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B and Activator Protein-1 Transcription Blocks Allergic Airway Inflammation in a Mouse Asthma Model1
,
Departments of
* Medicine,
Pathology, and
Pathobiology, University Washington, Seattle, WA 98195; and
Pacific Northwest Research Institute, Seattle, WA 98122
 |
Abstract |
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 Top Abstract IntroductionMaterials and MethodsResultsDiscussionReferences |
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B and AP-1.
We examined the effect of the small molecule inhibitor of
redox-regulated NF-B and AP-1 transcription, MOL 294 on airway
inflammation and airway hyperreactivity (AHR) in a mouse model of
asthma. MOL 294 is a potent nonpeptide inhibitor of NF-B and AP-1
based upon a 
-strand template that binds to and inhibits the
cellular redox protein thioredoxin. BALB/c mice after i.p. OVA
sensitization (day 0) were challenged with intranasal OVA on days 14,
25, 26, and 27. MOL 294, administered intranasal on days 25–27,
blocked the airway inflammatory response to OVA assessed 24 h
after the last OVA challenge on day 28. MOL 294 reduced eosinophil,
IL-13, and eotaxin levels in bronchoalveolar lavage fluid and airway
tissue eosinophilia and mucus hypersecretion. MOL 294 also decreased
AHR in vivo to methacholine. These results support redox-regulated
transcription as a therapeutic target in asthma and demonstrate that
selective inhibitors can reduce allergic airway inflammation and
AHR. |
Introduction |
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TopAbstractIntroductionMaterials and MethodsResultsDiscussionReferences |
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10 times the
concentration of the antioxidant glutathione than the plasma, with
reduced levels found in asthmatic lungs (3). Increased
amounts of oxidized glutathione are found in the airways of asthmatics
to indicate increased oxidative stress. However, the mechanisms by
which increased oxidative stress leads to the molecular hallmarks of
acute asthma (e.g., Th2 cytokine release) or chronic asthma and
development of fibrosis have not been ascertained. The development of
an oxidant/antioxidant imbalance in the lungs of asthmatics may lead to
activation of redox-sensitive transcription factors, NF-B and AP-1.
NF-B, originally identified as a factor that regulates L chain
expression in B lymphocytes, is now known to be present in most cell
types, and plays a critical role in immune and inflammatory responses
(4, 5, 6, 7). Many of the stimuli that increase inflammation in
asthmatic airways result in the activation of NF-B, particularly
proinflammatory cytokines. The airways of asthmatic patients have
increased NF-B activity, with predominant localization by
immunocytochemistry to epithelial cells and macrophages
(8). Many of the inflammatory proteins that are expressed
in asthmatic airways are regulated, at least partially, by NF-B.
These include cytokines (e.g., IL-1, IL-4, IL-5, IL-9, IL-15, and
TNF-
), chemokines (e.g., RANTES, monocyte chemotactic protein-3, and
eotaxin), and adhesion molecules (e.g., ICAM-1 and VCAM-1)
(9, 10, 11, 12, 13). NF-B binds to DNA in the promoter region of
target genes as a dimer, the most common form composed of two Rel
family proteins, NF-B1 (p50) (14) and RelA (p65). Other
NF-B/Rel family members include c-Rel, RelB, p52, and v-Rel
(6, 15). Mice with a targeted deletion of the p50 Rel
family protein (p50-/-) are unable to produce
IL-5 or eotaxin, which are crucial for proliferation, differentiation,
and recruitment of eosinophils into asthmatic airways.
p50-/- mice are also deficient in the
production of macrophage inflammatory protein 1 and macrophage
inflammatory protein 1 that are critical for T cell recruitment to
sites of inflammation (16).
