| HOME | HELP | FEEDBACK | SUBSCRIPTIONS | ARCHIVE | SEARCH | TABLE OF CONTENTS |
|
|
|
|||||||
|
|||||||||
B and Activating Protein-11
*
Physiological Institute, University of Zurich-Irchel,
Department of Anesthesiology, and
Division of Nephrology, Department of Medicine, University Hospital, Zurich, Switzerland
 |
Abstract |
|---|
 Top Abstract IntroductionMaterials and MethodsResultsDiscussionReferences |
|---|
B and activating protein-1 DNA binding activity in MCT cells.
Transcript levels for the NF-B inhibitor IB
and for the
activating protein-1 constituents c-jun and
c-fos also increased in response to HA stimulation of
tubular cells. Inhibition of NF-B with the serine protease inhibitor
N-tosyl-L-phenylalanine chloromethyl ketone
blocked the HA-mediated expression of ICAM-1 and VCAM-1 in MCT cells.
In conclusion, HA displays proinflammatory effects by directly
stimulating the expression of the cell adhesion molecules ICAM-1 and
VCAM-1 in mouse kidney epithelial cells. HA could thereby play an
important role in leukocyte adhesion in inflammatory renal
diseases. |
Introduction |
|---|
|
TopAbstractIntroductionMaterials and MethodsResultsDiscussionReferences |
|---|
3)
N-acetyl-D-glucosamine (ß14)) and occurs in
its native form as a high molecular mass molecule, usually in the range
of 1 to 6 x 106 Da (2). Under normal conditions, HA
has a restricted tissue distribution and is mainly found in connective
tissues such as cartilage and joints. It is well known, however, that
HA accumulates at sites of immune-mediated tissue injury. In the
interstitium of the kidney cortex, for example, marked HA deposition
occurs in inflammatory renal diseases, including crescentic
glomerulonephritis (3), tubulointerstitial injury (4, 5), and allograft
rejection (6, 7). The functional significance of HA accumulation in immune-mediated tissue injury has not been elucidated. Because of its structural and physico-chemical characteristics, HA has long been considered an inert substance whose chief function is to regulate the hydration of the extracellular matrix (2). Recent evidence suggests, however, that HA displays a broader and more complex range of functions. Thus, HA fragments can display proinflammatory activities, inducing, for example, the release of chemokines by macrophages (8). The interaction of HA with the cell surface receptor CD44 could thereby lead to the recruitment of leukocytes and promote tissue injury in inflammatory processes (9).
The purpose of the present investigation was to study the
inter-relationship between HA accumulation and the expression of
adhesion molecules. We therefore examined the effects of HA and its
constituents on ICAM-1 and VCAM-1 expression by cultured kidney tubular
epithelial cells. We found that various HA preparations substantially
enhanced the expression of both ICAM-1 and VCAM-1 on tubular cells. We
also show that HA markedly increased sequence-specific DNA binding of
the transcription factors NF-B and AP-1 in these cells, preceding
the augmented expression of the adhesion molecules. We have thus
identified a proinflammatory mechanism by which HA potently
up-regulates ICAM-1 and VCAM-1 expression on kidney epithelium. Our
results suggest that HA could participate by this mechanism in the
recruitment and adhesion of leukocytes at sites of immune-mediated
renal injury.
|
Materials and Methods |
|---|
|
TopAbstractIntroductionMaterials and MethodsResultsDiscussionReferences |
|---|
Tissue culture reagents were obtained from Life Technologies (Gaithersburg, MD), and chemicals were obtained from Fluka (Buchs, Switzerland) or Sigma (St. Louis, MO). The high m.w. HA preparations Artzal and Healon were provided by Luitpold (Wien, Austria) and Pharmacia (Uppsala, Sweden), respectively. HA hexamer fragments were donated by Dr. Roland Buelow at SangStat (Menlo Park, CA). Hyaluronidase type V derived from sheep testes (Sigma) was used to generate Healon fragments according to the method of Knudson (10). Agarose gel electrophoresis was performed to check the sizes of the various HA preparations as described by Lee (11), comparing migration distances with m.w. standards, which were donated by Dr. Ove Wik (Pharmacia). The HA preparations were checked for LPS contamination using the Limulus polyphemus amebocyte assay (E-TOXATE kit, Sigma). Furthermore, selected experiments were performed in the presence of the LPS inhibitor polymyxin B (Calbiochem, La Jolla, CA).
Antibodies
Hybridomas producing the rat mAb for murine ICAM-1 (YN1/1.7.4, IgG2b) and VCAM-1 (M/K-2.7, IgG1) were obtained from the American Type Culture Collection (Rockville, MD). mAbs were purified from culture supernatants using protein G-Sepharose CL-6B columns. The mouse anti-rat ICAM-1 mAb 1A29 was purchased from Serotec (Oxford, U.K.).
