoskeleton may represent targets of
intracellular CagA modification. Phosphorylated CagA may recapitulate
intracellular events induced by Shigella flexneri IcsA and
bind directly to neural Wiskott-Aldrich syndrome protein (N-WASP) with
subsequent binding to the ARP2/3 actin nucleator (8), thus
stimulating actin polymerization and pedestal formation (Fig. 4).
Although this is unconfirmed, one may speculate that phosphorylation of
CagA within the host cell confers a survival advantage that allows
H. pylori to persist for prolonged periods of time within
the hostile gastric environment. An example of this mechanism is
utilization of forced actin polymerization that is mediated by tyrosine
phosphorylation of the vaccinia viral protein A36R, which is required
for propagation of virions from cell to cell (9).
 |
FUTURE DIRECTIONS |
Considerable efforts have focused on delineating the precise
mechanisms by which H. pylori may induce gastric
inflammation. However, another avenue for future research is to
consider that H. pylori may also possess means to
downregulate the host inflammatory response, a requirement seemingly
inherent for an organism that persists for the lifetime of its host.
Crabtree et al. (5) found that inactivation of a
cag island gene (cag10) results in a paradoxical
increase in IL-8 secretion compared with levels induced by wild-type
H. pylori. Recent studies in Salmonella
typhimurium, which contains a type III secretion system, have
identified dramatic differences between pathogenic and nonpathogenic
strains in the ability to regulate NF-
B-dependent IL-8 production.
Certain nonpathogenic Salmonella attenuate IL-8 secretion
induced by pathogenic bacteria or by inflammatory cytokines by
inhibiting the ubiquitination of I
B
, a novel mechanism for
dampening the inflammatory response (19). It must be
recognized, however, that contact between epithelial cells and H. pylori is likely to induce levels of host-bacteria adaptation that
are not found during cellular interactions with acute pathogens that
possess similar secretion systems. The question of whether H. pylori strains that are not associated with disease (i.e.,
cagA
strains) similarly inhibit signal
transduction pathways involved in generation of inflammatory cytokines
is a fertile area of interest.
 |
ACKNOWLEDGEMENTS |
The author thanks Dawn A. Israel for constructive review and
insightful critique of this manuscript.
 |
FOOTNOTES |
Address for reprint requests and other correspondence: R. M. Peek, Jr., Div. of Gastroenterology, Vanderbilt Univ. School of
Medicine, C-2104 Medical Center North, Nashville, TN 37232-2279 (E-mail: richard.peek{at}mcmail.vanderbilt.edu).
 |
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