The proinflammatory transcriptional element AP-1 is also an important contributor to the expression of Th2 cytokines, IL-4, IL-5, and IL-13. AP-1 consists of a dimer of Jun (c-Jun, JunB, and JunD) and Fos (c-Fos, FosB, Fra1, and Fra2) family members. Jun family members form homo- and heterodimers that recognize a TGAGTCA consensus DNA sequence. Fos family members, which are unable to dimerize with each other, augment transcriptional activation by association with Jun family members (17). AP-1 is inducible by a variety of cytokines and growth factors (18). The transcriptional activity of AP-1 is redox-sensitive. H2O2 and other ROS increase AP-1 transcription (19, 20, 21, 22). DNA-binding of AP-1 increases with the reduction of critical cysteine residues in the Jun and Fos families (e.g., cysteine 252 in cJun) and decreases when these residues are oxidized (23, 24). AP-1 binding sites are found in the promoter regions of many proinflammatory genes including Th2 cytokines, adhesion molecules, and cell proliferation growth factors (25, 26). The gene for Muc5B responsible for airway mucus production contains a putative AP-1 consensus site in its promoter (27). The IL-5 proximal promoter element contains an overlapping binding site for the constitutive binding factor Oct-1 and the inducible AP-1. Transcriptional induction has been ascribed to the inducible binding element, because a mutant binding element (that lost constitutive Oct-1 binding but maintained inducible AP-1 binding) exerted three times greater transcriptional activity than the wild type. The IL-4 promoter exists in multiple allelic forms, and a particular allele has high transcriptional activity. A single nucleotide polymorphism located just upstream of an NFAT site appears responsible for the increased promoter strength and markedly enhances the binding affinity of AP-1 complexes (28).
We have recently developed a novel small molecule inhibitor of NF-B
and AP-1 transcription, MOL 294 (29). The molecular target
of MOL-294 appears to be the oxidoreductase, thioredoxin (Trx). Our
goal was to determine the therapeutic potential of this selective small
molecule inhibitor of NF-B and AP-1, MOL 294 on allergic airway
inflammation and airway hyperreactivity (AHR) in a mouse asthma model.
We found that MOL 294 reduces airway eosinophil infiltration, mucus
hypersecretion, IL-13 and eotaxin release, and AHR to methacholine.
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Materials and Methods |
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TopAbstractIntroductionMaterials and MethodsResultsDiscussionReferences |
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B and AP-1 inhibitor, MOL 294
A -strand templated library (30), of the type
depicted in Fig. 1
, was used to develop
the inhibitor, MOL-294. As shown in Fig. 2, MOL 294 (methyl
(4R/S)-4-hydroxy-4-[((5S,8S)/(5R,8R))-8-methyl-1,2-dioxo-2-phenyl-2,3,5,8-tetrahydro-1H-[1,
2, 4]triazolo[1,2-a]pyridazin-5-yl]-2-butynoate) is a nonpeptide
and bioavailable inhibitor of NF-B and AP-1 transcription
(29).
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The effect of MOL 294 on cell-based Trx activity was assayed in
A549 lung epithelial cells by measuring the reduction of Ellman’s
reagent by Trx reductase (TR)-activated Trx (31). A549
cells (ATCC) were grown in RPMI 1640 supplemented with 10% FBS and 10
mM HEPES (HyClone Laboratories, Logan, VT). Plates (100-mm) of
confluent A549 cells were treated with MOL 294 (5–25 µM in 0.025%
DMSO) or 0.025% DMSO control for 1 h at 37°C in 5%
CO2. Whole-cell lysates were made using M-Per
(Pierce, Rockford, IL), and the Bio-Rad Protein Microassay (Bio-Rad,
Hercules, CA) was used to determine the protein concentration of each
sample. A total of 12 µg of total protein were used for each