Primers
Specific primers located on separate exons were designed to
assess gene expression of adhesion molecules and nuclear factors by
RT-PCR analysis. The primer sequences for ICAM-1 were 5'-CCT GTT TCC
TGC CTC TGA AG-3' (upstream) and 5'-GTC TGC TGA GAC CCC TCT TG-3'
(downstream), yielding a 528-bp fragment (12). Primer sequences for
IB (autoregulatory component of NF-B) were 5'-AGG ACG AGG AGT
ACG AGC AA-3' (upstream) and 5'-TAG GGC AGC TCA TCC TCT GT-3'
(downstream), yielding a 793-bp fragment (13). Sequences for the AP-1
constituent c-jun were 5'-ATG GGC ACA TCA CCA CTA CA-3'
(upstream) and 5'-TTT TGC GCT TTC AAG GTT TT-3' (downstream), yielding
a 628-bp fragment (14); sequences for the AP-1 constituent
c-fos were 5'-AGA ATC CGA AGG GAA CGG AA-3' (upstream) and
5'-ATG ATG CCG GAA ACA AGA AG-3' (downstream), yielding a 412-bp
fragment (15). For semiquantitative comparison, RT-PCR was also
performed with primers for the housekeeping gene GAPDH as previously
described (16).
cDNAs
The murine ICAM-1 cDNA was provided by Dr. A. Brian (12). A 1.3-kb EcoRI/PstI fragment was used to probe Southern blots. A mouse VCAM-1 cDNA was used for Northern blotting (2-kb NotI fragment given by Dr. R. Lobb) (17). A cDNA encoding murine c-jun (0.95-kb EcoRI/BglI fragment obtained from American Type Culture Collection) (14) and a 0.65-kb rat c-fos SalI/NcoI cDNA fragment were used for probing Southern blots (18). An 850-bp PstI ß-actin probe was used to reprobe Northern blots.
Cell lines and cell culture
The SV40-transformed mouse cortical tubule (MCT) cell line was obtained from Dr. T. Haverty (19). Murine 3T3 fibroblasts and rat lung epithelial L2 cells were obtained from American Type Culture Collection. Mouse endothelial cells (Eoma) were obtained from Dr. R. Auerbach (Madison, WI) (20). All cell lines were grown in DMEM supplemented with 10% FBS, 10 mM HEPES, 100 U/ml penicillin, and 100 µg/ml streptomycin.
Direct cell ELISA
Cell adhesion molecule expression in response to various HA
preparations was analyzed on adherent cells by direct cell ELISA in
96-well plates. After growing to confluence, cells were kept in DMEM
containing 1% FBS for 24 h and were then stimulated with HA in
DMEM containing 1% FBS. Cells were fixed with 3% paraformaldehyde and
washed with PBS. Cells were then incubated with primary anti-ICAM-1
or anti-VCAM-1 Ab in PBS containing 5% FCS for 1 h at 4°C.
Negative controls included omission of primary mAb or use of irrelevant
mAb. Cells were washed three times and incubated with
peroxidase-conjugated sheep anti-rat IgG Fab (Boehringer Mannheim,
Mannheim, Germany) at 1/500 in PBS/5% FCS for 1 h at 4°C. Cells
were washed again twice and were incubated with substrate (400 µg/ml
o-phenylenediamine dihydrochloride in 50 mM
phosphate-citrate buffer containing 400 µg/ml urea hydrogen
peroxide). After 10 min, 20% (v/v) of concentrated sulfuric acid was
added to stop the reaction. The OD in the supernatant was read at 492
nm on a Labsystems Multiskan RC ELISA reader. 
ODs were calculated
by subtracting the ODs of cells incubated with irrelevant Ab from cells
incubated with anti-ICAM-1 or anti-VCAM-1 mAb. The mean ±
SE were then calculated (n = 3). Experiments were
performed three to five times.
