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*
Department of Surgery, University of Louisville School of Medicine, Louisville, KY 40223;
Department of Pathology, University of Michigan Medical School, Ann Arbor, MI 48109; and
Department of Trauma Surgery, University of Freiburg, Freiburg, Germany
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Abstract |
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 Top Abstract IntroductionMaterials and MethodsResultsDiscussionReferences |
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B, was significantly increased in lung. In
addition, anti-IL-13 caused significant increases in
bronchoalveolar lavage levels of TNF-
, macrophage inflammatory
protein-2, and cytokine-inducible neutrophil chemoattractant but no
changes in lung vascular ICAM-1. These data suggest that during lung
inflammation endogenous IL-13 regulates NF-B activation and related
cytokine/chemokine generation, all of which determines the intensity of
the lung inflammatory response. |
Introduction |
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TopAbstractIntroductionMaterials and MethodsResultsDiscussionReferences |
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, IL-1 and
IL-1ß, IL-6, IL-8, and macrophage inflammatory protein
(MIP)3-1 (3, 4, 5). In
addition, IL-13 augments the production of IL-1 receptor antagonist
(6). The anti-inflammatory effects of IL-13 are remarkably similar
to those of IL-10; both down-regulate proinflammatory cytokine
production by monocytes and macrophages (7, 8, 9). In vivo, both IL-10 and
IL-13 (administered exogenously) have been shown to increase survival
in a murine model of endotoxic shock by reducing systemic levels of
TNF- (10, 11). In a rat model of acute inflammatory lung injury
induced by intrapulmonary deposition of IgG immune complexes, exogenous
administration of either IL-10 or IL-13 reduced lung production of
TNF- and diminished ICAM-1 up-regulation, neutrophil recruitment,
and lung injury (12, 13). These anti-inflammatory effects in lung
were subsequently shown to be due to suppression of NF-B activation
(14).
Earlier studies have demonstrated that IL-10 function in vivo is an
endogenous regulator of the lung inflammatory response (15). These
studies demonstrated that IL-10 was up-regulated during lung
inflammation and that blockade of IL-10 with Ab augmented pulmonary
TNF- production, neutrophil recruitment, and lung injury. In the
current study we sought to determine whether IL-13 is an important
endogenous mediator in the regulation of acute inflammatory lung injury
induced by deposition of IgG immune complexes. Our findings indicate
that IL-13 mRNA and protein are up-regulated during lung inflammation.
Blockade of endogenous IL-13 with Ab augments NF-B activation in
lung and causes increased intrapulmonary production of TNF-. These
effects are associated with increased accumulation of neutrophils and
increased vascular leak of albumin. The data suggest that IL-13 is an
intrinsic regulator of the lung inflammatory response.
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Materials and Methods |
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TopAbstractIntroductionMaterials and MethodsResultsDiscussionReferences |
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Pathogen-free male Long-Evans rats (275–300 g; Harlan
Sprague-Dawley, Indianapolis, IN) were anesthetized with ketamine HCl
(150 mg/kg, i.p.). For measurement of pulmonary vascular permeability,
rats received intratracheal administration of PBS, pH 7.4, 1.5 mg
anti-BSA (ICN Biomedicals, Costa Mesa, CA), and 0.5 mg nonspecific
goat IgG, or 1.5 mg anti-BSA and 0.25 or 0.5 mg goat polyclonal
anti-mouse IL-13 (R&D Systems, Minneapolis, MN) in a volume of 0.3
ml of PBS. Immediately thereafter, 10 mg of BSA (<1 ng endotoxin/mg)
containing trace amounts of 125I-labeled BSA in 0.5 ml of
PBS was injected i.v. Four hours after IgG immune complex deposition,
rats were exsanguinated, the pulmonary circulation was flushed with 10
ml of PBS by pulmonary artery injection, and the lungs were surgically
dissected. The extent of lung injury was quantified by calculating the
lung permeability index by dividing the amount of radioactivity
(125I-labeled BSA) in the perfused lungs by the amount of
radioactivity in 1.0 ml of blood obtained at the time the rats were
sacrificed. For measurement of lung NF-B activation, rats
received intratracheal administration of PBS (negative control), 0.25
mg anti-BSA, and 0.5 mg nonspecific goat IgG, or 0.25 mg
anti-BSA and 0.5 mg anti-IL-13 in a volume of 0.3 ml PBS. BSA
(10 mg) was injected i.v., and 4 h later lungs were surgically
removed and immediately frozen in liquid nitrogen. Unless otherwise
indicated, n 
5 for each experimental group described
in
Figs. 1–7
.