5,5'-dithiobis(2-nitrobenzoic acid) reduction assay summarized as
follows:
 |
Nitrosylation of p65
A549 cells, on 100-mm plates in 1640 RPMI, 10% FBS, and 10 mM HEPES, were treated with MOL 294 (5–25 µM) or 0.025% DMSO (vehicle) for 30 min before stimulation with 20 ng/ml LPS for 3 h at 37°C, 5% CO2. After washing with 10 ml of ice-cold PBS, the cells were scraped and transferred to prechilled 1.5-ml Eppendorf tubes using 1 ml of ice-cold PBS. The cells were centrifuged at 2500 rpm at 4°C for 5 min. After aspiration of PBS, nuclear and cytosolic extracts were made using NE-PER (Pierce). After determining the protein concentration of the nuclear extract using Bio-Rad Protein Microassay (Bio-Rad), 100 µg of nuclear protein were subjected to the NitroGlo Nitrosylation System (PerkinElmer, Boston, MA). In brief, 300 µl of blocker solution was added to each nuclear extract and reacted for 1 h at 50°C in the dark to block free thiols. The proteins were then precipitated, washed with cooled acetone, and solubilized in solubilization buffer. Nitrosylated proteins were reduced to free thiols using ascorbic acid and biotinylated using pyridyldithiol-biotin (PerkinElmer) for 1 h at room temperature. After addition of 26 µl of NuPAGE 4x LDS sample buffer (Invitrogen, Carlsbad, CA), samples underwent SDS gel electrophoresis using 4–12% acrylamide bis-Tris gel (Invitrogen) and MES-SDS running buffer (Invitrogen) under nonreducing conditions, at a constant voltage of 130 V. Proteins were then transferred onto a PVDF membrane at 105 V for 1 h in a cold room. The PVDF membrane was blocked with BLOTTO for 1 h at room temperature. After blocking, the membrane was treated with NitroGlo anti-biotin Ab, at a dilution of 1/5000 in BLOTTO, overnight at 4°C. The PVDF membrane was washed with TBST and treated with anti-biotin-HRP-conjugated secondary Ab, at a dilution factor of 1/5000 in BLOTTO for 1 h at room temperature. After washing with high salt TBST, the membrane was treated with ECL kit reagent (Amersham Pharmacia Biotech, Piscataway, NJ), exposed onto film, and developed to detect nitrosylated proteins which were visualized/quantitated using UN-SCAN-IT software (version 5.1; Silk Scientific, Orem, UT).
Drug treatment
All animal use procedures were approved by the University of Washington Animal Care Committee (Seattle, WA). Female BALB/c mice (6–8 wk of age at purchase; The Jackson Laboratory, Bar Harbor, ME and Pierce) received an i.p. injection of 100 µg of OVA (0.2 ml of 500 µg/ml) complexed with aluminum potassium sulfate (alum) from Sigma-Aldrich (St. Louis, MO), on days 0 and 14 as previously described (32). Mice were anesthetized with 0.2 ml i.p. of ketamine (6.5 mg/ml)/xylazine (0.44 mg/ml) in normal saline before receiving an intranasal (i.n.) dose of 50 µg OVA (50 µl of 1 mg/ml) on days 14, 25, 26, and 27. The control group received 0.2 ml of normal saline with alum i.p. on days 0 and 14 and 0.4 ml of saline without alum i.n. on days 14, 25, 26, and 27. MOL 294 was dissolved in PBS (pH 7.4) and given by i.n. administration (0.075 mg/kg, 50 µl/mouse) under ketamine/xylazine anesthesia. Mice received MOL 294 on days 25, 26, and 27, once daily 30 min before OVA challenge; control groups received PBS only.
Pulmonary function testing
In vivo airway responsiveness to i.v. methacholine was measured 24 h after the last OVA challenge on day 28 by invasive whole body plethysmography, as previously described (32). Dynamic compliance (Cdyn) was determined for both the control period and during the peak response to i.v. challenge with methacholine (120 µg/kg). At the completion of pulmonary function testing, each mouse underwent exsanguination by cardiac puncture and then bronchoalveolar lavage (BAL).
