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*
Department of Nephrology, Leiden University Medical Center, Leiden, The
Netherlands.
Department of Immunohematology and Blood Bank, Leiden University Medical
Center, Leiden, The Netherlands.
Correspondence to Dr. Cees van Kooten, Department of Nephrology, Leiden University Medical Center, Building 1, C3P, Albinusdreef 2, 2333 ZA Leiden, The Netherlands. Phone: 31 71 526 3964; Fax: 31 71 524 8118; E-mail: Kooten{at}LUMC.nl
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Abstract |
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 Top Abstract IntroductionMaterials and MethodsResultsDiscussionReferences |
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B and induction of cytokine
production by IL-17 and CD40L is prevented by addition of the NF-B
inhibitor pyrrolidine dithiocarbamate. These data suggest an important role
for T cells in renal allograft rejection by acting on parenchymal cells via
both soluble mediators and direct cellular contact. |
Introduction |
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TopAbstractIntroductionMaterials and MethodsResultsDiscussionReferences |
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In recent years, it has become clear that CD40-CD40L interactions are potentially involved in the regulation of inflammatory responses. CD40 expression and function has been studied extensively on B lymphocytes and other antigen-presenting cells (monocytes and dendritic cells) (7). In addition, CD40 is functionally expressed on endothelial cells, fibro-blasts, and epithelial cells (8). In vitro activation of these cells results in an increased inflammatory potential, such as expression of adhesion molecules and production of various cytokines. Concerning the kidney, TEC express CD40, and in vitro activation increases chemokine production (4). In addition, co-activation with IL-4 specifically increases the CD40L-induced RANTES production (9). Blockade of the CD40-CD40L pathway prevents chronic inflammation in various animal models, including glomerulonephritis (7,10). Moreover, treatment with anti-CD40L antibodies interferes with acute and chronic allograft rejection of different organs, including the kidney (11,12,13).
Recently, an IL-17 antagonist (mIL-17R:Fc fusion protein) has been presented as an additional tool to prolong allograft survival (14). IL-17 is a proinflammatory cytokine that is specifically produced by activated T cells (15,16,17). IL-17—producing cells were demonstrated in rejected human kidney allografts, either by immunofluorescence staining (18) or by reverse transcriptase-PCR (RT-PCR) analysis (19). The biologic activities of IL-17 are mostly restricted to the activation of nonhematopoietic cells. IL-17 stimulates the production of IL-6 and IL-8 by foreskin fibroblasts and synoviocytes, granulocyte colony-stimulating factor and prostaglandin E2 by synoviocytes, and IL-6 by epithelial and endothelial cells (15). Moreover, in vitro activation of renal TEC with IL-17 increases the production of IL-6, IL-8, and MCP-1 (18).
It was the purpose of the present study to explore the hypothesis that infiltrating T cells contribute to the renal inflammatory process by activating resident TEC. This study focuses on the interaction between CD40L/CD40 and IL-17/IL-17R, because (1) IL-17 and CD40L both are able to stimulate TEC, (2) IL-17 and CD40L are produced or expressed by activated T cells, and (3) neutralization of IL-17 or CD40L interferes with allograft rejection. We demonstrated that during renal allograft rejection, local expression of both CD40 and CD40L is strongly increased. In vitro, combined stimulation of TEC with IL-17 and CD40L results in a strong synergistic stimulation of chemokine and cytokine production, underlining the potential role of activated T cells in orchestrating the local inflammatory response.