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Total RNA from whole-lung tissue was extracted using a guanidinium-isothiocyanate method as described previously (16). RNA (1 µg) was reverse transcribed to cDNA. The cDNA products were amplified by PCR (35 cycles; 1 min each at 95°C, 55°C, and 72°C). The 5' primer (5'-CTGCAGTCCTGGCTCTCGC-3') and 3' primer (5'-CTTTTCCGCTATGGCCACTG-3') were complementary to 5' and 3' regions of the open reading frame of the murine IL-13 sequence. PCR products were sequenced for verification. RT-PCR of the glyceraldehyde-3-phosphate dehydrogenase gene was performed under the same conditions described above to confirm equal loading of RNA. Ethidium bromide-stained PCR products were photographed, digitized, and analyzed using image analysis software (Adobe Systems, San Jose, CA).
Western blot analysis
Lungs were homogenized in lysis buffer (10 mM HEPES, pH 7.9; 150 mM NaCl; 1 mM EDTA; 0.6% Nonidet P-40; 0.5 mM PMSF; 1 µg/ml leupeptin; 1 µg/ml aprotonin; 10 µg/ml soybean trypsin inhibitor; and 1 µg/ml pepstatin) on ice. Homogenates were sonicated and centrifuged at 5000 rpm to remove cellular debris. Protein concentrations were determined as described for nuclear extracts. Samples were separated in a denaturing 10% polyacrylamide gel and transferred to a 0.1 µm-pore nitrocellulose membrane. Nonspecific binding sites were blocked with TBS (40 mM Tris, pH 7.6, and 300 mM NaCl) containing 5% nonfat dry milk for 12 h at 4°C. Membranes were then incubated in 2.5 µg/ml anti-IL-13 in TBS with 0.1% Tween-20 (TBST). After three washes in TBST, membranes were incubated in a 1:25,000 dilution of horseradish peroxidase-conjugated donkey anti-goat IgG (Jackson ImmunoResearch, West Grove, PA). Immunoreactive proteins were detected by enhanced chemiluminescence.
Assessment of NF-B activation by electrophoretic mobility shift
assay (EMSA)
Nuclear extracts of whole-lung tissues were prepared by the
method of Deryckere and Gannon (17). Protein concentrations were
determined by bicinchoninic acid assay with TCA precipitation using BSA
as a reference standard (Pierce, Rockford, IL). Double-stranded NF-B
consensus oligonucleotide (5'-AGTGAGGGGACTTTCCCAGGC-3'; Promega,
Madison, WI) was end-labeled with [
-32P]ATP (3000
Ci/mmol at 10 mCi/ml; Amersham, Arlington Heights, IL). Binding
reactions containing equal amounts of protein (10 µg for whole-lung
extracts and 5 µg for alveolar macrophage extracts) and 35 fmol
(
50,000 cpm, Cherenkov counting) of oligonucleotide were performed
for 30 min in binding buffer (4% glycerol, 1 mM MgCl2; 0.5
mM EDTA, pH 8.0; 0.5 mM DTT; 50 mM NaCl; 10 mM Tris (pH 7.6); and 50
µg/ml poly(dI · dC); Pharmacia, Piscataway, NJ). Reaction volumes
were held constant to 15 µl. Reaction products were separated in a
4% polyacrylamide gel and analyzed by autoradiography. NF-B
activation was quantitated from digitized autoradiography films using
image analysis software (Adobe Systems).
Bronchoalveolar lavage (BAL) fluid cytokine content
BAL fluids were collected by instilling and withdrawing 5 ml of
sterile PBS three times from the lungs via an intratracheal cannula.
Cellular contents were recovered by centrifugation, and neutrophils
were counted by microcytometry. BAL content of TNF- was measured
using a standard WEHI cell cytotoxicity assay as previously reported
(18). Measurement of MIP-2 and cytokine-inducible neutrophil
chemoattractant (CINC) in BAL fluids were performed using ELISA as
described elsewhere (19).
Statistical analyses
All values were expressed as mean ± SEM. Data were analyzed with a one-way analysis of variance, and individual group means were then compared with a Student-Newman-Keuls test. Differences were considered significant when p < 0.05. For calculations of percentage change, negative control values were subtracted from positive control and treatment group values.
