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Gastrointestinal Unit and Center for the Study of Inflammatory Bowel Disease, Department of Medicine, Massachusetts General Hospital and Harvard Medical School, Boston, MA, 02114
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Abstract |
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 Top Abstract IntroductionMaterials and MethodsResultsDiscussionReferences |
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B
transcription factor. However, the functional responses of intestinal
epithelial cells (IEC) to stimulation with LPS are unknown. Expression
of mRNA and protein for CD14 and TLRs were assessed by RT-PCR,
immunoblotting, and immunohistochemistry in mouse and human IEC lines.
LPS-induced activation of signaling pathways (p42/p44 mitogen-activated
protein kinase (MAPK), c-Jun NH2-terminal kinase (JNK),
p38, p65, NF-B) were assessed by immunoblotting and gel shifts. CD14
mRNA and protein expression were not detectable in IEC. However, human
TLR2, TLR3, and TLR4 mRNA were present in IEC. TLR4 protein was
expressed in all cell lines; however, TLR2 protein was absent in HT29
cells. Immunofluorescent staining of T84 cells demonstrated the
cell-surface presence of the TLRs. LPS-stimulation of IEC resulted in
activation (>1.5-fold) of the three members of the MAPK family. In
contrast, LPS did not significantly induce activation of JNK and p38 in
CMT93 cells, p38 in T84 cells and MAPK and JNK in HT29 cells.
Downstream, LPS activated NF-B in IEC in a time-, dose-, and
serum-dependent manner. IEC express TLRs that appear to mediate LPS
stimulation of specific intracellular signal transduction pathways in
IEC. Thus, IEC may play a frontline role in monitoring lumenal
bacteria. |
Introduction |
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TopAbstractIntroductionMaterials and MethodsResultsDiscussionReferences |
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Potential pathogenic bacteria are able to directly deposit their toxic and proinflammatory constituents, such as LPS, a glycolipid derived from the outermost membrane of pathogenic Gram-negative bacteria, at the intestinal epithelial, apical surface. LPS may then be internalized, recycled, stored, or transcytosed from the apical to the basolateral pole of the intestinal epithelium (4, 5).
LPS is a potent toxin that elicits several immediate proinflammatory responses in mammalian cells (6). LPS-induced activation of monocytes, macrophages, or polymorphonuclear neutrophils is mainly mediated through CD14, a GPI-anchored membrane receptor (7, 8, 9). Soluble CD14 is present in serum (10) and facilitates binding of LPS to cells that do not express membrane CD14 (11, 12, 13). Binding of LPS to CD14 is enhanced by the presence of the LPS binding protein (LBP) (12). LBP may also enhance binding of whole Gram-negative bacteria to cells via CD11/CD18 (14). However, because these integrins lack intracellular signaling domains, they probably function to transfer LPS to a second receptor that directly transduces the signal.
Recently, several Toll-like receptors (TLR) have been identified in
blood macrophages and monocytes based on homology to the
Drosophila protein (15, 16). Although initially
detected as orphan receptors, recent studies have demonstrated that
TLRs act as transmembrane coreceptors to CD14 in the cellular response
to LPS (reviewed in Refs. 17 and 18). Recent
studies have variably suggested that TLR2 or TLR4 serve as the main
mediator of responses to LPS in vitro and in vivo
(19, 20, 21, 22, 23, 24). It appears that TLR4 plays the major role as LPS
receptor (19, 21). However, the role of TLR2 still needs
to be further defined. Heine et al. have shown that the presence of
TLR2 is not essential for some cells to respond to LPS
(20). However, Yang et al. have clearly demonstrated that
TLR2 mediates LPS-induced intracellular signaling (22).
LPS-LBP binding to CD14 can result in rapid phosphorylation of p42/p44
mitogen-activated protein kinase (MAPK), p38, and c-Jun
NH2-terminal kinase (JNK) in monocytic cell lines
(25, 26, 27, 28, 29). Downstream, LPS signaling through TLRs rapidly
leads to NF-B activation in monocytic cells (24, 30, 31, 32).
A variety of recent studies have increasingly uncovered the important role of intestinal epithelial cells as a key component of the mucosal immune system (33). LPS is known to induce the proinflammatory cytokine IL-8 in HT29 and SW620 epithelial cells (12, 34). However, signaling pathways upstream of cytokine expression induced by LPS have not yet been fully established in IEC lines.
The effects of LPS on monocytes as one focal point of the host response to this key bacterial product have been well studied. We speculated that LPS may induce specific responses in IEC, the frontline of the mucosal immune system. To understand the functional role of the intestinal epithelium in mucosal host defense as part of the immune system, we characterized LPS-induced signal transduction pathways in IEC lines in vitro.
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Materials and Methods |
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TopAbstractIntroductionMaterials and MethodsResultsDiscussionReferences |
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LPS (Escherichia coli, O26:B6) prepared by phenol
extraction was purchased from Sigma (St. Louis, MO) and prepared as
dispersed sonicate in endotoxin-free water (Life Technologies,
Rockville, MD) before diluting to final concentration in supplemented
media. IL-1
was obtained from R&D Systems (Minneapolis, MD). PMA was
purchased from Sigma, and radiochemicals were obtained from NEN Life
Science (Boston, MA).