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Materials and Methods |
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TopAbstractIntroductionMaterials and MethodsResultsDiscussionReferences |
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Frozen tissue sections of 4 µm were fixed for 10 min in water-free acetone at room temperature. After washing and blocking endogenous peroxide with 0.03% H2O2, sections were incubated with 20 µg/ml mAb89 (msIgG1 anti-human CD40), 20 µg/ml LL56 (msIgG2a anti-human CD40L), or 20 µg/ml total msIgG in incubation buffer, containing 0.1 M Tris/HCl, 0.15 M NaCl with 0.5% Boehringer blocking reagent (Boehringer Mannheim, Mannheim, Germany) for 45 min. After sections were washed with phosphate-buffered saline (PBS), they were incubated in 1:50 diluted horseradish peroxidase-labeled rabbit anti-mouse Ig (DAKO, Glostrup, Denmark) in incubation buffer with 10% normal human serum for 30 min. Slides were washed with PBS/0.05% Tween 20 (pH 7.4; OPG Farma, Utrecht, The Netherlands), followed by washing in PBS, and incubated with 0.5 mg/ml tyramide-fluos (NEN-Dupont, Dordrecht, The Netherlands) in 0.2 M Tris/HCl, 10 mM imidazole (pH 8.8; Sigma Chemical Co., St. Louis, MO) with 0.01% H2O2, for 30 min (20). After slides were washed in PBS/Tween and PBS, they were mounted with 0.1% (wt/vol) P-phenylenediamine (Sigma) in glycerol. Photographs were taken using Kodak TX-400 films (San Diego, CA) on a Leitz microscope (Weesp, The Netherlands) with a 4 mmBG 38 + 5 mmBG 12 filter for FITC.
Cell Cultures
Tubular Epithelial Cells. Primary human TEC were cultured from
cortical tissue of human kidneys not suitable for transplantation because of
anatomical reasons or from pretransplant biopsies
(4). TEC monolayers were
cultured on a matrix of collagen type I (Sigma) and heat-inactivated fetal
calf serum (FCS; Gibco Life Technologies/Life Technologies Inc., Gaithersburg,
MD), in a selective medium, consisting of a 1:1 ratio of Dulbecco's modified
Eagle's medium and Ham F12 (both from Seromed Biochem KG, Berlin, Germany),
supplemented with insulin (5 µg/ml), transferrin (5 µg/ml), selenium (5
ng/ml), hydrocortisone (36 ng/ml), tri-iodothyronine (40 pg/ml), and epidermal
growth factor (10 ng/ml) (all from Sigma). Morphologic appearance and
immunofluorescence staining confirmed specific outgrowth of TEC
(4). Cells were used between
passages 2 and 9 of culture.
Foreskin Fibroblasts. The foreskin fibroblast cell line FS4 (21) was cultured in Iscove's modified Dulbecco's medium (IMDM) (Life Technologies), 10% heat-inactivated FCS, and penicillin/streptomycin.
Synoviocytes. Primary synoviocytes were cultured from the synovial tissue of patients with rheumatoid arthritis undergoing total or partial knee or elbow surgery (22). Synoviocytes were cultured in IMDM, 20% heat-inactivated FCS, and penicillin/streptomycin. Primary synoviocytes were used between passages 2 and 7 of culture.
L Cells. Mouse fibroblast L cells, stable transfected with human CD40L (L-CD40L) and parental nontransfected L cells (L-Orient), were cultured in IMDM supplemented with 10% heat-inactivated FCS and penicillin/streptomycin (23). For passage of the different cell cultures, cells were harvested by trypsinization (0.02% [wt/vol] ethylenediaminetraacetate/0.05% [wt/vol] trypsin in PBS; Sigma).
Culture and Activation Experiments
For induction of cytokine production, the cells were trypsinized and seeded
in a final concentration of 5 x 104 (TEC), 4 x
104 (FS4), or 3 x 104 (synoviocytes) cells/well in
48-well plates. CD40 activation was achieved by incubation with a chimeric
protein containing the extracellular domains of mouse CD8 
and human
CD40L (CD8CD40L) (23).
The original construct was recloned into an expression vector containing the
hygromycin resistance gene, and stably transfected Chinese hamster ovary cells
producing the chimeric protein were generated. Alternatively, TEC were
cocultured with irradiated (80 Gy) CD40L-transfected L cells in a 1:1 ratio
(4). Recombinant human IL-17
(50 ng/ml, unless indicated otherwise) was used for activation
(15). Neutralizing antibodies
against CD40L (LL48; IgG1) or IL-17 (mAb5; IgG1) were used at 10 µg/ml.
