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Up-Regulation: Involvement of IL-12 and IL-181
Department of General Surgery, University of Maastricht, Maastricht, The Netherlands
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Abstract |
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 Top Abstract IntroductionMaterials and MethodsResultsDiscussionReferences |
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-dependent up-regulation of MHC
class I and II Ag expression. Employing a murine model of renal
ischemia, we show that renal IL-18 mRNA up-regulation coincides with
caspase-1 activation at day 1 following ischemia. IFN- and IL-12
mRNA are subsequently up-regulated at day 6 following ischemia.
Combined, but not separate, in vivo neutralization of the IFN-
inducing cytokines IL-12 and IL-18 reduces IFN--dependent MHC class
I and II up-regulation to a similar extent as IFN- neutralization,
suggesting the involvement of functional IL-12, IL-18, and IFN-
protein. These results reveal a novel relationship between tissue
injury of nonmicrobial origin and the induction of IL-12 as well as
IL-18. The collaboration observed between endogenous IL-12 and IL-18 in
the induction of IFN- after renal ischemia/reperfusion, resembles
the immune response to bacterial infections. |
Introduction |
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TopAbstractIntroductionMaterials and MethodsResultsDiscussionReferences |
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(6, 7). However, the mechanisms by which IFN- is induced
after renal I/R still remain to be resolved.
IFN-, commonly associated with resistance against pathogens, is
produced largely by Th1 cells and large granular lymphocytes. In
particular, IL-12 (8), IL-18 (9), and, in an autocrine fashion, IFN-
(10) are involved in the intricate and tight regulation of IFN-
expression. Recently, Bohn et al. (11) reported that the LPS-induced
IL-12 production by peritoneal macrophages in vitro is inhibited by
IL-18. They subsequently showed that this inhibitory effect is
suppressed by IFN-. In addition, in vitro experiments indicated that
IL-12 and IL-18 synergistically enhance production of IFN- (12, 13).
This synergistic mechanism has been attributed to up-regulation of the
IL-18 receptor by IL-12 (14). On the other hand, IFN- production is
limited by cytokines capable of suppressing Th1 development, such as
IL-10 and IL-13 (15). In line with this, we recently demonstrated that
endogenously produced IL-10 limits IFN--induced renal MHC class I
and II expression after I/R (4). IL-12 and IL-18 are commonly produced
in response to pathogens and their products; however, in this study, we
investigate the role of IL-12, IL-18, and consequent IFN- production
triggered by tissue damage resulting from I/R.
We demonstrate that up-regulation of MHC class I and II Ags following
renal I/R can be prevented to a similar extent as in mice treated with
anti-IFN- Abs by combined, but not separate, administration of
Abs directed against IL-12 and IL-18. This demonstrates for the first
time that ischemic tissue damage initiates production of IL-12 as well
as IL-18. Moreover, with respect to the in vivo kinetics of IL-12 and
IL-18, we observe a resemblance between renal I/R injury and in vivo
immunoactivation by infectious agents.
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Materials and Methods |
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TopAbstractIntroductionMaterials and MethodsResultsDiscussionReferences |
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The following Abs were used: anti-murine IFN- mAb F3, was
kindly provided by Hycult Biotechnology (Uden, The Netherlands);
anti-murine IL-12 mAb C17.8, was kindly provided by Prof.
Trinchieri (Wistar Institute, Philadelphia, PA) (16); mAb GL113, a
control rat IgG1, was kindly provided by Dr. Savelkoul (Erasmus
University, Rotterdam, The Netherlands); anti-murine MHC class I
mAb m1/42.3.9.8 and mAb 5D7-producing hybridomas from the American Type
Culture Collection (ATCC; Manassas, VA); anti-murine MHC class II
mAb H82-168.10-producing hybridoma was kindly provided by Dr. Pierres
(Centre National de la Recherche Scientifique INSERM, Marseille,
France); anti-murine IL-18 polyclonal Ab (pAb; purified rabbit IgG)
was raised by immunizing rabbits with recombinant murine IL-18, kindly
provided by Dr. Kurimoto (Fujisaki Institute, Okayama, Japan).
Peroxidase-conjugated goat anti-rat IgG was purchased from Jackson
ImmunoResearch (West Grove, PA), Ac-YVAD-amc from the Peptide Institute
(Osaka, Japan). All other reagents were purchased from Sigma (St.
Louis, MO).