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Results |
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TopAbstractIntroductionMaterials and MethodsResultsDiscussionReferences |
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To determine whether IL-13 is up-regulated during the lung
inflammatory response, lung extracts were assessed for content of IL-13
mRNA and protein. Pulmonary expression of IL-13 mRNA in rats undergoing
IgG immune complex-induced lung injury was determined by RT-PCR. The
presence of a clearly detectable PCR product in lung RNA obtained at
time 0 indicated that IL-13 mRNA was constitutively expressed in the
noninflamed lung (Fig. 1
). IL-13 mRNA
expression was increased 30 min after initiation of the lung
inflammatory response. mRNA levels decreased somewhat at 1 h,
increased to near-maximal levels again at 2 h, and returned to
baseline 4 h after initiation of injury. In contrast to IL-13
mRNA, protein levels of IL-13 were undetectable by Western blot in
noninflamed lung extracts (time 0) (Fig. 2). However, IL-13 protein was detectable
within 30 min after initiation of injury, with increased expression at
1, 2, and 4 h.
Augmentation of IgG immune complex-induced neutrophil recruitment and lung injury by anti-IL-13
Because exogenous administration of IL-13 has been shown to
suppress lung injury induced by IgG immune complexes (13), we designed
experiments to assess the role of endogenous IL-13 in the lung
inflammatory response. The extent of lung injury was determined by
extravascular leak 125I-labeled albumin. Intrapulmonary
deposition of IgG immune complexes in the presence of 500 µg of
irrelevant goat IgG mixed with anti-BSA resulted in a more than
twofold increase in the lung permeability index (Fig. 3). Intratracheal administration of Ab to
IL-13 (along with the IgG anti-BSA) caused a dose-dependent
increase in the lung permeability index. In the presence of 250 µg or
500 µg anti-IL-13, the permeability index was increased 36%
(p = 0.029) and 62% (p
= 0.002), respectively. To determine whether the increased lung injury
induced by anti-IL-13 was related to enhanced pulmonary recruitment
of neutrophils, the effects of anti-IL-13 on the number of BAL
neutrophils recovered 4 h after IgG immune complex deposition was
determined. Intrapulmonary deposition of IgG immune complexes caused an
almost sixfold increase in BAL neutrophil numbers (Fig. 4). In the presence of 500 µg of
anti-IL-13, the number of neutrophils present in BAL fluids was
increased by 65% (p = 0.005).
Effects of anti-IL-13 on BAL levels of TNF- and CXC
chemokines and pulmonary vascular expression of ICAM-1
Intrapulmonary production of TNF- is known to drive the lung
inflammatory response induced by deposition of IgG immune complexes
(20). Because exogenous administration of IL-13 has been shown to
suppress lung inflammation in this model with an associated reduction
in TNF- levels in BAL fluids (13), we assessed whether endogenous
IL-13 serves to regulate lung production of TNF-. BAL fluids were
obtained 4 h after IgG immune complex deposition, and TNF-
content was determined by the WEHI bioassay. IgG immune complex
deposition caused a 20-fold increase in BAL levels of TNF- (Fig. 5A). Coadministration of 500
µg of anti-IL-13 (along with the IgG anti-BSA) augmented
TNF- production by 75% (p = 0.03).
Since TNF- is known to regulate the expression of lung vascular
ICAM-1 (21), we assessed the effects of 500 µg of anti-IL-13 or
normal goat IgG on ICAM-1 expression in the pulmonary vasculature.
Expression of ICAM-1 in lung was determined by the binding index of
125I-labeled anti-rat ICAM-1. As expected,
intrapulmonary deposition of IgG immune complexes caused a significant
increase in the ICAM-1 binding index (Fig. 5B). In spite of
the effects of anti-IL-13 on BAL levels of TNF-, there was,
unexpectedly, no effect on the binding index for ICAM-1. Because
TNF- may facilitate expression of the CXC chemokines MIP-2 and CINC,
which, like ICAM-1, are required for pulmonary neutrophil recruitment
(19), the effects of anti-IL-13 on lung production of MIP-2 and
CINC were determined. BAL levels of MIP-2 and CINC were measured by
ELISA. In the presence of irrelevant IgG, IgG immune complexes caused
dramatic increases in the content of MIP-2 and CINC in BAL fluids (Fig. 6). The presence of anti-IL-13
modestly but significantly augmented BAL levels of MIP-2 and CINC by
18% (p = 0.048) and 20%
(p = 0.003), respectively.