Bronchoalveolar lavage
BAL (0.4 ml of saline three times) of the right lung was performed after tying off the left lung at the mainstem bronchus. Total BAL fluid cells were counted from a 0.05 ml aliquot, and the remaining fluid was centrifuged at 200 x g for 10 min at 4°C. Cell pellets were resuspended in saline containing 10% BSA, and smears were made on glass slides. Eosinophils were stained for 5 min with 0.05% aqueous eosin and 5% acetone in distilled water, rinsed with distilled water, and counterstained with 0.07% methylene blue as described previously (32).
Lung histopathology
After BAL, the trachea and upper and lower lobes of the left lung were removed and fixed for 24 h in 10% neutral buffered formalin solution. The tissues were embedded in paraffin and cut into 5-µm sections. The tissue sections were stained with Discombe’s solution to identify eosinophils, H&E to identify other inflammatory cells, and alcian blue (pH 2.5) with nuclear fast red counterstaining to identify airway goblet cells and mucus. The degree of airway inflammatory cell infiltration (0–4+), number of eosinophils per unit airway area (2200 µm2), and mucus occlusion of airway diameter (0–4+) were determined by morphometry, performed by individuals blinded to the protocol design as previously described (32, 33, 34).
IL-13 and eotaxin assays
Levels of IL-13 (
1.5 pg/ml) and eotaxin (3 pg/ml) in the BAL
fluid were determined by ELISA (R&D Systems, Minneapolis, MN).
Statistical analyses
The data are reported as the mean ± SEM. Differences were analyzed for significance (p < 0.05) by either Student’s two-tailed t test or ANOVA using the protected least significant difference method (Statview II; Abacus Concepts, Berkeley, CA) as indicated.
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Results |
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TopAbstractIntroductionMaterials and MethodsResultsDiscussionReferences |
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B and AP-1 inhibitor MOL 294
The ability of MOL 294 to inhibit the activity of Trx in a
cell-based assay was determined by the reduction of Ellman’s reagent
in the presence of TR. Trx activity in A549 cells was determined when
activated by TR with the reaction monitored by analyzing the reduction
of Ellman’s reagent. As shown in Fig. 3, cell-based Trx activation was reduced in a dose-dependent manner by MOL
294 (5–25 µM). Equivalent amounts of Trx were present in each A549
cell sample by Western blot analysis (data not shown).
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).
Compared with unstimulated A549 cells, LPS-stimulated cells had 37%
nitrosylated p65 (i.e., 63% decrease in nitrosylated p65). The
reduction of the S-NO group of a cysteine residue of p65 induced
by LPS was inhibited in a dose-dependent manner by MOL 294 (5–25 µM;
Fig. 4). Treatment with MOL 294 at 25 and 5 µM concentrations before
LPS stimulation increased nitrosylated p65 to 80 and 56%,
respectively, of the amount in unstimulated cells.
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B and AP-1 inhibitor MOL 294 on
allergen-induced airway inflammation
On day 28, 24 h after the final i.n. OVA or saline treatment
in mice from each experimental group, BAL was performed on the right
lung, and left lung tissue was obtained to assess inflammatory cell
infiltration and mucus release. The effect of the NF-B and AP-1
inhibitor MOL 294 on airway inflammation was determined.
BAL fluid cells.
OVA-sensitized/challenged mice had a 7.5-fold increase in total BAL
fluid cells compared with the saline group (Fig. 5A; p <
0.0001, OVA vs saline). A total of 34.8% of the BAL fluid cells were
eosinophils in the OVA-treated mice, compared with 1.0% of total BAL
fluid cells in saline-treated controls (Fig. 5B;
p < 0.0001, OVA vs saline). The mean number of
eosinophils in the BAL fluid in the saline-treated controls was
1.0 ± 0.0 x 105 cells. The
OVA-sensitized/challenged mice had a 290-fold increase in eosinophils
recovered in the BAL fluid to 2.9 ± 0.8 x
105 cells (Fig. 5C; p
< 0.0001, OVA vs saline). In OVA-sensitized/challenged mice, treatment
with MOL 294 reduced the influx of eosinophils into the BAL fluid by
79.6% (Fig. 5C; p = 0.0375, 294/OVA vs
OVA).