Cell culture
The human colon cancer cell lines HT29, Caco2, and T84 and the
mouse rectal carcinoma cell line CMT93 were obtained from the American
Type Culture Collection (Manassas, VA). Cells were grown in DMEM
(Cellgro, Herndon, VA) containing 4.5g/L glucose and 10% (HT29, CMT93)
or 20% (Caco2) FBS (Sigma). T84 cells were grown in a 1:1 mix of DMEM
and Ham’s F-12 medium (Cellgro) containing 10% FBS. All media were
supplemented with 4 mmol/L L-glutamine (Life Technologies),
50 U/ml penicillin, and 50 µg/ml streptomycin (Sigma). Cells were
grown in 5% CO2 at 37°C within a humidified
incubator. T84 and Caco2 cells were grown on filters (0.4 µM; Becton
Dickinson, Franklin Lanes, NJ) to confluent monolayers to achieve a
polarized and differentiated state within 14–21 days
(35). Transepithelial resistance was used to monitor
changes in epithelial cell culture integrity and confluency and ranged
from >1500 
cm2 for confluent T84 and >500
cm2 for Caco2 cells (Millicell Electrical
Resistance System; Millipore, Bedford, MA) before each experiment. THP1
cells were kindly provided by Dr. Ramnik Xavier and were seeded into
culture flasks in DMEM supplemented with PMA (10 ng/ml) to induce
differentiation and CD14 expression (26). U937 cells were
grown in RPMI 1640 (Cellgro) containing 10% FBS and supplemented with
PMA (10 ng/ml) to induce differentiation and CD14 expression and cell
adherence. Whole-cell lysates from the monocytic cell line U937 were
used as positive control for TLR protein expression.
Assessment of LPS receptor mRNA expression: RT-PCR analysis
Expression of human TLR2, 3, and 4 mRNA (16) were assessed using total RNA by RT-PCR from HT29 and T84 cells (RNeasy Mini Kit; Qiagen, Valencia, CA). PCR primers for human TLR2 (346 bp) and human TLR4 (506 bp) have been previously described (31). PCR primers used for human TLR3 (320 bp) were 5'-AAA TTG GGC AAG AAC TCA CAG G and 5'-GTG TTT CCA GAG CCG TGC TAA. THP1 cDNA was used as positive source of human TLR expression to confirm the specificity of the primers and PCR, as recently shown (31). Human TLR2 cDNA from T84 cells and human TLR3 and TLR4 cDNAs from HT29 cells were inserted into pCR2.1 vector (TA Cloning Kit; Invitrogen, San Diego, CA), and subsequently sequenced (Massachusetts General Hospital DNA Sequencing Core Facility, Boston, MA).
Expression of human and murine CD14 mRNAs in HT29, T84, and CMT93 cells, respectively, were also assessed by RT-PCR (36). PCR primers used for human CD14 were 5'-GGT GCC GCT GTG TAG GAA AGA and 5'-GGT CCT CGA GCG TCA GTT CCT (450 bp). The PCR primers used for mouse CD14 (1326 bp) have previously been described (37). Species nonspecific GAPDH primers were 5'-CGG AGT CAA CGG ATT TGG TCG TAT and 5'-AGC CTT CTC CAT GGT GGT GAA GAC (306 bp). All PCR products were resolved by 1–2% agarose gel electrophoresis, and DNA bands were visualized by staining the gel with ethidium bromide.
Assessment of receptor and signaling proteins: immunoblotting
Cells, grown on 60 mm dishes or filters, were rinsed in cold PBS and placed on ice in 400 µl lysis buffer per well (1% Triton X-100, 150 mM NaCl, 20 mM Tris-HCl, pH 7.5, 2 mM EDTA, containing 10 µg/ml leupeptin, 10 µg/ml aprotinin, 1 mM sodium fluoride, 1 mM sodium orthovanadate, and 2 mM PMSF). Lysates were centrifuged (12,000 x g, 15 min at 4°C), and protein concentration in each supernatant was determined by colorimetric Bradford protein assay (Bio-Rad, Hercules, CA). Proteins (per lane, 15–25 µg) from the resulting supernatants were heated (85°C, 2 min), subjected to SDS-PAGE (4–12% Bis-Tris; Novex, San Diego, CA), and then transferred onto a polyvinylidene difluoride membrane (Millipore) followed by immunoblotting (according to the manufacturer’s instructions) with specific polyclonal Abs to tyrosine-phosphorylated p42/p44 MAPK, JNK, or p38 (Promega, Madison, WI, and New England Biolabs, MA). Whole-cell lysates were used as positive controls after stimulation with PMA (10-7 M for 30 min). The positive and negative control for phosphorylation of p38 (C6 glioma whole-cell lysates prepared with and without anisomycin treatment) were obtained from New England Biolabs. To confirm equal loading, immunoblots were stripped with 62.5 mM Tris-HCl, pH 6.8, 2% SDS containing 100 mM 2-ME at 50°C for 30 min and reprobed with polyclonal anti-extracellular signal-related kinase (ERK)-2 or anti-p38 Abs (Santa Cruz Biotechnology, Santa Cruz, CA). The membrane was developed with an enhanced chemiluminescence detection kit (NEN Life Science). Only results with significant increase of at least 1.5-fold phosphorylation of MAPK activation are presented. All experiments were repeated at least three times, and a representative result is shown for each experiment.
Anti-TLR2 and anti-TLR4 antisera (1:1000) were gifts from Tularik (San Francisco, CA) and have been previously described (31).