Pyrrolidine dithiocarbamate (PDTC; Sigma) was used as an inhibitor of
NF-B activation.
Determination of Cytokines and Chemokines
The concentration of cytokines and chemokines in supernatants of cultured
cells was measured by enzyme-linked immunosorbent assay (ELISA). Details on
the measurement of IL-6, IL-8, MCP-1, and RANTES have been described in
previous reports
(4,18).
Fluorescence-Activated Cell Sorter Analysis
For fluorescence-activated cell sorter (FACS) experiments, cells were
harvested by brief trypsinization to prevent proteolysis of surface receptors.
After the cells were washed with FACS buffer (1% BSA, 1% decomplemented normal
human serum, and 0.02% sodium azide in PBS), 2 x 105 cells
were incubated with 10 µg/ml mAb89 (CD40) or 10 µg/ml mAb M203
(IL-17R; a kind gift of Dr. M. Kubin, Immunex, Seattle, WA)
(24). After incubation for 45
min at 4°C, the cells were washed twice with FACS buffer and subsequently
incubated with goat anti-mouse Ig-PE (DAKO) for 30 min at 4°C. Finally,
the cells were washed, fixed with 1% paraformaldehyde, and assessed for
fluorescence using a FACScan. Data analysis was performed using LYSIS-II
software (Becton Dickinson, Mountain View, CA). Receptor expression was
calculated by the ratio of mean fluorescence intensity (MFI), i.e.,
the quotient of MFI with and without specific antibody.
Electrophoretic Mobility Shift Assay
TEC were stimulated with IL-17 and/or CD8 CD40L for 1 h. Nuclear
extracts were prepared according to the protocol described by Gobin et
al. (25). For each
nuclear extract, 3 µg of protein was tested for NF-B—binding
activity using two different NF- B—binding probes: a
32P-labeled NF-B consensus oligo (5'-AGT TGA GGG GAC
TTT CCC AGG C; Promega, Madison, WI) and a 32P-labeled oligo
containing the B-site from human leukocyte antigen-A (HLA-A)
(5'-GTG GGG ATT CCC CAC TGC A)
(25). Competition experiments
were performed using cold B-probe from HLA-A and a cold divergent
B-probe from HLA-B, which is unable to bind NF- B
(25). For the supershift
assays, the following antibodies were used: anti-p50 Ab (sc-114), anti-p65 Ab
(sc-109), anti-c-Rel Ab (sc-71), and the irrelevant Ab anti-mouse-IRF-1 Ab
(sc-640), all from Santa Cruz Biotechnology (Santa Cruz, CA). Each Ab (1
µg) was added to the nuclear extract and probe mixture and incubated for r
1 h at 4°C. Samples were run on a 6% polyacrylamide gel in 0.25 x
Tris-borate/ethylenediaminetetraacetate buffer and analyzed by
autoradiography.
Statistical Analyses
The production of chemokines and cytokines is presented as mean
concentration ± SD from representative experiments. To quantitatively
express synergy between IL-17 and CD40L, we defined an index of synergy, which
was statistically tested using the Wilcoxon matched pairs signed-ranks test.
An index of synergy >1 and P < 0.05 was considered
significantly synergistic.
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Results |
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TopAbstractIntroductionMaterials and MethodsResultsDiscussionReferences |
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CD40L expression was not detectable in any of the control tissues (0 of 7) but was clearly positive in 6 of 8 tissues derived from patients with ongoing rejection (Figure 2, Table 1). In contrast with the staining for CD40, expression of CD40L was completely restricted to graft infiltrating cells, presumably T cells, as suggested by parallel staining for CD4+ T cells.