Effects of anti-IL-13 on lung NF-B activation
We have previously shown that exogenous administration of IL-13
suppresses lung NF-B activation induced by intrapulmonary deposition
of IgG immune complexes (14). Since anti-IL-13 augmented IgG immune
complex-induced BAL TNF-, MIP-2, and CINC, and in view of the fact
that these mediators are regulated by NF-B (22, 23, 24), we sought to
determine whether endogenous IL-13 might regulate lung NF-B
activation during the inflammatory response. For these experiments, the
intratracheal dose of anti-BSA employed was very low (250 µg),
designed to produce minimal activation of NF-B so that effects of
anti-IL-13 might be more sensitively evaluated. Lung nuclear
extracts obtained 4 h after initiation of lung injury were
assessed by EMSA. Intrapulmonary deposition of IgG immune complexes
(using 250 µg of anti-BSA and 500 µg of normal goat IgG)
resulted in little, if any, activation of lung NF-B (Fig. 7A). However, in the presence
of 500 µg of anti-IL-13, there was a measurable increase
(40%) in the amount of lung NF-B activation. Image analysis of
digitized EMSA blots indicated that anti-IL-13 significantly
increased nuclear localization of lung NF-B
(p = 0.003) (Fig. 7B).
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Discussion |
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TopAbstractIntroductionMaterials and MethodsResultsDiscussionReferences |
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and IL-1, which are generated
by lung macrophages (20, 25). These cytokines promote lung inflammation
by stimulating pulmonary vascular endothelial cells to express adhesion
molecules, which mediate the adhesion and transmigration of neutrophils
from the vascular lumen into the lung interstitial spaces. Both
E-selectin and ICAM-1 seem to play essential roles in the lung
recruitment of neutrophils in this model (26, 27). However, this
inflammatory response is in some manner self-regulated inasmuch as
neutrophil accumulation and vascular leakage of albumin do not progress
after 4 h. The present report provides evidence that endogenous
IL-13 may represent one such regulatory factor. IL-13 was up-regulated
during the development of lung injury after IgG immune complex
deposition. RT-PCR analysis indicated that IL-13 mRNA was increased as
early as 30 min, peaking between 0.5 and 2 h and returning to
baseline after 4 h. Western blot analysis of whole-lung extracts
demonstrated that IL-13 protein expression was increased 30 min after
initiation of lung injury, with increasing expression at 1, 2, and
4 h.
The anti-inflammatory properties of IL-13 are well established. In
vitro, IL-13 prevents production of proinflammatory cytokines by
activated macrophages and monocytes (3, 4, 5). In vivo, IL-13 has been
shown to protect against LPS-induced lethality and to suppress lung
inflammatory injury following deposition of IgG immune complexes (11, 13). In both models, the protective effects of IL-13 were associated
with reduced production of TNF-. In the current studies, we show
that neutralization of endogenous IL-13 caused enhanced production of
TNF-, suggesting that intrinsic IL-13 regulates the production of
early response cytokines during acute lung inflammation. In addition,
BAL levels of MIP-2 and CINC are increased under these same conditions,
although much more modestly when compared with larger increases in BAL
levels of TNF-. The mechanism(s) by which IL-13 regulates
proinflammatory cytokine production seems to involve suppression of the
transcription factor, NF-B. We have recently shown that IL-13
inhibits NF-B activation in alveolar macrophages in vitro and in
vivo (14). In addition, those studies demonstrated that exogenously
administered IL-13 inhibited nuclear translocation of NF-B in
whole-lung nuclear extracts. The NF-B-suppressing effects of IL-13
were found to be mediated by stabilization of the cytoplasmic NF-B
inhibitory protein, IB (14). In the current studies, we found
that neutralization of endogenous IL-13 caused significantly more
NF-B activation in lung. These data suggest that endogenous IL-13
regulates pulmonary NF-B activation and subsequent proinflammatory
mediator expression during the development of lung injury.
In this model of acute lung injury, it is likely that TNF-
stimulates ICAM-1 expression on vascular endothelial cells via
activation of NF-B (21, 28, 29). Despite increases in BAL TNF-
and lung NF-B activation induced by anti-IL-13, there were no
detectable increases in expression of pulmonary vascular ICAM-1.
However, lung accumulation of neutrophils was increased by 65%. Under
the experimental conditions employed, it is possible that ICAM-1
expression was maximally stimulated. Alternatively, augmented lung
neutrophil accumulation might be explained by enhanced E-selectin
up-regulation and enhanced chemokine generation. At present there is no
reliable methodology for the quantitative assessment of E-selectin
expression on the rat pulmonary vasculature. Like TNF- and ICAM-1,
gene expression of the CXC chemokines MIP-2 and CINC is regulated by
NF-B (23, 24). In parallel with increased lung NF-B activation,
BAL levels of both MIP-2 and CINC were augmented (20%) in the
presence of anti-IL-13. These data suggest that the increased
number of neutrophils in lung induced by anti-IL-13 could be
attributed to augmented production of MIP-2 and CINC. Furthermore, the
data suggest that intrinsic IL-13 may regulate CXC chemokine production
via effects on NF-B.