Immunohistochemistry
T84 and U937 cells were seeded at different states of confluency onto plastic tissue culture slides. Slides were then washed with cold PBS and fixed in 4% paraformaldehyde/PBS containing 0.1% Triton X-100 for 60 min at 4°C (detergent was omitted for CD14 staining). After blocking with normal goat serum (Sigma), anti-TLR2, anti-TLR4, or normal anti-rabbit IgG (Santa Cruz Biotechnology) were added (1:100, 16 h), followed by FITC goat anti-rabbit (Vector Laboratories, Burlingame, CA). After blocking with horse serum (Life Technologies), anti-CD14 ("UCH-M1" from Santa Cruz Biotechnology and "MY4" from Coulter, Palo Alto) or normal anti-mouse IgG (Santa Cruz Biotechnology) were added (1:100, 16 h), followed by FITC horse anti-mouse (Vector Laboratories). Cells were then immediately viewed on an inverted immunofluorescence microscope (x40 objective, model IX70; Olympus, New Hyde Park, NY).
Nuclear extracts and assessment of NF-B activation by Western
blotting and EMSA
Nuclear extracts were prepared according to the protocol
described by Schreiber et al. (38). Nuclear content of the
NF-B subunit p65 was determined by Western blot analysis
(anti-p65; Santa Cruz Biotechnology), as described above. NF-B
consensus (5'-AGT TGA GGG GAC TTT CCC AGG C) and mutant (5'-AGT TGA GGC
GAC TTT CCC AGG C) oligonucleotides were obtained from Santa Cruz
Biotechnology. Double-stranded oligonucleotides were 5'-end labeled
with [
-32P]ATP using T4 polynucleotide
kinase (Promega). For competition, an 100-fold excess of cold
oligonucleotide was added to the reaction. The reaction was conducted
in a total volume of 20 µl, using 0.5 ng of labeled oligonucleotide,
10–15 µg of nuclear protein extract, and 1 µg of poly(dI-dC)
(Amersham Pharmacia, Piscataway, NJ) in 1x buffer (10 mM Tris-HCl, pH
7.5, 50 mM NaCl, 5 mM MgCl2, 1 mM DTT, 1 mM EDTA,
5% glycerol). The samples were loaded onto a 6% polyacrylamide gel
and run in 0.25x TBE buffer. The resultant DNA-protein complexes were
then detected by autoradiography.
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Results |
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TopAbstractIntroductionMaterials and MethodsResultsDiscussionReferences |
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Expression of CD14 mRNA in human (T84, HT29) and mouse (CMT93) IEC
lines was initially assessed by RT-PCR. U937 (differentiated) and mouse
macrophage cDNAs were used as known sources of human and mouse CD14
expression, respectively, to confirm the specificity of the primers and
PCR (Fig. 1
). No PCR product was detected
in any of the intestinal epithelial-derived T84, HT29, or CMT93 cells
using CD14-specific human or murine primers. However, signals of
appropriate sizes were detected in U937 and macrophages. RT-PCR
analysis of GAPDH expression confirmed the quality of all RNA
preparations used for RT-PCR.
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B, 1,
immunofluorescence, 2, phase contrast). The monocytic
differentiated cell line U937 (Fig. 1B, 3) was
used as a positive control and demonstrated specific cell-surface CD14
staining (Fig. 1B, 4, mouse IgG as negative
control). This result was confirmed using two different anti-CD14
Abs (results for anti-CD14 (My4) are shown).
Primarily based on published cDNA sequences of human TLR2, TLR3, and
TLR4 (15, 16) were used for RT-PCR to assess the presence
of these TLRs in IEC. Primers specific for human TLRs were synthesized
and used to assess expression of human TLR2, TLR3, and TLR4 mRNA in
HT29 or T84 cells. Human THP1 cells served as positive sources of human
Toll-like mRNA and confirmed the specificity of the primers and PCR. As
shown in Fig. 2, TLR2, TLR3, and TLR4
mRNAs were present in both HT29 and T84 cells. The PCR products (346,
320, 506 bp) detected in T84 or HT29 cells were isolated, subcloned,
and sequenced. The obtained sequences of these PCR products were >92%
identical with the known nucleotide sequences of human TLRs (GenBank
accession no. U88878, U88879, U88880).
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A).
However, TLR2 protein was not detectable in HT29 cells or the monocytic
cell line U937. Human TLR4 protein was expressed in all three human IEC
lines. LPS stimulation did not modulate TLR4 protein expression in T84
cells. The presence of TLR2 (Fig. 3B, 1) and TLR4
(Fig. 3B, 2) on the cell surface of T84 cells
(rabbit IgG as negative control; Fig 3B, 3) was
confirmed by immunofluorescent histochemistry.
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CMT93, T84, and HT29 cells were incubated with LPS for various
time periods, and phosphorylation of MAPK, p38, and JNK was assessed by
Western blotting. PMA (10-7 M for 30 min) was
used as a positive control of MAPK phosphorylation in these cell lines.
As demonstrated in Fig. 4A,
LPS (10 µg/ml) strongly up-regulated p42/p44 Mapk in CMT93 cells
within 5 min after stimulation. In contrast, LPS did not affect
significantly activation of p38 and JNK (data not presented). In the
absence of LPS stimulation (negative control), minimal baseline MAPK
activity was measured, presumably reflecting primarily physical stress
(change of the media). p42/p44 MAPK phosphorylation, as measured by
immunoblotting, was proportional to increasing concentrations of LPS
and required the presence of FBS (Fig. 4B). The absence of
serum completely abolished the activation of MAPK in LPS-treated CMT93
cells.