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IL-17 and CD40L Synergistically Enhance IL-6 Production by TEC
In the results above and in other studies, it was observed that TEC and T
cells are frequently in close proximity during allograft rejection
(26). Because the T-cell
products IL-17 and CD40L both are expressed during renal allograft rejection,
a possible cooperation between IL-17 and CD40L was investigated. Activation of
TEC with either IL-17- or CD40L-transfected L cells (L-CD40L) increased IL-6
production over base-line levels (Figure
3). Stimulation of TEC with a combination of IL-17 and CD40L
resulted in synergistic effects on IL-6 production. The mean index of synergy
of nine independent experiments was statistically significant
(MISIL-6 = 2.08; range, 1.06 to 4.03; P = 0.008).
Neutralizing antibodies against either CD40L or IL-17 significantly inhibited
IL-6 production induced by the combination of CD40L and IL-17
(Figure 3).
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The Effect of IL-17 and CD40L Interaction on the Production of
Chemokines by TEC
The production of chemokines at the site of inflammation is a central event
in the regulation of interstitial infiltration. Therefore, we investigated the
effect of IL-17 and CD40L on the production of chemokines by TEC, including
IL-8, MCP-1, and RANTES. Production of both IL-8 and MCP-1 was increased by
single stimulation with either IL-17 or CD40L but was enhanced more strongly
after combined stimulation (Figure 4, A and
B). Titration of both IL-17 and CD40L showed that IL-8 production
was upregulated in a dose-dependent fashion
(Figure 5A). As demonstrated
for surface-bound CD40L (L-CD40L; Figure
4A), this soluble chimeric protein also showed synergy with IL-17
on the production of IL-8 by TEC. Synergistic effects on IL-8 production were
found over a wide range of IL-17 (1.2 to 100 ng/ml) and CD8CD40L (1:20
to 1:5) concentrations (Figure
5A). Addition of increasing concentrations of IL-17 to
CD40L-stimulated TEC also caused a strong dose-dependent enhancement of MCP-1
production, which was blocked by addition of neutralizing anti-IL-17
antibodies (Figure 5B).
Statistical analysis revealed that the co-stimulatory effect of IL-17 and
CD40L on the production of IL-8 was significantly synergistic, whereas the
co-stimulatory effect on the production of MCP-1 was additive
(Table 2).
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Production of RANTES was not detectable in supernatant of nonstimulated or IL-17—stimulated TEC (Figure 4C). Even after a 5-d culture period, IL-17 did not induce detectable RANTES production, either by ELISA (Figure 6) or by RT-PCR analysis (data not shown). In accordance with previous studies, we found that CD40 activation did induce RANTES production (Figures 4C and 6). Combined treatment with CD40L demonstrated that IL-17 synergistically increased CD40L-induced RANTES production at all time points (Figure 6, Table 2).
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Synergistic Effects of IL-17 and CD40L Are Not Specific for
Epithelial Cells
To investigate whether the synergy between IL-17 and CD40L is specific for
renal TEC, we studied two different fibroblast populations. Stimulation of
primary synoviocytes with either IL-17 or CD40L increased the production of
IL-6 and IL-8 (Figure 7), and
combined treatment showed a significant synergy between IL-17 and CD40L
(Table 2). Similarly,
simultaneous stimulation with IL-17 and CD40L resulted in dose- and
time-dependent synergistic effects on IL-6 and IL-8 production by the foreskin
fibroblast cell line FS4 (Table
2, Figure 8).
Co-stimulation showed a synergistic effect on the production of MCP-1 by FS4,
which was not observed with synoviocytes. For both fibroblast populations, no
significant increase in RANTES production was found in culture supernatants
after either single or simultaneous stimulation
(Table 2).
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Regulation of IL-17 Receptor and CD40 Expression
Specific regulation of IL-17R and CD40 expression might contribute to the
observed synergistic effect on cytokine production. FACS analysis using
specific monoclonal antibodies demonstrated a homogeneous expression of CD40
and IL-17R on TEC, synoviocytes, and FS4
(Figure 9A). Activation with
CD8CD40L did not affect IL-17R expression on any of these cell types.
Also, IL-17 treatment of synoviocytes and FS4 did not alter surface expression
of CD40. However, activation of TEC with IL-17 resulted in a twofold increase
in CD40 expression (Figure 9B).