IL-10 and IL-13 appear to be the most powerful of the "regulatory
cytokines." Exogenous administration (intratracheally) of these ILs
in very low amounts (1–5 µg) profoundly suppresses lung inflammatory
responses by blocking NF-B activation (this report and Refs. 12–14,
26, and 28). In turn, production of TNF- is reduced, vascular ICAM-1
expression diminishes, and fewer neutrophils are recruited into lung.
It is now clear that both IL-10 and IL-13 interfere with NF-B
activation by causing retention of IB, which prevents nuclear
translocation of NF-B (14). How the proteolysis of IB is
prevented is not known. Exogenous administration of regulatory ILs into
lungs of rats undergoing deposition of IgG immune complexes reveals the
following rank order of inhibitory activity (in descending order):
IL-10 = IL-13 > IL-4 > IL-6 > IL-12 (13). Our
recent studies together with the current report indicate that, except
for IL-4, which does not appear to be expressed in the lung, each of
these ILs is up-regulated during the inflammatory response and each is
playing a regulatory role, as defined by a more intense inflammatory
response when any of these ILs is blocked by the presence of an Ab. The
lack of available reagents has not allowed for precise measurements of
each of these ILs in lung during initiation of the inflammatory
response as well as over the course of the next several hours.
Consequently, we cannot yet quantify the precise contributions for each
of these ILs. On the other hand, it might be predicted that
blockade of all relevant regulatory ILs might cause the inflammatory
response to be uncontrolled, resulting in a greatly increased intensity
and, perhaps, in irreversible lung damage, proceeding to interstitial
fibrosis.
The source of these regulatory ILs in lung is not completely known. In the case of IL-13, our own attempts to resolve this issue have employed immunostaining techniques. BAL macrophages obtained from normal lung have failed to demonstrate any staining, while BAL macrophages obtained 4 h after initiation of the inflammatory response have shown positive staining (A. B. Lentsch, R. L. Warner, and P. A. Ward, unpublished observation). It is possible that there are additional sources of IL-13, such as T cells or epithelial cells, but this has not yet been determined.
The current studies suggest that IL-13 is an important endogenous
regulatory cytokine during IgG immune complex-induced lung injury. The
anti-inflammatory properties of endogenous IL-13 seem to operate by
suppressing activation of lung NF-B and the subsequent production of
the early response cytokine TNF- and the CXC chemokines MIP-2 and
CINC. These combined effects appear to contribute to the resolution of
lung inflammation and may represent a potential point of therapeutic
intervention in humans.
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Footnotes |
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2 Address correspondence and reprint requests to Dr. Peter A. Ward, Department of Pathology, University of Michigan Medical School, 1301 Catherine Road, Ann Arbor, MI 48109-0602. E-mail address:
3 Abbreviations used in this paper: MIP, macrophage inflammatory protein; EMSA, electrophoretic mobility shift assay; BAL, bronchoalveolar lavage; CINC, cytokine-inducible neutrophil chemoattractant.
Received for publication July 21, 1998. Accepted for publication September 30, 1998.
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References |
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TopAbstractIntroductionMaterials and MethodsResultsDiscussionReferences |
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or IL-10. J. Immunol. 151:6370.[Abstract]
production from human alveolar macrophages and monocytes. Am. J. Respir. Cell Mol. Biol. 15:382.[Abstract]
expression by IL-10: differential sensitivities in human blood monocytes and alveolar macrophages. J. Immunol. 155:4412.[Abstract]
, IFN-, and IL-12 production. J. Immunol. 158:2898.[Abstract]
by interleukin-10 and interleukin-13. J. Clin. Invest. 100:2443.[Medline]
regulates in vivo intrapulmonary expression of ICAM-1. Am. J. Pathol. 142:1739.[Abstract]
transcription in macrophages: involvement of four kappa B-like motifs and of constitutive and inducible forms of NF-kappa B. Mol. Cell. Biol. 10:1498.B. Mol. Cell. Biol. 13:7191.B activation during IgG immune complex-induced lung injury: requirements for TNF- and IL-1ß but not complement. Am. J. Pathol. 152:1327.[Abstract]
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