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). JNK was minimally activated by LPS in
a time-dependent fashion in differentiated T84 cells. However, we
failed to detect activation of p38 in T84 cells in response to LPS
(data not presented). Phosphorylation of p38 was assessed in lysates of
HT29 cells prepared at various times after the addition of LPS. As
shown in Fig. 6, a major peak of p38
activity was observed at 15 min. However, cell lysates of HT29
stimulated with 5 µg/ml LPS did not exhibit specific induction of JNK
or p42/p44 MAPK activity at any time (data not presented). As PMA did
not induce significant phosphorylation of p38 in HT29 cells (data not
shown), the positive and negative controls provided from the
manufacturer are presented.
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B consensus sequence binding in IEC. As shown in Fig. 7A, LPS up-regulated the
binding of proteins to the NF-B consensus sequence in a time- and
dose-dependent manner. Activation was specifically inhibited by
addition of 100-fold excess of unlabeled NF-B oligonucleotides
containing a wild-type NF-B binding sequence. This result was
confirmed (Fig. 7B) by Western blot analysis of the
expression of the NF-B subunit p65 in nuclear extracts of HT29 cells
after stimulation for 10 min with LPS (0.5 or 5 µg/ml). As
demonstrated in Fig. 7C, LPS-induced nuclear translocation
of p65 required the presence of serum in T84 cells.
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Discussion |
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TopAbstractIntroductionMaterials and MethodsResultsDiscussionReferences |
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We hypothesized that LPS, a key product of pathogenic Gram-negative bacteria, might stimulate different signal transduction pathways in IEC. LPS activates myeloid lineage cells by binding to membrane-bound CD14 (mCD14) (9). To determine whether the receptor mCD14 could be involved in LPS-induced IEC activation, we examined CD14 mRNA and protein expression in IEC lines. However, none of the three tumor IEC lines used in this study expressed constitutive mRNA for CD14. Using immunohistochemistry, CD14 cell-surface protein expression was not detectable in our in vitro studies of intestinal tumor cell lines. However, mCD14 expression has been shown to be significantly up-regulated in response to LPS in various systems in vivo (40). Despite the inability to detect mCD14 in these cell lines in vitro, possibly exposure to abnormal high concentrations of lumenal LPS during acute bacterial infection in vivo might produce mCD14 gene expression by IEC. Interestingly, IL-2-deficient (-/-) mice overexpress intestinal epithelial mCD14 RNA, which is not detectable in the wild type (41).
CD14 also exists as a soluble plasma protein (sCD14), which, together with another serum protein designated LBP, can facilitate binding of LPS to epithelial and endothelial cells (12). Our results demonstrate that to activate distinct intracellular signal transduction pathways in IEC by LPS, serum is required, presumably as a source of soluble CD14 and LBP (10). These proteins may function as opsonins that capture pathogenic microbes facilitating recognition of lumenal bacterial pathogens by the mCD14-negative intestinal epithelium. These serum proteins may be released from the vascular space when the intestinal epithelial monolayer is disrupted and invaded by pathogens. Injury of the intestinal mucosa may also lead to recruitment and migration of acute inflammatory cells into the mucosa (42), which could release sCD14 by cleavage of mCD14 (43), inducing a defensive response of the intestinal epithelium to bacterial toxins.
Recently, CD14-deficient mice have been shown to be highly resistant to shock induced by purified LPS or bacteremia (44). In active inflammatory bowel disease, CD14 is highly up-regulated in recruited monocytes of the intestinal mucosa (45) and could play an important role promoting hyperresponsiveness of the intestinal epithelium to LPS. TLR appear to act cooperatively with CD14 in LPS-induced cellular signal transduction in peripheral blood leucocytes. Yang et al. have shown that TLR2 expression is activated by LPS in a response that depends on LBP and is enhanced by CD14 (22). The present study demonstrates that IEC express at least two TLRs. Recently, it has been shown that TLR mRNA is absent in macrophages from normal mucosa but is expressed in macrophages in inflamed mucosa of patients with inflammatory bowel disease (46). In vivo studies are needed to clarify the role of CD14 and TLR proteins in the intestinal epithelium as well as inflammatory cells in the pathogenesis of inflammatory bowel diseases. Immune imbalance in these patients could result from undue activation by LPS and bacteria through these epithelial receptors. Conceptually, neutralizing Abs against CD14 and/or LBP could ameliorate colitis.
MAPK appears to be an important mediator of LPS activation in IEC. We show that p42/p44 MAPK is selectively activated in a concentration-dependent manner by LPS. Of interest, stimulation of p42/p44 MAPK was less strong than that observed after PMA. This suggests that IEC may be partially desensitized or tolerant of LPS, limiting activation of the underlying immune cells in the face of constant exposure to LPS at the apical surface of the epithelium. Hyporesponsiveness may primarily result from the absence of mCD14. The time courses of activation of these kinases in IEC lines following stimulation with LPS was maximal for p42/p44 at 5–10 min and for p38 and JNK at later time points (10–30 min), which is consistent with observations in other cell lines (25, 26, 47). LPS activation of p42/p44 in differentiated T84 cells was delayed and peaked later at 30 min.
Interestingly, LPS-induced stimulation of different IEC lines involves selected activation of MAPK pathways. Thus, we did not observe significant LPS-induced activation (>1.5 fold) of JNK or p38 in CMT93 cells, p38 in T84 cells or MAPK, and JNK in HT29 cells. These results may reflect cell-specific features, including the state of differentiation or idiosyncratic alterations of signal transduction pathways in these colon cancer cell lines. It is known that LPS stimulation does not always result in the activation of p42/p44 MAPK, JNK, or p38 in other cell lines, including subgroups of peripheral blood leukocytes. Nick et al. have shown that neither p42/p44 MAPK nor JNK are activated by LPS stimulation of neutrophils (47).
