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B Activation and Chemokine Production by Human Mesangial Cells
Nephrology Division, Department of Internal Medicine, and The Heart Lung Research Institute, The Ohio State University, Columbus, Ohio.
Correspondence to Dr. Brad H. Rovin, Nephrology Division, The Ohio State University, N210 Means Hall, 1654 Upham Drive, Columbus, OH 43210-1250. Phone: 614-293-4997; Fax: 614-293-3073; E-mail: rovin.1{at}osu.edu
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Abstract |
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 Top Abstract IntroductionMaterials and MethodsResultsDiscussionReferences |
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12,14-prostaglandin J2
blocked interleukin-1ß—induced monocyte chemoattractant protein-1
mRNA expression and protein production. This correlated with failure of the
transcription factor nuclear factor-
B (NF-B) to translocate to
the nucleus and bind to its recognition motif, a step required for
cytokine-induced monocyte chemoattractant protein-1 gene activation.
NF-B failed to translocate because the cyclopentenone prostaglandins
attenuated degradation of the NF-B inhibitor IB-
. These
data suggest that certain prostaglandins can limit the extent of renal
chemokine expression and thus may have an important role in resolving renal
inflammation. |
Introduction |
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TopAbstractIntroductionMaterials and MethodsResultsDiscussionReferences |
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Recent work suggests that certain J series prostaglandins derived from
prostaglandin D2 (PGD2) may function as intrinsic
regulators of inflammation. PGD2 undergoes dehydration to
9-deoxy-9-PGD2 (PGJ2) in aqueous
environments and is dehydrated further to
9-deoxy-9,12,-dihydroprostaglandin
D2 and 15-deoxy-12,14-prostaglandin J2
(15-d-PGJ2) in the presence of protein
(3,4).
These J series prostaglandins have a cyclopentenone ring that contains a
reactive, electrophilic carbon. This ring can bind covalently to intracellular
nucleophiles, such as free sulfhydryls and cysteines, and in so doing modify
protein function (3). In
addition, the cyclopentenone prostaglandins (cyPG) are taken up by cells and
incorporated into the nucleus
(5). The potential
anti-inflammatory role of cyPG is illustrated clearly in a mouse model of
pleural inflammation. In this model, cyclooxygenase (COX) inhibitors worsened
inflammation when used beyond the acute phase of disease
(6). This was associated with a
decrease in the concentration of PGD2 and 15-d-PGJ2 in
the pleural space (6).
Replacement of these prostaglandins led to resolution of inflammation
(6).
Three lines of evidence suggest that cyPG of the J series are reasonable
endogenous candidates for modulating renal chemokine expression: (1)
J series cyPG are found in the kidney; murine mesangial cells make
PGJ2 after treatment with interleukin-1ß (IL-1)
(7), and
9-deoxy-9,12,-dihydroprostaglandin D2 is
present in normal human urine
(8); (2)
15-d-PGJ2 has been shown to block induction of nuclear
factor-B (NF-B), a transcription factor necessary for chemokine
gene transcription in most renal cell types
(9,10,11,12);
(3) 15-d-PGJ2 is a natural agonist of peroxisome
proliferator-activated receptor
(PPAR)
(13). PPAR is a nuclear
hormone receptor and transcription factor that has a role in regulating fatty
acid homeostasis
(4,13)
and a role in glucose disposition that was realized when it became clear that
the thiazolidinedione class of antidiabetic drugs are specific PPAR
ligands (14). Relevant to the
theme of this investigation, recent studies have shown that PPAR also
has significant anti-inflammatory activities that include attenuating monocyte
cytokine production, promoting macrophage apoptosis, and inhibiting
NF-B activation
(15,16,17,18).
This investigation was undertaken to examine the effect of the cyPG
15-d-PGJ2 on IL-1—induced production of MCP-1 by cultured
human mesangial cells. In addition, because NF-B is a key regulatory
factor for mesangial MCP-1 expression, studies to determine whether
15-d-PGJ2 modulates NF-B activity were conducted. This work
demonstrated 15-d-PGJ2 to be a potent inhibitor of mesangial MCP-1
expression and NF-B activation. 15-d-PGJ2 acts at the level
of IB- degradation but is not dependent on PPAR for its
antichemokine effects.