Animal model and protocol
All experiments were approved by the Institutional Animal Care Committee of the University of Maastricht. Renal ischemia was induced as follows. In brief, male Swiss mice (Charles River Breeding Laboratories, Heidelberg, Germany) were anesthetized, and body temperature was maintained at 39°C. After laparotomy, ischemia was induced by clamping the left renal pedicle for 45 min, during which the wound was covered. Subsequent to removal of the clamp, the contralateral kidney was removed and stored. After closing the abdomen, 0.25% bupivacaine was applied topically for postoperative pain management, and mice were supplemented with prewarmed PBS to maintain fluid balance. At the time of sacrifice (1 and 6 days after ischemia), blood was collected, and the left kidney was harvested.
Mice subjected to ischemia were treated 10 min before reperfusion with
0.5 ml PBS i.p. containing 300 µg anti-IFN- mAb F3
(n = 20), 1 mg anti-IL-12 mAb C17.8
(n = 20), 1 mg anti-IL-18 pAb (n =
20), a combination of 0.5 mg anti-IL-12 mAb C17.8 and 0.5 mg
anti-IL-18 pAb (n = 20), or PBS only
(n = 20). Two additional groups that received
isotype-matched control Ab (5D7, a control rat IgG2a mAb; GL113, a
control rat IgG1 mAb; n = 6 each) when compared with
the ischemia/PBS group showed no significant differences (data not
shown), indicating that aspecific IgG does not affect the evaluated
parameters. Treatment of animals to be sacrificed at day 6 was repeated
at day 4 after ischemia. A sham-group (n = 12)
underwent the same surgical procedure as animals subjected to ischemia,
except for clamping of the renal pedicle. Sham-operated animals were
only treated with PBS. The capacity of the anti-IL-18 pAb to block
biological activity was determined by measuring the ability of the
anti-IL-18 pAb to neutralize IL-18-mediated enhancement of IFN-
production in vitro by stimulated T cells (1 mg IgG/ml inhibits the
biological activity of 100 µg of IL-18) (data not shown). Also, the
in vivo neutralizing capacity of the anti-IL-18 pAb used was
confirmed by its effectiveness in combination with anti-IL-12 mAb
as shown by the present results. Dosages of anti-IFN- and
anti-IL-12 mAb are based on published results (16, 17).
Measurements of renal IL-12, IL-18, and IFN- mRNA content
Total RNA was extracted from kidneys and transcribed into copy
DNA (cDNA) of which the concentration was subsequently standardized
based on the ß-actin cDNA fraction. To determine renal IL-12 and
IL-18 mRNA content, four 2-fold serial dilutions of cDNA were amplified
with specific primers (18, 19). IFN- mRNA expression was
quantitatively measured by RT-PCR employing a multispecific control
fragment as an internal standard (20). Relative amounts of IFN- cDNA
in specimens were estimated from concentrations of control fragment DNA
added to achieve equal amplification compared with IFN- cDNA
employing IFN--specific primers (20). After separation on 1.5%
agarose gel, all PCR products were estimated by imaging the intensity
of ethidium bromide luminescence with a computer-controlled
display camera (Imagemaster, Pharmacia, Piscataway, NJ) and image
analysis with Sigma Gel software (SPSS, Chicago, IL).
Quantification of renal caspase-1-like activity
To quantify renal caspase-1 activity, samples were homogenized, snap frozen, and stored at -70°C in a buffer containing 200 mM NaCl, 10 mM Tris-HCl (pH 7.0), 5 mM EDTA, 10% glycerol, 1 mM PMSF, 0.1 µM aprotinin, 1.0 µM leupeptin, and 5 mM oxidized glutathion. Renal lysates (containing 40 µg total protein) were incubated with 50 µM of the fluorogenic substrate Ac-YVAD-amc (caspase-1-like) in a cell-free system buffer containing 10 mM HEPES (pH 7.4), 220 mM mannitol, 68 mM sucrose, 2 mM NaCl, 2.5 mM KH2PO4, 0.5 mM EGTA, 2 mM MgCl2, 5 mM pyruvate, 0.1 mM PMSF, and 1 mM DTT (21). The release of fluorescent 7-amino-4-methylcoumarin was measured for 1 h at 2-min intervals by spectrofluorometry (Cytofluor, Per Septive Biosystems, Cambridge, MA). Data are expressed as the increase in fluorescence as a function of time, normalized against data obtained from the sham-operated group.