In 10 independent experiments, IL-17 increased the ratio mean fluorescence
(CD40 staining over control staining) from 4.5 (range, 1.2 to 8.7) to 9.2
(range, 3.8 to 14.9).
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IL-17- and CD40L-Induced Cytokine and Chemokine Production Is
NF-B Dependent
Electrophoretic mobility shift assays were performed to investigate
NF-B activation. Nonstimulated TEC showed low NF-B—binding
activity, which was not significantly influenced by IL-17. CD40L activation
strongly increased NF-B binding, which was not further increased by
co-stimulation with IL-17 (Figure
10A). The specificity of the binding was tested by competition
with cold B probes. Binding of the complex was prevented when using the
cold B probe containing the homologous sequence, but was not affected
with a cold divergent B probe (B-mut;
Figure 10B). Supershift
analysis with antisera specific for p50, p65, and c-Rel determined the nuclear
proteins present in the bound complex
(Figure 10C). The upper band
of the complex was shown to contain p50 and p65, because this band shifted
with both anti-p50 and anti-p65 antibodies. This protein/DNA complex probably
represents the p50/p65 heterodimer. The intense lower band showed a
significant reduction in intensity by addition of anti-p50 antibody, most
likely representing the p50/p50 homodimer. No marked difference was observed
by using anti-c-Rel antibody. No supershift was obtained with an irrelevant
antibody.
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The involvement of NF-B in CD40L- and IL-17—induced cytokine
production was investigated using PDTC, an inhibitor of NF-B
activation. Two-h preincubation of TEC with 3 to 30 µM PDTC and subsequent
activation with IL-17, CD40L, or the combination showed a dose-dependent
inhibition of IL-6 production (Figure
11A). Complete inhibition was found by addition of 30 µM PDTC
to the cultures. Similar inhibition was obtained for IL-8 and RANTES
production by TEC (data not shown) and IL-6
(Figure 11B) and IL-8
production by synoviocytes and FS4 (data not shown).
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Discussion |
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TopAbstractIntroductionMaterials and MethodsResultsDiscussionReferences |
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Normal kidneys show expression of CD40, which is restricted to a limited number of proximal and distal tubuli and some endothelial cells (4,27,28). In the present study, we demonstrated that tubular expression of CD40 is strongly increased during allograft rejection. This means that not only CD40L is an inducible T-cell activation marker, but also that expression of the CD40 receptor is subject to regulation upon local inflammation. In accordance, we found that proinflammatory cytokines, such as IL-1 (29) and IL-17, can increase CD40 expression in TEC. Although in normal renal tissue TEC express low CD40, cultured TEC shows a strong homogeneous CD40 surface expression, suggesting that other, as yet unidentified signals might also regulate CD40 expression.
Immunofluorescence staining showed that during rejection, both CD40 and CD40L are broadly expressed on graft-infiltrating lymphocytes. As shown by others, we also found that CD40L was exclusively expressed on infiltrating cells (Figure 2) (28). In addition, we were not able to detect CD40L expression by cultured TEC using FACS or RT-PCR analysis (data not shown). However, it has been suggested that during chronic rejection, CD40L might also be expressed on TEC (30). The expression of CD40L in renal biopsies was performed on the same biopsies as used for the detection of IL-17 (18). In consecutive sections of these biopsies, IL-17 and CD40L expression overlapped the area of infiltrating cells and paralleled the staining for CD4+ T cells (data not shown). Local expression of IL-17 and CD40L within the kidney will favor the activation of IL-17R- and CD40-expressing cells, which might include renal TEC, endothelial cells, and graft-infiltrating monocytes, B cells and T cells, all of which can contribute to the rejection process. Analysis of CD40L expression, at either the protein or the mRNA level, was shown to correlate with renal allograft rejection (28,30), and a similar situation has been described for cardiac allograft rejection (31). However, expression of CD40L is not specific for rejection. This is best illustrated by the observation of increased CD40L expression in lupus nephritis and other renal diseases (27), in which auto-antigens rather than allo-antigens are the driving force of T cell activation.