RNA extraction and RT-PCR analysis
MCT cells were stimulated with HA for various time periods. Total RNA from cultured MCT cells was then extracted as previously described (16). Total RNA from MCT cells was analyzed by RT-PCR using a kit (Perkin-Elmer, Branchburg, NJ). Random hexanucleotide primers and murine leukemia virus RT were used for cDNA synthesis. The 20-µl reaction mixture contained 1 µg of total RNA, 1 mM dNTP, 2.5 µM random hexamers, 5 mM MgCl2, and 2.5 U/µl RT. RT was performed at 42°C for 45 min. RT was then inactivated at 95°C for 5 min. PCR reactions were performed in 100 µl containing 0.15 µM of each primer, 2.5 U/100 µl of AmpliTaq DNA polymerase (Perkin Elmer), 2 mM MgCl2, and 0.2 mM dNTPs. Cycling parameters were as follows: 94°C for 40 s, 58°C for 120 s, and 72°C for 150 s over 20 to 40 cycles, followed by 72°C for 7 min using a GeneAmp PCR System 2400 thermocycler (Perkin-Elmer). RT-PCR products were resolved on 1% agarose gels and stained with ethidium bromide. Gels were then photographed with UV light. To ensure specificity of the RT-PCR reactions we also performed Southern blot analysis. RT-PCR products were resolved on 1% agarose gels in TBE buffer, and gels were denatured, neutralized, and blotted onto nylon membranes. Membranes were then hybridized with [32P]dCTP-labeled cDNA probes.
Northern blotting
The expression of adhesion molecules was also assessed by Northern blotting. Total RNA (25 µg) was electrophoresed on 1.5% agarose gels in 20 mM MOPS buffer and blotted onto nylon membranes. Membranes were hybridized overnight at 42°C with the 32P-labeled cDNA probe in 50% formamide, 6x SSC, 5x Denhardt’s solution, 100 µg/ml sheared denatured salmon sperm DNA, and 1% SDS. Blots were then washed under stringent conditions (final wash in 0.1x SSC/1% SDS at 62°C) and were exposed to Kodak XAR-5 film (Eastman Kodak, Rochester, NY). Blots were also rehybridized with a [32P]dCTP-labeled ß-actin probe to control for equal RNA loading.
Nuclear extracts
MCT cells were grown to confluence in six-well plates. Cells
were then stimulated with HA (100 µg/ml) or TNF- (100 ng/ml) for
1, 2.5, 4, or 6 h; rapidly detached with trypsin-EDTA; and washed
with Tris-buffered saline. Nuclear extracts were then prepared
according to the method of Schreiber et al. (21). Cells (1–2 x
106) were resuspended in 400 µl of ice-cold buffer A (10
mM HEPES (pH 7.9), 10 mM KCl, 0.1 mM EDTA, 0.1 mM EGTA, 1 mM DTT, and
0.5 mM PMSF) and were then lysed with 25 µl of 10% Nonidet P-40.
After centrifugation, the nuclear pellets were resuspended in ice-cold
buffer C (20 mM HEPES (pH 7.9), 0.4 M NaCl, 1 mM EDTA, 1 mM EGTA, 1 mM
DTT, and 1 mM PMSF) and rocked vigorously at 4°C. The extracts were
then centrifuged for 5 min at 4°C in a microfuge, and the
supernatants were frozen at -70°C until use. The protein
concentration of the extracts was determined using the Bradford method
(Bio-Rad, Hercules, CA).
Electrophoretic mobility shift assays
Nuclear extracts were analyzed for the presence of NF-B and
AP-1 using double-stranded oligonucleotides containing the specific DNA
binding domains for NF-B (5'-AGT TGA GGG GAC TTT CCC AGG
C-3', 22-mer) or AP-1 (5'-CGC TTG ATG AGT CAG CCG GAA-3',
21-mer; consensus sites are underlined; Promega, Madison, WI) (22, 23).
Oligonucleotides were end labeled with [
-32P]ATP using
T4 polynucleotide kinase. Extracts were then incubated for 20 min at
room temperature with labeled NF-B or AP-1 oligonucleotides in
binding buffer (50 µg/ml poly(dI-dC), 4% glycerol, 1 mM
MgCl2, 0.5 mM EDTA, 0.5 mM DTT, 50 mM NaCl, and 10 mM
Tris-HCl, pH 7.5) in the presence or the absence of 1.75 pmol
(
50-fold excess) of unlabeled competitor (NF-B or AP-1) or
noncompetitor oligonucleotides (AP-2). DNA-protein complexes were
resolved on nondenaturing 4% acrylamide gels in 0.5x TBE buffer at
100 V. Gels were then dried and exposed to Kodak XAR-5 film.
|
Results |
|---|
|
TopAbstractIntroductionMaterials and MethodsResultsDiscussionReferences |
|---|
HA preparations from various sources were screened for their
ability to up-regulate ICAM-1 and VCAM-1 expression in MCT cells. Table I
summarizes the findings and
demonstrates that several HA preparations markedly up-regulated both
ICAM-1 and VCAM-1 cell surface expression. Intermediate m.w. HA
preparations (from human umbilical cord and from bovine trachea) were
found to stimulate ICAM-1 and VCAM-1 most effectively, whereas
chondroitin sulfate (of comparable m.w.) did not change ICAM-1 or
VCAM-1 expression. The low m.w. forms of HA and its monosaccharide
constituents (D-glucuronic acid and
N-acetyl-D-glucosamine, as well as the HA
disaccharide and an HA hexamer preparation consisting of three
disaccharide units) did not induce detectable changes in ICAM-1 and
VCAM-1 cell surface expression. Gel filtration-purified high m.w. HA
preparations such as Healon (Pharmacia) and Artzal (Luitpold) also did
not significantly up-regulate ICAM-1 and VCAM-1.