Enzyme immunoassay (EIA) and immunohistology for MHC class I and II
For the quantification of MHC class I and II Ags in the kidney, an EIA was employed, as previously described (4). In brief, renal tissue was homogenized in PBS (20 mg/ml) plus 8 nM deoxyribonuclease I, 0.4 mM PMSF, incubated with either mAb m1/42.3.9.8 or mAb H82-168.10, washed, incubated with peroxidase-conjugated goat anti-rat IgG, and washed again. Next, 3,3',5,5'-tetramethyl-benzidine (TMB) substrate was added in a 96-well sample plate (Costar, Cambridge, MA) to resuspended pellets, and OD was determined at 450 nm. All samples were measured in triplicate. MHC class I and II content were calculated per mg of renal tissue and standardized to a standard horseradish peroxidase titration curve. The obtained MHC class I and II contents are presented relative to the amount of MHC class I and II in the contralateral control kidney.
For immunohistology of renal MHC class I and II, specimens of harvested kidneys were immediately frozen and stored at -70°C. Frozen sections (5 µm) were stained for MHC class I with mAb m1/42.3.9.8 (22) and for MHC class II with mAb H82–168.10 using peroxidase-labeled goat anti-rat IgG as the secondary detection mAb and 3-amino-9-ethylcarbazole as a chromogen, followed by a hematoxylin counterstain. To block aspecific peroxidase activity, sections were pretreated for 10 min with PBS containing 0.03% H2O2. No significant staining was detected in slides incubated with control mAb instead of the primary detecting mAb, indicating the absence of significant background staining.
Assays for renal myeloperoxidase (MPO) and blood urea nitrogen (BUN)
To quantify the extent of renal neutrophil accumulation, renal MPO content was determined (23). In brief, tissue samples were homogenized in 0.5% hexadecyltrimethylammonium bromide in 50 mM PBS (pH 6.0), 0.17 g tissue/ml. After heat incubation (2 h, 60°C) and three freeze-thaw cycles, MPO content was measured in triplicate by incubating supernatants with TMB substrate in a 96-well sample plate (Costar), followed by measurement of OD at 450 nm. MPO activity was calculated per mg renal tissue by comparing OD of samples with a standard titration curve of horseradish peroxidase. Data were standardized with respect to wet:dry ratios of the assayed renal tissue and are presented relative to the amount of MPO present in the contralateral kidney harvested immediately after ipsilateral reperfusion. BUN was measured in serum obtained at the time of sacrifice using a BUN unimate 5 kit in a Cobas Fara autoanalyzer (Roche, Basel, Switzerland).
Statistics
Data are expressed as means ± SEM, and statistical analysis was performed by Student’s t test. A value of p < 0.05 was taken to denote statistical significance.
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Results |
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TopAbstractIntroductionMaterials and MethodsResultsDiscussionReferences |
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-dependent MHC class I and II up-regulation
At day 1 after ischemia, increased levels of kidney-derived IL-18
mRNA were detected (Fig. 1
), while
IFN- mRNA expression remained constitutive (data not shown).
Interestingly, at this time point, constitutive IL-12 p40 mRNA levels
slightly decreased (Fig. 1). In animals sacrificed at 6 days after
ischemia, significant renal IL-18 mRNA levels were undetectable,
whereas renal IL-12 p40 mRNA levels increased compared with
constitutive levels (Fig. 1). At this time, anti-IL-12 or
anti-IL-18 Ab administration neither affected renal IFN- mRNA
levels (Fig. 2) nor MHC class I and II
expression (Fig. 3) when compared with
PBS-treated controls. However, the combined administration of
anti-IL-12 and anti-IL-18 Ab prevented the increase in renal
IFN- mRNA levels (Fig. 2), as well as the up-regulation of renal MHC
I and II (Figs. 3 and 4) at day 6. In
contrast to IL-12, the protein product of IL-18 mRNA translation
requires further processing by activated caspase-1 to become mature
IL-18 (9, 18). The observed increase in renal caspase-1-like activity
(Fig. 5) indicates that the conditions
for processing IL-18 protein are met. Indeed, the effectiveness of
combined anti-IL-12/18 as well as anti-IFN- treatment
indicate that IL-12, IL-18, and IFN- protein are induced in the
present model.
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-dependent MHC class I and II up-regulation after
renal I/R
To explore the mechanisms by which I/R injury initiates IFN-
production and consequent enhanced MHC class I and II expression, we
investigated renal IFN- mRNA levels by means of RT-PCR as well as
MHC class I and II expression by employing EIA and immunohistology. In
line with previous reports (6, 24), the present findings reveal
significantly increased levels of IFN- mRNA (Fig. 2
) coinciding with
significant MHC class I and II (Figs. 3 and 4) up-regulation at 6 days
after I/R when compared with sham-operated controls. At day 6, tubular
epithelium and arterial endothelium stained intensely positive for MHC
class I (Fig. 4), whereas MHC class II immunoreactivity was confined
mainly to tubular epithelium (data not shown). The immunohistological
data additionally showed that the contribution of infiltrating immune
cells to I/R-induced MHC class I and II up-regulation was insignificant
and that MHC class I and II immunostaining was most prominent in the
outer stripe of the outer medulla. As previously reported (6, 24), the
observed postischemic renal MHC class I and II up-regulation is an
IFN--dependent process, since the present results show a significant
reduction in anti-IFN--treated mice when compared with
PBS-treated controls (Fig. 3).