The increased MCP-1 production and the synergistically enhanced IL-8 and RANTES production by TEC in response to IL-17 and CD40L emphasize the important role for these T-cell products during rejection episodes. An elevated production of chemokines leads to further attraction of inflammatory cells (6) and hence an amplification of the initial (allo)antigen-specific response. It is thought that the rejection process is predominantly driven by a Th1 immune response (32). Expression of CD40L on activated T cells is not restricted to a specific Th type and can be induced in Th0, Th1, and Th2 cells (33). Because of its high chemotactic capacity on T cells, especially Th1 cells, the production of RANTES plays an important role in the rejection process (5,26,34,35). Activation via CD40 seems to be a critical step in the production of RANTES by TEC. Previous reports have demonstrated that both IL-1 (29) and IL-4 (9) synergize with CD40L in the enhancement of RANTES production by TEC. IL-1 is mainly produced by monocytes and macrophages (36), and IL-4 is a Th2-derived cytokine (37). In contrast, production of IL-17 is specific for activated T cells, predominantly of the Th1 type, but not by Th2 cells (17). Therefore, the combination of IL-17 and CD40L might play a prominent role in the Th1-mediated renal allograft response.
It will be interesting to test the combined inhibition of IL-17 and CD40L in a model of renal transplantation, because individual blocking has already demonstrated prolongation of graft survival in different experimental models (12,14). Although CD40 activation is critical for upregulation of B7 molecules and for further T-cell activation and cytokine production, prevention of chemokine production by TEC might be part of the observed effects of anti-CD40L treatment.
IL-17—induced CD40 upregulation on TEC might partially explain the
mechanism of synergy between IL-17 and CD40L. Because synergistic activation
of fibroblasts was independent of IL-17—induced CD40 upregulation, it is
most likely that other mechanisms, such as the convergence of intracellular
pathways, also contribute to this process. In accordance with previous studies
using other epithelial cells and fibroblasts
(38,39),
we showed an increased NF-B binding activity after CD40L activation of
TEC. We did not observe a further increase in NF-B activity by
co-stimulation of TEC with IL-17 and CD40L. However, induction of IL-6 and
IL-8 production was completely prevented by an inhibitor of NF-B. This
supports the role of NF-B as a pivotal transcription factor in chronic
inflammation (40). These data
suggest that part of the action of corticosteroids, which are used in
post-transplantation therapy and block NF-B activation
(41), is via the inhibition of
resident epithelial cells.
We showed that combination of IL-17 and CD40L synergistically activates fibroblasts. Although little information is available on human renal fibroblasts, it is evident that they participate in the pathologic changes of renal inflammation and chronic allograft rejection (42). More is known about the role of synoviocytes in rheumatoid arthritis or lung fibroblasts in chronic lung inflammation and fibrosis. Expression of IL-17 and CD40L has been demonstrated in rheumatoid arthritis synovium supernatants (43) and in synovial biopsies (44). Administration of soluble CD40L in the lung was demonstrated to induce pulmonary inflammation (45), whereas treatment with anti-CD40L or use of CD40L-knockout mice prevented the development of lung inflammation and fibrosis (46,47). In the skin, keratinocytes are responsive to both CD40L (48) and IL-17 (49). Therefore, local expression of CD40/CD40L and cooperation with IL-17 most likely is not restricted to the kidney but is operational in different organs.
In conclusion, the T-cell products IL-17 and CD40L, which both are expressed during renal allograft rejection, synergistically increase cytokine and chemokine production by renal epithelial cells and fibroblasts. IL-17 and CD40L might potentially explain the link between (allo)specific immune reactivity and nonspecific inflammation. This study extends the recent findings that interaction between cells of the hematopoietic system (especially T cells) and nonhematopoietic cells might play an important role in the regulation of inflammation.
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Acknowledgments |
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Footnotes |
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References |
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