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Materials and Methods |
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TopAbstractIntroductionMaterials and MethodsResultsDiscussionReferences |
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Mesangial cells were grown in RPMI-1640 plus 10% fetal calf serum (Bio
Whittaker, Walkersville, MD) and changed to RPMI-1640 plus 0.25% bovine serum
albumin at the time of use. The cells were treated for the indicated times
with 1.1 ng/ml human recombinant IL-1ß (R&D Systems, Minneapolis, MN)
in the presence or absence of cyPG. All prostaglandins were purchased from
Cayman Chemical (Ann Arbor, MI), as solutions in methyl acetate. Ciglitazone,
a PPAR agonist of the thiazolidinedione class, was obtained from Biomol
(Plymouth Meeting, PA) and dissolved in ethanol. Bisphenol A diglycidyl ether
(BADGE), a synthetic PPAR antagonist
(20), was purchased from Fluka
(Milwaukee, WI). In each experiment, the organic solvents were added to
control or IL-1—treated cells at the same concentrations as cells
treated with prostaglandins or ciglitazone. Mesangial cells were pretreated
with prostaglandins or ciglitazone, as indicated in the individual
experiments. Reagents used in this study were endotoxin free. The effects of
the various treatments on mesangial cell viability were measured by trypan
blue exclusion.
Measurement of Mesangial Cell MCP-1 Expression
MCP-1 mRNA was measured by Northern blotting of total mesangial cell RNA,
as we have previously described
(19). The MCP-1 probe was an
XhoI fragment from phJE34 (American Type Culture Collection,
Rockville, MD). The blots were reprobed for glyceraldehyde-3-phosphate
dehydrogenase by use of a full-length human cDNA (Clontech, Palo Alto, CA), to
confirm equal RNA loading.
Mesangial cell production of immunoreactive MCP-1 was determined by use of a modification (21) of the double-ligand enzyme-linked immunosorbent assay (ELISA) originally developed by Evanoff et al. (22). The capture antibody was a mouse monoclonal anti-human MCP-1 (R&D Systems), and the upper antibody was a rabbit polyclonal anti-human MCP-1 (Pepro Tech, Rock Hill, NJ). A horseradish peroxidase—conjugated goat anti-rabbit antibody was used for detection. The standard curve was constructed with human recombinant MCP-1 (Pepro Tech). The ELISA was sensitive to 100 pg/ml. The prostaglandins did not interfere with the ELISA. Mesangial cells were grown to confluence in six-well plates before use. All MCP-1 concentrations were corrected for small variations in the number of mesangial cells present in individual tissue culture wells by use of total cellular protein as an index of cell density.
Electrophoretic Mobility Shift Analysis
Nuclear proteins were harvested from mesangial cells as described
previously (10). Ten µg of
nuclear protein were incubated with 0.2 ng of double-stranded oligonucleotide
probe containing a tandem repeat of the consensus NF-B motif
(5'-GATCCAAGGGGACTTTCCGCTG-3'; Life Technologies BRL,
Grand Island, NY). Probes were 32P-end—labeled with
T4 polynucleotide kinase (Life Technologies BRL) plus
[-32P]ATP (3000 Ci/mmol; New England Nuclear, Boston, MA).
Binding of the nuclear proteins to the NF-B oligonucleotide was
performed at 27°C in 25 µl of buffer containing 10 mM Tris (pH 7.5),
100 mM NaCl, 1 mM dithiothreitol, 5 mM ethylenediaminetetraacetate, 4%
glycerol, and 2 µg poly(dI-dC) for 20 min. Oligonucleotide bound by
NF-B protein was separated from unbound oligonucleotide by
electrophoresis on a 6% nondenaturing polyacrylamide gel in 0.25x
Tris-borate-ethylenediaminetetraacetate buffer at 4°C. Transcription
factors bound to the radiolabeled probes were identified by the appearance of
bands with retarded mobility relative to unbound probe in autoradiographs of
these gels. Specificity of the binding reaction was confirmed by use of excess
(100-fold) unlabeled oligonucleotide to compete with labeled probes binding to
nuclear proteins.
Western Blot Analyses
Prostaglandin-treated mesangial cells were lysed in 10% sodium dodecyl
sulfate at specific times after addition of IL-1. Fifty µl of cell lysate
were separated by electrophoresis on 15% polyacrylamide gels and transferred
to nitrocellulose with the use of a semidry technique
(23). The nitrocellulose was
dried and quenched in phosphate-buffered saline, 0.1% Tween-20 with 2% bovine
serum albumin for 120 min. After washing, the nitrocellulose was blotted
overnight at 4°C with a 1:1000 dilution of rabbit polyclonal antibodies
that recognize either native IB- or IB- that had
been phosphorylated on the serine residue at position 32 (New England Biolabs,
Beverly, MA). Control blots (not shown) were probed with nonspecific rabbit
IgG (Zymed, South San Francisco, CA) to confirm specificity of the band
identified as IB- bands. The blots then were washed and
incubated with biotinylated goat anti-rabbit antibody (Zymed) for 45 min.