|
demonstrates that when Healon was
incubated with hyaluronidase for 5 or 30 min such a stimulatory
activity could be induced. The stimulatory effect of
hyaluronidase-digested Healon was slightly less than the effect seen
with umbilical cord-derived HA (Fluka). Monitoring the size of the
digested Healon on agarose gels revealed that the size had decreased
from 4 x 106 Da to approximately 1.5 x
105 Da (not shown). Collectively, these data and the data
presented in Table I
demonstrate that MCT cells are responsive to
intermediate molecular mass HA (80,000–600,000 Da) but not to high
molecular mass HA (>600,000 Da) or low molecular mass HA (<80,000
Da).
|
).
Whereas the stimulation of ICAM-1 and VCAM-1 with LPS was completely
abrogated with polymyxin B, the stimulation in response to HA was only
partially reduced. The slight inhibitory effect on HA-stimulated
adhesion molecule expression could be due to its known inhibitory
effect on protein kinase C (24). Together these results demonstrate
that the adhesion molecule-stimulating effects of HA are not mediated
by contaminating LPS.
|
or IL-1. Furthermore, boiling
of the HA preparations did not abolish their stimulatory effect on
ICAM-1 and VCAM-1 expression (not shown), excluding possible
contamination by known stimulatory proteins.
We then examined the time course and dose response of HA-stimulated
ICAM-1 and VCAM-1 expression on MCT cells by direct cell ELISA. Figure 1 shows that detectable increases in
ICAM-1 and VCAM-1 occurred with HA concentrations between 1 and 10
µg/ml, reaching a maximum around 500 µg/ml. Detectable increases of
cell surface ICAM-1 and VCAM-1 were seen within 3 h of
stimulation, peaking around 18 h and decreasing again thereafter.
|
To examine changes in steady state mRNA levels encoding for ICAM-1 and
VCAM-1 in response to HA we then isolated RNA from MCT cells after
stimulation with HA and performed RT-PCR and Southern blot, or Northern
blot analysis. Figure 2 demonstrates that
HA induced a progressive increase in both ICAM-1 and VCAM-1 mRNA
transcript levels in MCT cells. The increase was detectable within
1 h and increased further to peak after 3 h. The increase in
transcript levels seen with HA was comparable to the increase seen with
TNF- stimulation of MCT cells.
|
We also tested mouse fibroblasts (3T3 cells) and endothelial cells
(Eoma) and rat lung epithelial cells (L2) for up-regulation of ICAM-1
or VCAM-1 in response to HA. Table IV
demonstrates that human umbilical cord-derived HA (Fluka) at
concentrations between 10 and 1000 µg/ml did not stimulate ICAM-1 and
VCAM-1 expression on 3T3 cells. However, HA dose dependently stimulated
both adhesion molecules on mouse Eoma cells and enhanced ICAM-1
expression in the rat lung epithelial cell line L2. These results
demonstrate that a response to HA is seen in additional cell lines but
that certain cell lines, such as 3T3, are not responsive.
|
It is known that the expression of adhesion molecules such as
ICAM-1 and VCAM-1 involves sequence-specific binding of
cis-acting transcription factors, particularly NF-B and
AP-1 (c-jun/c-fos heterodimer) (25, 26). We
therefore sought to determine whether these nuclear transcription
factors were participating in HA-mediated up-regulation of ICAM-1 and
VCAM-1. Nuclear extracts were prepared from HA- and TNF--treated MCT
cells and were tested for gel retardation in electromobility shift
assays. Figure 3A demonstrates
that some NF-B binding activity was constitutively present in MCT
cells. Upon exposure to HA, NF-B binding was markedly up-regulated
within 1 h in these cells. The binding of NF-B was specific and
could be blocked with unlabeled competing NF-B oligonucleotide, but
not with the noncompeting AP-2 oligonucleotide (Fig. 3B).