NF-B is an abundantly expressed transcription factor that is central
to several immune and inflammatory responses, leading to rapid
induction of cytokine secretion (48). Awane et al. have
recently shown that NF-B-inducing kinase serves as the common
mediator in the NF-B signaling cascades triggered by IL-17, TNF-
,
and IL-1 in IEC (49). In immune effector cells like
monocytes, bacterial LPS has been demonstrated to be a potent stimulus
of NF-B (50). After stimulation with LPS, TLR4 can
activate NF-B transcription and induces expression of inflammatory
cytokines and costimulatory molecules, suggesting that human TLRs
participate in the innate immune response and signal the activation of
adaptive immunity (15). Enteropathogenic Escherichia
coli are known to activate NF-B in IEC, which is causally
linked to IL-8 production (51). Naumann et al. have
suggested that the activation of NF-B in epithelial cells is
independent of penetration and invasion of pathogenic bacteria
(52). We demonstrate by gel shift assays and Western
blotting that, in the absence of bacteria, the pathogenic toxin LPS
itself is an effective inducer of NF-B expression in the IEC lines
HT29 and T84. LPS induction of NF-B activation is time- (maximal at
15 min) and concentration-dependent in these cell lines. LPS-induced
activation of NF-B factor in IEC depends on the presence of serum.
Whether LPS directly transduces activation of NF-B via
TLR in IEC needs to be further investigated. Held et al. have shown
that IFN- may trigger LPS activity in macrophages by LPS-induced
NF-B transcription (53). Synergistic induction of
NF-B activation might also play an important role in host defense of
the intestinal epithelium, enabling quiescent cells to respond quicker
to bacterial Ags.
Finally, we conclude that the lack of constitutive mCD14 may make IEC hyporesponsive and tolerant to the constant lumenal exposure of resident microflora and nondangerous amounts of pathogenic bacterial toxins. However, our results also suggest that any release or expression of specific serum mediator proteins may turn quiescent IEC into defensive immune cells with the capability to immediately recognize serious infectious challenges. IEC constitutively express TLRs that might be a critical link to readily up-regulate distinct intracellular signal transduction pathways as stress response—analogous to primary effector cells of the immune system.
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Acknowledgments |
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Footnotes |
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2 Address correspondence and reprint requests to Dr. Daniel K. Podolsky, Massachusetts General Hospital, Gastrointestinal Unit GRJ719, 32 Fruit Street, Boston, MA 02114. E-mail address:
3 Abbreviations used in this paper: IEC, intestinal epithelial cells; ERK, extracellular regulated kinase; p-ERK, phosphorylated ERK; JNK, c-Jun NH2-terminal kinase; p-JNK, phosphorylated JNK; MAPK, mitogen-activated protein kinase; p-MAPK, phosphorylated MAPK; TLR, Toll-like receptor; LBP, LPS binding protein; mCD14, membrane-bound CD14; sCD14, soluble CD14.
Received for publication July 20, 1999. Accepted for publication November 4, 1999.
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S. Chabot, J. S. Wagner, S. Farrant, and M. R. Neutra TLRs Regulate the Gatekeeping Functions of the Intestinal Follicle-Associated Epithelium J. Immunol., April 1, 2006; 176(7): 4275 - 4283. [Abstract] [Full Text] [PDF]
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Y. Hirata, T. Ohmae, W. Shibata, S. Maeda, K. Ogura, H. Yoshida, T. Kawabe, and M. Omata MyD88 and TNF Receptor-Associated Factor 6 Are Critical Signal Transducers in Helicobacter pylori-Infected Human Epithelial Cells J. Immunol., March 15, 2006; 176(6): 3796 - 3803. [Abstract] [Full Text] [PDF]
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A. S. Ismail and L. V. Hooper Epithelial Cells and Their Neighbors. IV. Bacterial contributions to intestinal epithelial barrier integrity Am J Physiol Gastrointest Liver Physiol, November 1, 2005; 289(5): G779 - G784. [Abstract] [Full Text] [PDF]
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C. Rumio, D. Besusso, M. Palazzo, S. Selleri, L. Sfondrini, F. Dubini, S. Menard, and A. Balsari Degranulation of Paneth Cells via Toll-Like Receptor 9 Am. J. Pathol., August 1, 2004; 165(2): 373 - 381. [Abstract] [Full Text] [PDF]
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S. T. Magness, H. Jijon, N. Van Houten Fisher, N. E. Sharpless, D. A. Brenner, and C. Jobin In Vivo Pattern of Lipopolysaccharide and Anti-CD3-Induced NF-{kappa}B Activation Using a Novel Gene-Targeted Enhanced GFP Reporter Gene Mouse J. Immunol., August 1, 2004; 173(3): 1561 - 1570. [Abstract] [Full Text] [PDF]