After further washing, the bands of interest were demonstrated by use of
enhanced chemiluminescence (Amersham Life Sciences, Inc., Arlington Heights,
IL).
Nuclear proteins isolated from mesangial cells were immunoblotted with a
rabbit polyclonal anti-PPAR antibody (Affinity BioReagents, Golden,
CO). Nonimmune rabbit IgG served as a control. Blots were developed by use of
enhanced chemiluminescence, as described above.
Statistical Analyses
Data are presented as mean ± SEM. Comparisons were made with the use
of the paired t test. P < 0.05 was considered
significant.
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Results |
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TopAbstractIntroductionMaterials and MethodsResultsDiscussionReferences |
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15-d-PGJ2 Inhibits NF-B Activation in
IL-1—Treated Mesangial Cells
In mesangial cells, the transcription factor NF-B seems to be
necessary for activation of the MCP-1 gene by IL-1, and most manipulations
that downregulate mesangial MCP-1 also prevent NF-B activation
(10,24,25).
This was found to be true for 15-d-PGJ2 as well. Mobility shift
analysis of nuclear proteins from mesangial cells treated with IL-1 plus
varying concentrations of 15-d-PGJ2 demonstrated a dose-dependent
decrease in nuclear protein binding to a consensus NF-B recognition
motif (Figure 3). This effect
was apparent with 10 µM 15-d-PGJ2, and 25 µM caused complete
inhibition. The effects of 15-d-PGJ2 were not limited to cells
activated by IL-1; a similar inhibition of NF-B induction after phorbol
ester treatment also was observed (data not shown). 15-d-PGJ2 alone
had no effect on mesangial NF-B activation.
|
To examine the mechanism of 15-d-PGJ2-mediated NF-B
inhibition, we looked at the effects of this prostaglandin on the NF-B
inhibitory protein IB-. Degradation of IB- by the
26S proteasome complex is necessary for NF-B nuclear translocation and
occurs after phosphorylation of IB- serine residues at positions
32 and 36 and ubiquitination of the protein
(26). As shown in
Figure 4A, IL-1 induced a rapid
(within 2 to 5 min) phosphorylation of serine 32 of IB-,
followed by a decline in the phospho—IB- level within 10
min that was progressive and consistent with degradation of this protein. In
cells treated with IL-1 plus 15-d-PGJ2, the phosphorylation of
IB- was slower, occurring within 5 to 10 min, and there was no
tendency for the level of phospho—IB- to decline after
peak phosphorylation (Figure
4A). Levels were maintained for 20 min. To confirm an impairment
in IB- degradation by 15-d-PGJ2, we immunoblotted
cells for total IB- (Figure
4B). Cells treated with IL-1 alone showed a near absence of
IB- 10 to 20 min after IL-1 was added. IB- levels
began to recover by 30 to 60 min (not shown), as we documented previously
(10). In contrast, this rapid
and profound decline in IB- levels was not observed in cells
treated with IL-1 plus 15-d-PGJ2, which showed only a mild decrease
in IB- after 15 to 20 min of incubation
(Figure 4B).
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Effect of Other Prostaglandins on Mesangial Cells
To determine whether the modulation of mesangial cell activation is
specific to 15-d-PGJ2, we incubated cells with other
15-deoxy-12,14-prostaglandin derivatives, or
PGJ2, the parent prostaglandin of 15-d-PGJ2. Like
15-d-PGJ2, 15-d-PGA1 and 15-d-PGA2 are cyPG,
formed by the dehydration of PGE1 and PGE2,
respectively. As shown in Figure
5, 15-d-PGA1, 15-d-PGA2, and
15-d-PGD2 had little effect on IL-1—induced NF-B
activation or MCP-1 mRNA expression at concentrations that were effective for
15-d-PGJ2. Consistent with these results, 15-d-PGA1,
15-d-PGA2, and 15-d-PGD2 did not block MCP-1 protein
production by mesangial cells (data not shown). PGJ2 did, however,
cause a dose-dependent inhibition of NF-B activation similar to that of
15-d-PGJ2 (Figure
6). PGJ2 also blocked IL-1—induced MCP-1 mRNA
expression (Figure 5), and
incubation with 10 µM PGJ2 overnight reduced mesangial MCP-1
secretion by 45% (32.7 ± 2.5 ng/ml versus 58.9 ± 14.9
from cells treated with IL-1 alone). Although PGD2 is not a cyPG,
it was predicted that it could inhibit NF-B activation if it were
metabolized to J series prostaglandins. Although the brief administration (2
h) of PGD2 in concentrations up to 50 µM had little effect on
IL-1—induced NF-B activation, sustained exposure (up to 18 h) did
inhibit NF-B (Figure 6),
consistent with a requirement for the metabolism of PGD2. The 18-h
treatment with PGD2 had no effect on cell viability, assessed by
trypan blue exclusion and MTT assay.