Up-regulation of NF-B was seen with several intermediate m.w. HA
preparations, including HA derived from bovine trachea, human umbilical
cord, and rooster comb, but not with high m.w. Healon (Fig. 5, lane 2) and also not with the low m.w. HA hexamer preparation
(data not shown).
|
|
C). Binding activity could also be blocked with unlabeled
cold oligonucleotide but not with the unlabeled noncompeting AP-2
oligonucleotide (Fig. 3D).
To further examine the involvement of NF-B and AP-1 in HA-mediated
signaling we examined the mRNA levels for IB (an NF-B
inhibitor, which increases in response to NF-B activation) and also
for the AP-1 constituents c-jun and c-fos after
stimulation with HA. Figure 4
demonstrates that IB mRNA increased within 1 h of HA
treatment and peaked at 1.5 h in MCT cells. Transcript levels for
the AP-1 constituents c-jun and c-fos also
increased within 60 min in response to HA treatment. These results
confirm that both NF-B and AP-1 activities are induced in response
to HA and suggest that these transcription factors could participate in
the regulation of adhesion molecule expression in MCT cells.
|
B in HA-mediated adhesion
molecule expression we also tested the effect of the serine protease
inhibitor TPCK, a known blocker of NF-B (27, 28). Table V demonstrates that TPCK dose dependently
inhibited the cell surface expression of ICAM-1 and VCAM-1 in MCT
cells. Figure 5 shows that TPCK also
inhibited the HA-stimulated up-regulation of NF-B in MCT cells.
These data demonstrate that TPCK effectively suppresses NF-B
activation and adhesion molecule expression, suggesting that NF-B
could be one of the mediators of HA-stimulated adhesion molecule
expression in MCT cells.
|
|
Discussion |
|---|
|
TopAbstractIntroductionMaterials and MethodsResultsDiscussionReferences |
|---|
B and AP-1 in these cells
to enhance the expression of ICAM-1 and VCAM-1. We have therefore
identified an interesting proinflammatory mechanism by which a matrix
constituent (HA and its fragments) could promote leukocyte adherence
through induction of ICAM-1 and VCAM-1 expression in immune-mediated
tissue injury.
Of all the preparations tested we found that the stimulatory HA
molecules were polydisperse and of intermediate m.w., whereas the more
uniform high m.w. HA preparations were without effect on ICAM-1 and
VCAM-1 expression in MCT cells. Our results are consistent with other
studies documenting the lack of a stimulatory effect by high m.w. HA
preparations on macrophage TNF-, chemokine, and nitric oxide
production compared with HA preparations of lower m.w. that are
stimulatory (8, 29, 30). In fact high m.w. HA is known to display
anti-inflammatory activities under certain conditions, particularly
when used at high doses. Intra-articular injection of high m.w. HA, for
example, improves arthritic symptoms in patients with osteoarthritis
(31, 32). High m.w. HA is also capable of inhibiting phagocytosis by
macrophages and inhibits the secretion of certain cytokines (33, 34).
Hodge-Dufour et al. reported recently that high m.w. could inhibit the
stimulation of macrophage IL-12 by low m.w. HA, suggesting that
the anti-inflammatory effect of high m.w. HA could be accomplished
by competition with low m.w. HA at the level of the CD44 receptor (34).
In our experiments the HA constituents (mono- and disaccharides) and an HA hexamer preparation did not stimulate adhesion molecule expression in MCT cells. HA hexamers represent the minimal binding motif for CD44 (35), suggesting that binding or cross-linking of several adjacent CD44 molecules could be required for up-regulation of adhesion molecules. CD44 is very abundant on MCT cells (36); however, other HA binding proteins, for example, the receptor for HA-mediated mobility, is also expressed by MCT cells (our unpublished observation). At present we do not known precisely how the m.w. of HA determines the level of expression of adhesion molecules by epithelial cells. We suspect that additional factors inherent to the molecular configuration of HA and its fragments modulate the HA receptor signaling pathways. The nature of these factors remains to be investigated.
Pathologic HA accumulation is a feature of many immunologic processes affecting the kidney and other organs, such as joints and lungs. HA is normally not present in the kidney cortex but it accumulates in the tubulointerstitial space and around glomeruli in immune-mediated renal injury, including crescentic glomerulonephritis (3), tubulointerstitial nephritis (4, 5), and allograft rejection (6, 7). The functional significance of this renal HA accumulation has not been clear, but it has been proposed that HA could regulate interstitial water content, thereby playing a role in tissue edema formation (37). The hyaluronan receptor CD44 is also up-regulated on renal parenchymal cells in immune-mediated injury, including the proximal tubules (16, 38, 39) and colocalizes with accumulated HA at sites of immune injury (5). From our data we speculate that the interaction of HA with the tubular epithelium could participate in the induction and maintenance of ICAM-1 and VCAM-1 expression in inflammatory renal diseases, thereby contributing directly to leukocyte adherence.