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S. Ishihara, M. A. K. Rumi, Y. Kadowaki, C. F. Ortega-Cava, T. Yuki, N. Yoshino, Y. Miyaoka, H. Kazumori, N. Ishimura, Y. Amano, et al. Essential Role of MD-2 in TLR4-Dependent Signaling during Helicobacter pylori-Associated Gastritis J. Immunol., July 15, 2004; 173(2): 1406 - 1416. [Abstract] [Full Text] [PDF]
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J.-M. Otte and D. K. Podolsky Functional modulation of enterocytes by gram-positive and gram-negative microorganisms Am J Physiol Gastrointest Liver Physiol, April 1, 2004; 286(4): G613 - G626. [Abstract] [Full Text] [PDF]
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K. Kojima, M. W. Musch, M. J. Ropeleski, D. L. Boone, A. Ma, and E. B. Chang Escherichia coli LPS induces heat shock protein 25 in intestinal epithelial cells through MAP kinase activation Am J Physiol Gastrointest Liver Physiol, April 1, 2004; 286(4): G645 - G652. [Abstract] [Full Text] [PDF]
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C. F. Benjamim, C. M. Hogaboam, and S. L. Kunkel The chronic consequences of severe sepsis J. Leukoc. Biol., March 1, 2004; 75(3): 408 - 412. [Abstract] [Full Text] [PDF]
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L. Guillot, S. Medjane, K. Le-Barillec, V. Balloy, C. Danel, M. Chignard, and M. Si-Tahar Response of Human Pulmonary Epithelial Cells to Lipopolysaccharide Involves Toll-like Receptor 4 (TLR4)-dependent Signaling Pathways: EVIDENCE FOR AN INTRACELLULAR COMPARTMENTALIZATION OF TLR4 J. Biol. Chem., January 23, 2004; 279(4): 2712 - 2718. [Abstract] [Full Text] [PDF]
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E. S. Van Amersfoort, T. J. C. Van Berkel, and J. Kuiper Receptors, Mediators, and Mechanisms Involved in Bacterial Sepsis and Septic Shock Clin. Microbiol. Rev., July 1, 2003; 16(3): 379 - 414. [Abstract] [Full Text] [PDF]
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B. Su, P. J. M. Ceponis, S. Lebel, H. Huynh, and P. M. Sherman Helicobacter pylori Activates Toll-Like Receptor 4 Expression in Gastrointestinal Epithelial Cells Infect. Immun., June 1, 2003; 71(6): 3496 - 3502. [Abstract] [Full Text] [PDF]
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M. Suzuki, T. Hisamatsu, and D. K. Podolsky Gamma Interferon Augments the Intracellular Pathway for Lipopolysaccharide (LPS) Recognition in Human Intestinal Epithelial Cells through Coordinated Up-Regulation of LPS Uptake and Expression of the Intracellular Toll-Like Receptor 4-MD-2 Complex Infect. Immun., June 1, 2003; 71(6): 3503 - 3511. [Abstract] [Full Text] [PDF]
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J. D. Schilling, S. M. Martin, C. S. Hung, R. G. Lorenz, and S. J. Hultgren Toll-like receptor 4 on stromal and hematopoietic cells mediates innate resistance to uropathogenic Escherichiacoli PNAS, April 1, 2003; 100(7): 4203 - 4208. [Abstract] [Full Text] [PDF]
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Y. Asai, T. Jinno, and T. Ogawa Oral Treponemes and Their Outer Membrane Extracts Activate Human Gingival Epithelial Cells through Toll-Like Receptor 2 Infect. Immun., February 1, 2003; 71(2): 717 - 725. [Abstract] [Full Text] [PDF]
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G. Melmed, L. S. Thomas, N. Lee, S. Y. Tesfay, K. Lukasek, K. S. Michelsen, Y. Zhou, B. Hu, M. Arditi, and M. T. Abreu Human Intestinal Epithelial Cells Are Broadly Unresponsive to Toll-Like Receptor 2-Dependent Bacterial Ligands: Implications for Host-Microbial Interactions in the Gut J. Immunol., February 1, 2003; 170(3): 1406 - 1415. [Abstract] [Full Text] [PDF]
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K. E. Weatherby, B. S. Zwilling, and W. P. Lafuse Resistance of Macrophages to Mycobacterium avium Is Induced by {alpha}2-Adrenergic Stimulation Infect. Immun., January 1, 2003; 71(1): 22 - 29. [Abstract] [Full Text] [PDF]
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J. E. Butler, P. Weber, M. Sinkora, D. Baker, A. Schoenherr, B. Mayer, and D. Francis Antibody Repertoire Development in Fetal and Neonatal Piglets. VIII. Colonization Is Required for Newborn Piglets to Make Serum Antibodies to T-Dependent and Type 2 T-Independent Antigens J. Immunol., December 15, 2002; 169(12): 6822 - 6830. [Abstract] [Full Text] [PDF]
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E. E. Putnins, A.-R. Sanaie, Q. Wu, and J. D. Firth Induction of Keratinocyte Growth Factor 1 Expression by Lipopolysaccharide Is Regulated by CD-14 and Toll-Like Receptors 2 and 4 Infect. Immun., December 1, 2002; 70(12): 6541 - 6548. [Abstract] [Full Text] [PDF]
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F M Ruemmele, J F Beaulieu, S Dionne, E Levy, E G Seidman, N Cerf-Bensussan, and M J Lentze Lipopolysaccharide modulation of normal enterocyte turnover by toll-like receptors is mediated by endogenously produced tumour necrosis factor {alpha} Gut, December 1, 2002; 51(6): 842 - 848. [Abstract] [Full Text] [PDF]