|
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Effects of 15-d-PGJ2 Are Not Mediated through
PPAR
15-d-PGJ2 is a potent ligand and activator of PPAR. In
some cell types, such as monocytes, activation of PPAR by
15-d-PGJ2 seems to block the expression of
NF-B—dependent cytokine genes. Two approaches were used to
determine whether the effects of 15-d-PGJ2 on mesangial MCP-1
production were PPAR dependent. First, mesangial cells were treated
with IL-1 in the presence or absence of ciglitazone, a thiazolidinedione and
specific PPAR agonist
(14). As shown in
Figure 7, A and B, treatment of
mesangial cells with ciglitazone in concentrations as high as 100 to 200 µM
had no effect on IL-1—induced MCP-1 mRNA expression or NF-B
expression. This was not because of a lack of expression of PPAR by
human mesangial cells. PPAR was found to be constitutively present in
nuclear protein extracts of untreated mesangial cells and seemed to increase
after ciglitazone (10 µM) treatment
(Figure 7C). The apparent
molecular mass of the protein identified by the anti-PPAR antibody is
51.7 kD (n = 5), consistent with the molecular mass of the
PPAR1 isoform
(27,28,29).
|
In a second set of experiments, mesangial cells were pretreated with BADGE,
a synthetic PPAR antagonist
(20), to determine whether the
inhibitory effect of 15-d-PGJ2 could be reversed. BADGE is a
competitive inhibitor of PPAR, binding to but not activating this
receptor (20). As shown in
Figure 8, BADGE was unable to
reverse the effect of 15-d-PGJ2 on NF-B activation. Although
it seems that NF-B binding was reduced further in cells treated with
both BADGE and 15-d-PGJ2, compared with 15-d-PGJ2 alone
(Figure 8), BADGE had no effect
on IL-1—induced NF-B activation (data not shown).
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Discussion |
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TopAbstractIntroductionMaterials and MethodsResultsDiscussionReferences |
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B activation in response to
proinflammatory stimuli, along with published reports indicating that J series
prostaglandins can be produced by renal cells
(7) and are found in human
urine (8). That PGJ2
and 15-d-PGJ2 also prevent nuclear translocation of NF-B
suggests that these prostaglandins may downregulate not only MCP-1 expression
but also the transcription of other chemokines and cytokines that require
NF-B.
15-d-PGJ2 seems to interfere directly with IB-
processing. Although IL-1—induced IB- phosphorylation was
slower in 15-d-PGJ2—treated cells, the main inhibitory effect
was at the level of IB- degradation. Preventing the degradation
of IB- provides a mechanistic explanation for
15-d-PGJ2—mediated inhibition of NF-B nuclear
translocation. These data suggest further that 15-d-PGJ2 interferes
with either the process of IB- ubiquitination after its
phosphorylation, a step necessary for proteasomal degradation, or the function
of the 26S proteasome complex, which is responsible for digesting
IB- (26). Which
of these novel activities is to be added to the growing list of ways that
15-d-PGJ2 interferes with the NF-B activation cascade
remains to be determined. At present, it seems that, in some cells, the
reactive cyclopentenone ring may alkylate cysteine residues in the p50 and p65
subunits of NF-B and thus block DNA binding
(12). Alternatively, a number
of recent reports demonstrated that IB- phosphorylation is
prevented by 15-d-PGJ2, because 15-d-PGJ2 directly
blocks the activity of IB kinases
(11,12,31).
This presumably occurs via covalent modification of critical residues of
IB kinase by the cyclopentenone ring. It is conceivable that cyPG could
modify the structure of the proteasome in this manner and alter its function.