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, B vs A).
By morphometric analysis of the histologic sections, administration of
MOL 294 at an i.n. dose of 0.075 mg/kg significantly decreased the
influx of total inflammatory cells and eosinophils into the lung
interstitium (Fig. 6, C vs B; Fig. 7, A and B).
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, B vs
A). Mucus gland hyperplasia (Fig. 6, C vs
B) and occlusion of airway diameter by mucus hypersecretion
(Fig. 7C) were reduced by inhibitor MOL 294.
BAL fluid IL-13 and eotaxin.
Induction of significant levels of IL-13 and eotaxin were observed in
the BAL fluid of the OVA-treated mice compared with the saline controls
(Fig. 8). Inhibition by MOL 294
significantly reduced the levels of both IL-13 and eotaxin in the BAL
fluid of the OVA-treated mice (Fig. 8).
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Pulmonary mechanics was assessed in response to i.v. methacholine
on day 28, which was 24 h after the last i.n. challenge with OVA,
by invasive in vivo plethysmography. A significant decrease in
Cdyn was seen in the OVA-sensitized/challenged
mice compared with the saline-treated controls
(p < 0.05) after i.v. methacholine (120
µg/kg) to indicate AHR in the OVA-treated mice (Fig. 9). In contrast, the methacholine-induced
lung response in OVA-sensitized/challenged mice administered MOL 294 at
a dose of 0.075 mg/kg was not significantly different
(p > 0.05) from that of saline-treated
controls (Fig. 9).
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Discussion |
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TopAbstractIntroductionMaterials and MethodsResultsDiscussionReferences |
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B and AP-1. General antioxidants, such as
N-acetylcysteine have been evaluated in animal models and in
human subjects (35, 36); however, controversy exists
regarding the beneficial effects of antioxidants in asthma
(37). Our data indicate that inhibiting NF-B and AP-1
transcription by MOL 294, a selective small molecule inhibitor of the
oxidoreductase Trx, reduces airway eosinophilia, mucus hypersecretion,
IL-13 and eotaxin release, and AHR in OVA-sensitized/challenged
mice.
Trx was originally isolated in Escherichia coli as a
hydrogen donor for ribonucleotide reductase (38). Trx is a
small multifunctional protein that has a redox-active disulfide/dithiol
with a conserved (Cys-Gly-Pro-Cys) sequence (24, 38, 39).
Adult T cell leukemia-derived factor is the human analog of Trx that
enhances IL-2R chain production in human T cell leukemia
virus-1-infected lymphocytes (40). Trx is a member
of a growing family of small redox active proteins (41, 42). Trx is known to translocate from the cytosol to the nucleus
under a variety of stress-inducing stimuli and to regulate the
expression of the AP-1 family of genes through redox effector factor-1
(43, 44) and the NF-B family directly
(45). redox effector factor-1 is a protein which has both
endonuclease and redox activity and is involved in the reduction of
cysteine residues in Fos and Jun. Gronenborn and colleagues
(46) have shown by nuclear magnetic resonance that
peptides derived from NF-B bind to the active site of Trx in an
extended strand conformation. Trx has been implicated in the reduction
of an oxidized form of cysteine 62 in NF-B (likely the S-nitroso
species), which is required for full transcriptional activation. Based
upon the x-ray structure of the p50 homodimeric NF-B complexed with
its oligonucleotide binding site (47, 48), C62 makes an
important contact with the 3' phosphate of the oligonucleotide.
We have previously reported (29) that MOL 294 is a potent
(2.5 µM IC50) inhibitor of NF-B-mediated
VCAM-1 expression in HUVECs and bound and inhibited the reductase
activity of Trx in vitro. We now show that treatment of A549 lung
epithelial cells with MOL 294 leads to a dose-dependent reduction of
cellular Trx activity with an IC50 <5 µM.