Endogenous IL-12 and/or IL-18 do not mediate the early inflammatory response induced by renal I/R
Compared with sham-operated animals, I/R increased kidney
neutrophil accumulation and impaired kidney function (Fig. 6) at day 1 after ischemia, as measured
by renal MPO and BUN content, respectively. We investigated whether
endogenous IL-12 and/or IL-18 mediate these early consequences of
ischemic tissue injury. The administration of anti-IL-12 Ab,
anti-IL-18 Ab, or a combination of both regimens failed to attenuate
kidney neutrophil accumulation and deterioration of renal function
(Fig. 6), suggesting that these cytokines at this stage do not mediate
reperfusion injury.
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Discussion |
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TopAbstractIntroductionMaterials and MethodsResultsDiscussionReferences |
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is produced by T cells and NK cells following stimulation
with IL-12 and/or IL-18. The production of the heterodimeric cytokine
IL-12 is tightly controlled by expression of the p40 subunit gene in
macrophages, but also in tubular epithelial cells (25) when stimulated
with, among others, bacteria or bacterial products (18). IL-18, on the
other hand, is an IFN--inducing cytokine expressed by a far wider
range of cell types and tissues than IL-12 (18). This may account for
the observed renal IL-18 mRNA increase coinciding with the absence of
significant IL-12 p40 mRNA induction after I/R. Alternatively, based on
experiments with Yersinia enterocolitica infected mice, Bohn
et al. (11) suggested that IL-18 down-regulates local production of
IL-12, which can be overruled by IFN-. They showed that low amounts
of IL-18-induced IFN-, in turn, may activate macrophages to produce
IL-12, which subsequently synergizes with IL-18 to produce high amounts
of IFN-. Interestingly, in the present model, such a mechanism may
account for the observed down-regulation of renal IL-12 p40 mRNA
expression at day 1 and subsequent up-regulation at day 6 (Fig. 1).
Moreover, it may account for our finding that only anti-IFN- and
combined anti-IL-12/18 treatment prevented I/R-induced enhanced
renaI IFN- mRNA production (Fig. 2) and subsequent MHC class I and
II expression (Figs. 3 and 4).
Local tissue damage as a result of an infection may facilitate
penetration of additional pathogens in an infected organ. It is
tempting to speculate that IL-12- and IL-18-driven IFN- and
subsequent MHC up-regulation in response to tissue injury is a
functionally important mechanism that primes injured tissue for
enhanced immunosurveillance. If microbial-induced cell death would lead
to the observed late cytokine alterations and consequent induction of
MHC Ags, this mechanism would target infected cells for recognition and
elimination by T cells (26, 27). Hence, MHC Ag up-regulation as a
consequence of I/R-induced tissue damage may also facilitate the T cell
response to invading pathogens. Besides ischemic damage, IFN-
production as well as MHC up-regulation are associated with poor
allograft survival (28).
Previous studies mainly focused on the potential involvement of IL-12-
and/or IL-18-induced IFN- production in host defense. The present
findings for the first time indicate a relationship between tissue
injury of nonpathogenic origin and the induction of both IL-12 and
IL-18 collaborating in enhancing IFN- production in vivo. The
similarities observed between mechanisms of IFN- induction during
bacterial infections and nonmicrobial lesions, such as renal I/R
injury, raise the hypothesis that aspecific tissue damage contributes
extensively to regulation of IFN- production. However, to which
extent these findings apply to other (non) microbial stimuli remains to
be elucidated.
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Acknowledgments |
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Footnotes |
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2 Address correspondence and reprint requests to Dr. W. A. Buurman, Department of General Surgery, University of Maastricht, P.O. Box 616, 6200 MD Maastricht, The Netherlands. E-mail address:
3 Abbreviations used in this paper: I/R, ischemia/reperfusion; BUN, blood urea nitrogen; cDNA, copy DNA; EIA, enzyme immunoassay; MPO, myeloperoxidase; pAb, polyclonal Ab; TMB, 3,3',5,5'-tetramethylbenzidine.
Received for publication October 13, 1998. Accepted for publication February 8, 1999.
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