Cytokines and LPS are the classical stimulatory factors for ICAM-1 and VCAM-1 expression (40). Only a few other regulating factors have been described. Fibrin, for example, has been shown to directly stimulate ICAM-1 expression by HUVEC and provides an example how coagulation products could promote leukocyte adhesion (41). To our knowledge it has not been shown before that matrix constituents could stimulate ICAM-1 and VCAM-1 expression. Our results support the concept that matrix is not only an inert structure displaying architectural functions, but that its components could participate in inflammation.
We were particularly interested to examine the cellular mechanisms that
are involved in HA-mediated up-regulation of adhesion molecules by
kidney tubular epithelial cells, since knowledge of these pathways
could help design therapeutic strategies to block overexpression of
adhesion molecules. The promoter regions of both murine and human
ICAM-1 and VCAM-1 genes contain two types of DNA consensus sequences
that are important in inflammation, namely the NF-B and AP-1 sites
(25, 26). Both transcription factors play a crucial role in regulation
of the expression of important mediators in inflammation, including
cytokines, adhesion molecules, and matrix metalloproteinases (42, 43, 44, 45).
We therefore determined whether HA also elicits these pathways to
up-regulate adhesion molecules in epithelial cells. Our results
demonstrate that both transcription factors are induced in response to
HA. HA not only increased NF-B DNA binding activity but it also
activated the IB autoregulatory loop. IB is a specific inhibitor
of the NF-B transcription factor whose induction is necessary to
terminate NF-B-induced gene activation (46). IB mRNA
transcript levels increased within 1 h of HA stimulation,
presumably resulting in the subsequent inactivation of NF-B. Our
findings in MCT cells are in agreement with studies documenting such a
mechanism in macrophages (13, 30). DNA binding activity for AP-1, a
heterodimeric complex consisting of the c-jun and
c-fos proto-oncogenes, was also enhanced after HA
stimulation, at both the mRNA transcript and the protein level. To our
knowledge activation of AP-1 DNA binding through HA has not been
documented previously. Although NF-B and AP-1 may not be the only
mediators induced by HA, we conclude from our results that HA initiates
a cascade of intracellular mediators involving, among others, NF-B
and AP-1. The engagement of these nuclear factors with
sequence-specific DNA segments in the 5' regulatory region of ICAM-1
and VCAM-1 could thereby initiate transcription of these adhesion
molecules.
In summary, we have shown that the matrix constituent HA is capable of
directly up-regulating ICAM-1 and VCAM-1 expression by kidney tubular
epithelial cells. The HA-induced intracellular signaling mechanism
appears to involve classical inflammatory pathways, including
sequence-specific DNA binding of the nuclear factors NF-B and AP-1.
We speculate that through this mechanism, the accumulation of HA in
inflammatory renal diseases could provide a potent stimulus for the
expression of cell adhesion molecules, thereby promoting leukocyte
adherence at sites of immune-renal injury.
|
Acknowledgments |
|---|
|
Footnotes |
|---|
2 Current address: Department of Vascular Biology, Scripps Research Institute, La Jolla, CA 92037.
3 Current address: Renal Division, Brigham and Women’s Hospital, Harvard Institutes of Medicine, Boston, MA 02115.
4 Address correspondence and reprint requests to Dr. Rudolf P. Wüthrich, Division of Nephrology, University Hospital, Rämistr. 100, 8091 Zurich, Switzerland. E-mail address:
5 Abbreviations used in this paper: HA, hyaluronan, hyaluronic acid; AP-1, activating protein-1; GAPDH, glyceraldehyde-3-phosphate dehydrogenase; MCT, mouse cortical tubule; ACTD, actinomycin D; CHX, cycloheximide; TPCK, N-tosyl-L-phenylalanine chloromethyl ketone.
Received for publication February 5, 1998. Accepted for publication May 21, 1998.
|
References |
|---|
|
TopAbstractIntroductionMaterials and MethodsResultsDiscussionReferences |
|---|
B/I-B autoregulatory loop in murine macrophages. J. Exp. Med. 183:2373.B: a pleiotropic mediator of inducible and tissue-specific gene control. Cell 58:227.[Medline]
B- is necessary for activation of transcription factor NF-B. Nature 365:182.[Medline]
(TNF-) by interferons: implications for the pleiotropic activities of TNF-. J. Clin. Invest. 93:1661.
B-dependent mechanism. J. Biol. Chem. 272:8013.B: a pleiotropic mediator of inducible and tissue-specific gene control. Cell 58:227.