The exact mechanism(s) involved in NF-B inhibition may depend on the
specific cell type. Indeed, one investigation showed that despite clear
inhibition of IB kinase activity in a macrophage cell line,
15-d-PGJ2 had no effect on IB kinase activity in HeLa cells
(12). Studies to evaluate
proteasome function in 15-d-PGJ2—treated mesangial cells are
under way in our laboratory.
Although 15-d-PGJ2 is a potent agonist of PPAR and human
mesangial cells express this receptor, this study found no evidence supporting
a role for PPAR in the modulation of MCP-1 or NF-B by
15-d-PGJ2 in mesangial cells. In contrast, there is a report that
the thiazolidinedione troglitazone attenuates MCP-1 production in mesangial
cells (32). Many effects of
troglitazone may, however, be drug specific rather than class specific and do
not necessarily involve PPAR
(33). In our system, the
thiazolidinedione ciglitazone did not reproduce the effects of
15-d-PGJ2, nor were the effects of 15-d-PGJ2 inhibited
by a PPAR antagonist. Similar conclusions have been reached by other
investigators
(11,31,34),
although it seems clear that PPAR can modulate NF-B activity and
cytokine expression in at least some types of cells
(17,18,35).
This may depend on the level of PPAR expression in a given cell type.
This also raises the interesting possibility that therapeutically increasing
PPAR levels in a tissue compartment may augment the intrinsic
anti-inflammatory effects of the cyPG.
The exact J series prostaglandins that are functional in vivo in
the kidney remain to be determined. Although there is some evidence that
15-d-PGJ2 is produced at sites of inflammation
(6), other investigators have
questioned whether PGJ2 is metabolized to 15-d-PGJ2
in vivo (36). In
addition, although the effects of 15-d-PGJ2 seem to be due to its
reactive cyclopentenone ring
(12), it is clear from our
data that not all cyPG are equally active, at least in human mesangial cells.
15-d-PGA1 and 15-d-PGA2 were less effective inhibitors
of IL-1—induced NF-B activation and MCP-1 expression than
15-d-PGJ2. It is interesting that other studies also showed J
series cyPG to be more potent when compared with A series cyPG
(34,37).
Despite this selectivity, the concentration of 15-d-PGJ2
required to inhibit cytokine expression seems to be cell specific. In some
cells, cytokine expression and NF-B activation were inhibited by
15-d-PGJ2 with IC50s of <5 µM
(11,17).
In other cells, the concentration of 15-d-PGJ2 for NF-B and
cytokine inhibition was found to be in the 5- to 30-µM range
(35,38),
similar to that of the mesangial cell.
The data from this study may help explain the observation that COX inhibitors can worsen renal inflammation in experimental models of nephritis. In anti—glomerular basement membrane antibody nephritis and anti—Thy-1 nephritis, administration of nonselective COX inhibitors increased glomerular leukocyte infiltration and MCP-1 expression (39,40). Timing of the administration of COX inhibitors may determine whether these agents treat or exacerbate inflammation. For example, in the model of pleural inflammation discussed previously (6), two peaks of COX-2 activity were observed. An early peak was associated with production of proinflammatory prostaglandins, whereas a delayed rise in COX-2 activity was associated with the production of PGD2 and cyPG. Appropriate use of COX inhibition in humans may require a detailed analysis of the time course of appearance of specific prostaglandins.
Activation of cyPG production in the kidney thus may be an endogenous
mechanism that contributes to the resolution of the renal inflammation by
attenuating NF-B—dependent proinflammatory gene expression. It is
tempting to speculate that clinically observed variations in tissue injury in
response to inflammatory stimuli are determined by the level of J series
prostaglandins that an individual is able to produce. Supporting the
feasibility of this idea, a defect in the production of PGJ2 has
been described in mesangial cells from lupus-prone mice
(7). Such defects may lead to a
more severe disease phenotype because of uncontrolled inflammation.
Understanding how to augment the production of cyPG in human disease therefore
may prove therapeutically useful in treating renal inflammation.
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Acknowledgments |
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References |
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B correlates with MCP-1 expression by human mesangial cells.
Kidney Int 48:1263
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Natl Acad Sci USA 97:4844
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B kinase and I B phosphorylation by
15-deoxy-delta 12,14-prostaglandin J2 in activated murine macrophages.
Mol Cell Biol 20:1692
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