Furthermore, we demonstrate that the treatment of A549 cells with MOL
294 leads to a dose-dependent inhibition of the LPS-induced (presumably
Trx-mediated) reduction of the S-NO group of a cysteine residue of p65.
Additionally, the dose response of inhibition of Trx parallels the dose
response seen for inhibition of S-NO reduction. To the best of our
knowledge, this is the first demonstration of small molecule inhibition
of an oxidoreductase interfering with NF-B activation via the
preservation of an S-NO group, which is required to be reduced for gene
transcription.
NF-B/Rel transcription factors are induced in thoracic lymphocytes
from OVA-sensitized/challenged mice (49). OVA-treated
c-Rel-/- mice do not develop the airway
eosinophilia or AHR to methacholine observed in wild-type controls
(49). c-Rel-/- mice have reduced
production of total serum IgE and pulmonary monocyte chemotactic
protein-1 mRNA expression compared with wild-type mice after OVA
treatment (49). p50-/- mice also
lack a pulmonary eosinophilic inflammatory response after allergen
sensitization/challenge compared with wild-type mice (16).
The lack of airway eosinophilia in OVA-treated
p50-/- mice is associated with the failure of
these mice to produce IL-5 and eotaxin (16). Inhibition of
NF-B activity in p50-/- mice prevents
expression of the Th2 transcription factor GATA-3 and Th2 cytokine
production (IL-4, IL-5, and IL-13) in allergen-induced developing, but
not committed, Th2 cells (50).
Inhaled glucocorticoids, important anti-inflammatory agents in
asthma management (51), inhibit NF-B and AP-1
transcription via binding to a specific glucocorticoid receptor and
transrepressing the expression of responsive genes (52).
However, glucocorticoids, particularly at high doses, have significant
and severe adverse effects (53). Additionally, a group of
severe asthmatic patients has a poor response to glucocorticoid
treatment and may be glucocorticoid-resistant (54).
Selective small molecule inhibitors of redox-regulated transcription
may provide a novel alternative to glucocorticoids for the treatment of
asthma.
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Acknowledgments |
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Footnotes |
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2 Address correspondence and reprint requests to Dr. William R. Henderson, Jr., Department of Medicine, University of Washington, Box 356523, 1959 Northeast Pacific Street, Seattle, WA 98195-6523. E-mail address: joangb{at}u.washington.edu
3 Abbreviations used in this paper: ROS, reactive oxygen species; AHR, airway hyperreactivity; alum, aluminum potassium sulfate; BAL, bronchoalveolar lavage; Cdyn, dynamic compliance; i.n., intranasal; Trx, thioredoxin; TR, Trx reductase; PVDF, polyvinylidene difluoride; BLOTTO, bovine lacto transfer optimizer.
Received for publication March 19, 2002. Accepted for publication August 19, 2002.
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A. Almolki, C. Taille, G. F. Martin, P. J. Jose, C. Zedda, M. Conti, J. Megret, D. Henin, M. Aubier, and J. Boczkowski Heme oxygenase attenuates allergen-induced airway inflammation and hyperreactivity in guinea pigs Am J Physiol Lung Cell Mol Physiol, July 1, 2004; 287(1): L26 - L34. [Abstract] [Full Text] [PDF]
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 A. KUMAR, S. LNU, R. MALYA, D. BARRON, J. MOORE, D. B. CORRY, and A. M. BORIEK Mechanical stretch activates nuclear factor-kappaB, activator protein-1, and mitogen-activated protein kinases in lung parenchyma: implications in asthma FASEB J, October 1, 2003; 17(13): 1800 - 1811. [Abstract] [Full Text] [PDF]
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A. Iwata, K. Nishio, R. K. Winn, E. Y. Chi, W. R. Henderson Jr., and J. M. Harlan A Broad-Spectrum Caspase Inhibitor Attenuates Allergic Airway Inflammation in Murine Asthma Model J. Immunol., March 15, 2003; 170(6): 3386 - 3391. [Abstract] [Full Text] [PDF]
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