B: a pivotal transcription factor in chronic inflammatory diseases. N. Engl. J. Med. 336:1066.B: a specific inhibitor of the NF-B transcription factor. Science 242:540.This article has been cited by other articles:
|
|
 |
|
  L. Zheng, R. Sinniah, and S. I-H. Hsu Pathogenic Role of NF-{kappa}B Activation in Tubulointerstitial Inflammatory Lesions in Human Lupus Nephritis J. Histochem. Cytochem., May 1, 2008; 56(5): 517 - 529. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
Y. Sawa, T. Ueki, M. Hata, K. Iwasawa, E. Tsuruga, H. Kojima, H. Ishikawa, and S. Yoshida LPS-induced IL-6, IL-8, VCAM-1, and ICAM-1 Expression in Human Lymphatic Endothelium J. Histochem. Cytochem., February 1, 2008; 56(2): 97 - 109. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 K. Mohib, Q. Guan, H. Diao, C. Du, and A. M. Jevnikar Proapoptotic activity of indoleamine 2,3-dioxygenase expressed in renal tubular epithelial cells Am J Physiol Renal Physiol, September 1, 2007; 293(3): F801 - F812. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 M A Dentener, R Louis, R H E Cloots, M Henket, and E F M Wouters Differences in local versus systemic TNF{alpha} production in COPD: inhibitory effect of hyaluronan on LPS induced blood cell TNF{alpha} release Thorax, June 1, 2006; 61(6): 478 - 484. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
M A Dentener, J H J Vernooy, S Hendriks, and E F M Wouters Enhanced levels of hyaluronan in lungs of patients with COPD: relationship with lung function and local inflammation Thorax, February 1, 2005; 60(2): 114 - 119. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 X. L. Zhang, W. Selbi, C. de la Motte, V. Hascall, and A. Phillips Renal Proximal Tubular Epithelial Cell Transforming Growth Factor-{beta}1 Generation and Monocyte Binding Am. J. Pathol., September 1, 2004; 165(3): 763 - 773. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 J. Lesley, I. Gal, D. J. Mahoney, M. R. Cordell, M. S. Rugg, R. Hyman, A. J. Day, and K. Mikecz TSG-6 Modulates the Interaction between Hyaluronan and Cell Surface CD44 J. Biol. Chem., June 11, 2004; 279(24): 25745 - 25754. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 M. Ohno-Nakahara, K. Honda, K. Tanimoto, N. Tanaka, T. Doi, A. Suzuki, K. Yoneno, Y. Nakatani, M. Ueki, S. Ohno, et al. Induction of CD44 and MMP Expression by Hyaluronidase Treatment of Articular Chondrocytes J. Biochem., May 1, 2004; 135(5): 567 - 575. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 W. Selbi, C. de la Motte, V. Hascall, and A. Phillips BMP-7 Modulates Hyaluronan-Mediated Proximal Tubular Cell-Monocyte Interaction J. Am. Soc. Nephrol., May 1, 2004; 15(5): 1199 - 1211. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 C. Fieber, P. Baumann, R. Vallon, C. Termeer, J. C. Simon, M. Hofmann, P. Angel, P. Herrlich, and J. P. Sleeman Hyaluronan-oligosaccharide-induced transcription of metalloproteases J. Cell Sci., January 15, 2004; 117(2): 359 - 367. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
M. Ikegami-Kawai, A. Suzuki, I. Karita, and T. Takahashi Increased Hyaluronidase Activity in the Kidney of Streptozotocin-Induced Diabetic Rats J. Biochem., December 1, 2003; 134(6): 875 - 880. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 J.-W. Chen, Y.-H. Chen, F.-Y. Lin, Y.-L. Chen, and S.-J. Lin Ginkgo biloba Extract Inhibits Tumor Necrosis Factor-{alpha}-Induced Reactive Oxygen Species Generation, Transcription Factor Activation, and Cell Adhesion Molecule Expression in Human Aortic Endothelial Cells Arterioscler Thromb Vasc Biol, September 1, 2003; 23(9): 1559 - 1566. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 E. Eriksson, L. Dons, A. G. Rothfuchs, P. Heldin, H. Wigzell, and M. E. Rottenberg CD44-Regulated Intracellular Proliferation of Listeria monocytogenes Infect. Immun., July 1, 2003; 71(7): 4102 - 4111. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
P. E. Pummill and P. L. DeAngelis Alteration of Polysaccharide Size Distribution of a Vertebrate Hyaluronan Synthase by Mutation J. Biol. Chem., May 23, 2003; 278(22): 19808 - 19814. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