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S. Agelaki, C. Tsatsanis, A. Gravanis, and A. N. Margioris Corticotropin-Releasing Hormone Augments Proinflammatory Cytokine Production from Macrophages In Vitro and in Lipopolysaccharide-Induced Endotoxin Shock in Mice Infect. Immun., November 1, 2002; 70(11): 6068 - 6074. [Abstract] [Full Text] [PDF]
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D. Haller, M. P. Russo, R. B. Sartor, and C. Jobin IKKbeta and Phosphatidylinositol 3-Kinase/Akt Participate in Non-pathogenic Gram-negative Enteric Bacteria-induced RelA Phosphorylation and NF-kappa B Activation in Both Primary and Intestinal Epithelial Cell Lines J. Biol. Chem., October 4, 2002; 277(41): 38168 - 38178. [Abstract] [Full Text] [PDF]
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P. Cameron, D. Bingham, A. Paul, M. Pavelka, S. Cameron, D. Rotondo, and R. Plevin Essential Role for Verotoxin in Sustained Stress-Activated Protein Kinase and Nuclear Factor Kappa B Signaling, Stimulated by Escherichia coli O157:H7 in Vero Cells Infect. Immun., October 1, 2002; 70(10): 5370 - 5380. [Abstract] [Full Text] [PDF]
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R. M. Hershberg The Epithelial Cell Cytoskeleton and Intracellular Trafficking: V. Polarized compartmentalization of antigen processing and Toll-like receptor signaling in intestinal epithelial cells Am J Physiol Gastrointest Liver Physiol, October 1, 2002; 283(4): G833 - G839. [Abstract] [Full Text] [PDF]
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N. Tsuboi, Y. Yoshikai, S. Matsuo, T. Kikuchi, K.-I. Iwami, Y. Nagai, O. Takeuchi, S. Akira, and T. Matsuguchi Roles of Toll-Like Receptors in C-C Chemokine Production by Renal Tubular Epithelial Cells J. Immunol., August 15, 2002; 169(4): 2026 - 2033. [Abstract] [Full Text] [PDF]
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J. Fierer, M. A. Swancutt, D. Heumann, and D. Golenbock The Role of Lipopolysaccharide Binding Protein in Resistance to Salmonella Infections in Mice J. Immunol., June 15, 2002; 168(12): 6396 - 6403. [Abstract] [Full Text] [PDF]
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S. Dessus-Babus, T. L. Darville, F. P. Cuozzo, K. Ferguson, and P. B. Wyrick Differences in Innate Immune Responses (In Vitro) to HeLa Cells Infected with Nondisseminating Serovar E and Disseminating Serovar L2 of Chlamydia trachomatis Infect. Immun., June 1, 2002; 70(6): 3234 - 3248. [Abstract] [Full Text] [PDF]
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S. Dahan, V. Busuttil, V. Imbert, J.-F. Peyron, P. Rampal, and D. Czerucka Enterohemorrhagic Escherichia coli Infection Induces Interleukin-8 Production via Activation of Mitogen-Activated Protein Kinases and the Transcription Factors NF-{kappa}B and AP-1 in T84 Cells Infect. Immun., May 1, 2002; 70(5): 2304 - 2310. [Abstract] [Full Text] [PDF]
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K. Vidal, A. Donnet-Hughes, and D. Granato Lipoteichoic Acids from Lactobacillus johnsonii Strain La1 and Lactobacillus acidophilus Strain La10 Antagonize the Responsiveness of Human Intestinal Epithelial HT29 Cells to Lipopolysaccharide and Gram-Negative Bacteria Infect. Immun., April 1, 2002; 70(4): 2057 - 2064. [Abstract] [Full Text] [PDF]
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H. Kohler, S. P. Rodrigues, and B. A. McCormick Shigella flexneri Interactions with the Basolateral Membrane Domain of Polarized Model Intestinal Epithelium: Role of Lipopolysaccharide in Cell Invasion and in Activation of the Mitogen-Activated Protein Kinase ERK Infect. Immun., March 1, 2002; 70(3): 1150 - 1158. [Abstract] [Full Text] [PDF]
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Z. H. Nemeth, E. A. Deitch, C. Szabo, Z. Fekete, C. J. Hauser, and G. Hasko Lithium Induces NF-kappa B Activation and Interleukin-8 Production in Human Intestinal Epithelial Cells J. Biol. Chem., March 1, 2002; 277(10): 7713 - 7719. [Abstract] [Full Text] [PDF]
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M. W. Hornef, T. Frisan, A. Vandewalle, S. Normark, and A. Richter-Dahlfors Toll-like Receptor 4 Resides in the Golgi Apparatus and Colocalizes with Internalized Lipopolysaccharide in Intestinal Epithelial Cells J. Exp. Med., February 25, 2002; 195(5): 559 - 570. [Abstract] [Full Text] [PDF]
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T. G. A. M. Wolfs, W. A. Buurman, A. van Schadewijk, B. de Vries, M. A. R. C. Daemen, P. S. Hiemstra, and C. van 't Veer In Vivo Expression of Toll-Like Receptor 2 and 4 by Renal Epithelial Cells: IFN-{gamma} and TNF-{alpha} Mediated Up-Regulation During Inflammation J. Immunol., February 1, 2002; 168(3): 1286 - 1293. [Abstract] [Full Text] [PDF]
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X. Wang, C. Moser, J.-P. Louboutin, E. S. Lysenko, D. J. Weiner, J. N. Weiser, and J. M. Wilson Toll-Like Receptor 4 Mediates Innate Immune Responses to Haemophilus influenzae Infection in Mouse Lung J. Immunol., January 15, 2002; 168(2): 810 - 815. [Abstract] [Full Text] [PDF]