M. R. Horton, S. Boodoo, and J. D. Powell NF-kappa B Activation Mediates the Cross-talk between Extracellular Matrix and Interferon-gamma (IFN-gamma ) Leading to Enhanced Monokine Induced by IFN-gamma (MIG) Expression in Macrophages J. Biol. Chem., November 8, 2002; 277(46): 43757 - 43762. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
J. C. M. Morel, C. C. Park, K. Zhu, P. Kumar, J. H. Ruth, and A. E. Koch Signal Transduction Pathways Involved in Rheumatoid Arthritis Synovial Fibroblast Interleukin-18-induced Vascular Cell Adhesion Molecule-1 Expression J. Biol. Chem., September 13, 2002; 277(38): 34679 - 34691. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
J. C. Kim, D. Whitaker-Menezes, M. Deguchi, B. S. Adair, R. Korngold, and G. F. Murphy Novel Expression of Vascular Cell Adhesion Molecule-1 (CD106) by Squamous Epithelium in Experimental Acute Graft-versus-Host Disease Am. J. Pathol., September 1, 2002; 161(3): 763 - 770. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 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]
|
|
|
|
 |
|
 B. Beck-Schimmer, R. C. Schimmer, C. Madjdpour, J. M. Bonvini, T. Pasch, and P. A. Ward Hypoxia Mediates Increased Neutrophil and Macrophage Adhesiveness to Alveolar Epithelial Cells Am. J. Respir. Cell Mol. Biol., December 1, 2001; 25(6): 780 - 787. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 D. J. Mahoney, R. T. Aplin, A. Calabro, V. C. Hascall, and A. J. Day Novel methods for the preparation and characterization of hyaluronan oligosaccharides of defined length Glycobiology, December 1, 2001; 11(12): 1025 - 1033. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 S. L. Blass, E. Pure, and C. A. Hunter A Role for CD44 in the Production of IFN-{{gamma}} and Immunopathology During Infection with Toxoplasma gondii J. Immunol., May 1, 2001; 166(9): 5726 - 5732. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 P. Stenvinkel, B. Lindholm, M. Heimburger, and O. Heimburger Elevated serum levels of soluble adhesion molecules predict death in pre-dialysis patients: association with malnutrition, inflammation, and cardiovascular disease Nephrol. Dial. Transplant., October 1, 2000; 15(10): 1624 - 1630. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
Y. Ohkawara, G. Tamura, T. Iwasaki, A. Tanaka, T. Kikuchi, and K. Shirato Activation and Transforming Growth Factor-beta Production in Eosinophils by Hyaluronan Am. J. Respir. Cell Mol. Biol., October 1, 2000; 23(4): 444 - 451. [Abstract] [Full Text]
|
|
|
|
|
|
K. A. Fitzgerald, A. G. Bowie, B. S. Skeffington, and L. A. J. O'Neill Ras, Protein Kinase C{zeta}, and I{kappa}B Kinases 1 and 2 Are Downstream Effectors of CD44 During the Activation of NF-{kappa}B by Hyaluronic Acid Fragments in T-24 Carcinoma Cells J. Immunol., February 15, 2000; 164(4): 2053 - 2063. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
S. Rosseau, J. Selhorst, K. Wiechmann, K. Leissner, U. Maus, K. Mayer, F. Grimminger, W. Seeger, and J. Lohmeyer Monocyte Migration Through the Alveolar Epithelial Barrier: Adhesion Molecule Mechanisms and Impact of Chemokines J. Immunol., January 1, 2000; 164(1): 427 - 435. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
R. P. Wuthrich The proinflammatory role of hyaluronan-CD44 interactions in renal injury Nephrol. Dial. Transplant., November 1, 1999; 14(11): 2554 - 2556. [Full Text] [PDF]
|
|
|
|
|
|
G. K. Rangan, Y. Wang, Y.-C. Tay, and D. C. H. Harris Inhibition of NFkappa B activation with antioxidants is correlated with reduced cytokine transcription in PTC Am J Physiol Renal Physiol, November 1, 1999; 277(5): F779 - F789. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
A. Schawalder, B. Oertli, B. Beck-Schimmer, and R. P. Wuthrich Regulation of hyaluronan-stimulated VCAM-1 expression in murine renal tubular epithelial cells Nephrol. Dial. Transplant., September 1, 1999; 14(9): 2130 - 2136. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
J. Lesley, V. C. Hascall, M. Tammi, and R. Hyman Hyaluronan Binding by Cell Surface CD44 J. Biol. Chem., August 25, 2000; 275(35): 26967 - 26975. [Abstract] [Full Text] [PDF]
|
|
| ||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| HOME | HELP | FEEDBACK | SUBSCRIPTIONS | ARCHIVE | SEARCH | TABLE OF CONTENTS |