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C. Termeer, F. Benedix, J. Sleeman, C. Fieber, U. Voith, T. Ahrens, K. Miyake, M. Freudenberg, C. Galanos, and J. C. Simon Oligosaccharides of Hyaluronan Activate Dendritic Cells via Toll-like Receptor 4 J. Exp. Med., January 7, 2002; 195(1): 99 - 111. [Abstract] [Full Text] [PDF]
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Y. Tsutsumi-Ishii and I. Nagaoka NF-{kappa}B-mediated transcriptional regulation of human {beta}-defensin-2 gene following lipopolysaccharide stimulation J. Leukoc. Biol., January 1, 2002; 71(1): 154 - 162. [Abstract] [Full Text] [PDF]
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E. Cario, D. Brown, M. McKee, K. Lynch-Devaney, G. Gerken, and D. K. Podolsky Commensal-Associated Molecular Patterns Induce Selective Toll-Like Receptor-Trafficking from Apical Membrane to Cytoplasmic Compartments in Polarized Intestinal Epithelium Am. J. Pathol., January 1, 2002; 160(1): 165 - 173. [Abstract] [Full Text] [PDF]
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Y. Asai, Y. Ohyama, K. Gen, and T. Ogawa Bacterial Fimbriae and Their Peptides Activate Human Gingival Epithelial Cells through Toll-Like Receptor 2 Infect. Immun., December 1, 2001; 69(12): 7387 - 7395. [Abstract] [Full Text] [PDF]
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K. Watanabe, O. Yilmaz, S. F. Nakhjiri, C. M. Belton, and R. J. Lamont Association of Mitogen-Activated Protein Kinase Pathways with Gingival Epithelial Cell Responses to Porphyromonas gingivalis Infection Infect. Immun., November 1, 2001; 69(11): 6731 - 6737. [Abstract] [Full Text] [PDF]
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 P. I. Song, T. A. Abraham, Y. Park, A. S. Zivony, B. Harten, H. F. Edelhauser, S. L. Ward, C. A. Armstrong, and J. C. Ansel The Expression of Functional LPS Receptor Proteins CD14 And Toll-Like Receptor 4 in Human Corneal Cells Invest. Ophthalmol. Vis. Sci., November 1, 2001; 42(12): 2867 - 2877. [Abstract] [Full Text] [PDF]
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R. A. Rozenfeld, X. Liu, I. Deplaen, and W. Hsueh Role of gut flora on intestinal group II phospholipase A2 activity and intestinal injury in shock Am J Physiol Gastrointest Liver Physiol, October 1, 2001; 281(4): G957 - G963. [Abstract] [Full Text] [PDF]
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T. Kawahara, S. Teshima, Y. Kuwano, A. Oka, K. Kishi, and K. Rokutan Helicobacter pylori lipopolysaccharide induces apoptosis of cultured guinea pig gastric mucosal cells Am J Physiol Gastrointest Liver Physiol, September 1, 2001; 281(3): G726 - G734. [Abstract] [Full Text] [PDF]
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V. Supajatura, H. Ushio, A. Nakao, K. Okumura, C. Ra, and H. Ogawa Protective Roles of Mast Cells Against Enterobacterial Infection Are Mediated by Toll-Like Receptor 4 J. Immunol., August 15, 2001; 167(4): 2250 - 2256. [Abstract] [Full Text] [PDF]
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M. T. Abreu, P. Vora, E. Faure, L. S. Thomas, E. T. Arnold, and M. Arditi Decreased Expression of Toll-Like Receptor-4 and MD-2 Correlates with Intestinal Epithelial Cell Protection Against Dysregulated Proinflammatory Gene Expression in Response to Bacterial Lipopolysaccharide J. Immunol., August 1, 2001; 167(3): 1609 - 1616. [Abstract] [Full Text] [PDF]
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T. Kawahara, S. Teshima, A. Oka, T. Sugiyama, K. Kishi, and K. Rokutan Type I Helicobacter pylori Lipopolysaccharide Stimulates Toll-Like Receptor 4 and Activates Mitogen Oxidase 1 in Gastric Pit Cells Infect. Immun., July 1, 2001; 69(7): 4382 - 4389. [Abstract] [Full Text] [PDF]
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H. H. Tong, Y. Chen, M. James, J. Van Deusen, D. B. Welling, and T. F. DeMaria Expression of Cytokine and Chemokine Genes by Human Middle Ear Epithelial Cells Induced by Formalin-Killed Haemophilus influenzae or Its Lipooligosaccharide htrB and rfaD Mutants Infect. Immun., June 1, 2001; 69(6): 3678 - 3684. [Abstract] [Full Text] [PDF]
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D. P. Funda, L. Tuckova, M. A. Farre, T. Iwase, I. Moro, and H. Tlaskalova-Hogenova CD14 Is Expressed and Released as Soluble CD14 by Human Intestinal Epithelial Cells In Vitro: Lipopolysaccharide Activation of Epithelial Cells Revisited Infect. Immun., June 1, 2001; 69(6): 3772 - 3781. [Abstract] [Full Text] [PDF]
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 C. Alexander and E. Th. Rietschel Invited review: Bacterial lipopolysaccharides and innate immunity Innate Immunity, June 1, 2001; 7(3): 167 - 202. [Abstract] [PDF]
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, macrophage. B, Immunofluorescence
histochemistry was used to assess the CD14 surface protein expression
of T84 cells (1, immunofluorescence; 2,
phase contrast; 3, U937 cells as positive control;
4, normal mouse IgG as negative control).
