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Inducible Cyclooxygenase and Interleukin 6 Gene Expressions in Nasal Polyp Fibroblasts
Possible Implication in the Pathogenesis of Nasal Polyposis
Chia-Ming Liu, MD;
Chi-Yuan Hong, BDS, DMSc;
Chia-Tung Shun, MD;
Tzu-Yu Hsiao, MD;
Chih-Chiang Wang, MS;
Juo-Song Wang, BDS, MS;
Michael Hsiao, DVM, PhD;
Sze-Kwan Lin, BDS, MS, PhD
Arch Otolaryngol Head Neck Surg. 2002;128:945-951.
ABSTRACT
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Background Inflammation is believed to be related to the pathogenesis of nasal
polyp (NP). Inducible cyclooxygenase (COX-2) and interleukin (IL) 6 are important
mediators of inflammation. However, no information is available regarding
the expression of these mediators in nasal polyp fibroblasts (NPFs). The inductive
effects of proinflammatory cytokines (IL-1 or tumor necrosis factor )
alone or in combination with prostaglandin E2 on IL-6 and COX-2
messenger RNA (mRNA) synthesis in NPFs were investigated.
Design The expressions of IL-6 and COX-2 mRNAs in NPFs and in 34 surgical specimens
of NP were detected by Northern blot and in situ hybridization.
Results Significant amounts of constitutive IL-6 and COX-2 mRNAs were produced
in NPFs. Cytokines induced IL-6 and COX-2 mRNA synthesis in NPFs. Meloxicam
(a specific COX-2 inhibitor) suppressed the induction of cytokines on IL-6
mRNA levels, and these effects could be reversed by exogenous prostaglandin
E2. In situ hybridization revealed that IL-6 and COX-2 mRNAs were
detected primarily in fibroblasts, macrophages, and plasma cells. Aggregation
of plasma cells as well as collagen deposition in vicinity to IL-6 mRNA-producing
fibroblasts was found. Rich vascularity around COX-2 mRNA+ fibroblasts
was also identified.
Conclusions The pathogenesis of nasal polyposis involves NPFs through synthesizing
IL-6 to modulate the activation of immune responses (plasma cell formation)
and synthesis of stroma. Inducible cyclooxygenase also contributes to NP development
by promoting vasodilatation and modulating the cytokine-induced IL-6 gene
expression in NPFs.
INTRODUCTION
NASAL POLYP (NP) is the most common mass lesion in nose.1
Although the pathogenesis remains unclear, NP has been regarded, at least
by some authors, to be of inflammatory origin.2-3
During inflammation, a complex series of reactions including vascular proliferation
or dilatation, active extracellular matrix (ECM) remodeling, and activation
of immune mechanism will be elicited to promote wound healing. Elevated levels
of prostaglandins (PGs) and interleukin (IL) 6 are connected with the development
of these phenomena.4-5
Interleukin 6 is a multifunctional cytokine that is involved in a variety
of inflammatory conditions. One of its central roles is the modulation of
host immunity such as inducing the final differentiation of B cells into antibody-producing
plasma cells and stimulating T-cells proliferation with the subsequent leukocytosis.5 Interleukin 6 is also a TH2-type cytokine
that stimulates fibroblast proliferation, increases collagen deposition, and/or
decreases collagen breakdown. Therefore, elevated levels of IL-6 have been
connected with the pathogenesis of several fibrotic lesions such as systemic
sclerosis and cystic fibrosis in humans and pulmonary fibrosis in mice.6-7
Cyclooxygenase (COX) is the rate-limiting enzyme responsible for the
conversion of arachidonic acid to PGs.8 Two
isoforms of COX have been identified: COX-1 maintains tissue homeostasis whereas
inducible cyclooxygenase (COX-2) is responsible for the excessive PG synthesis
leading to pathological sequela.9 Of the PG
family, epoprostenol and prostaglandin E2 (PGE2) increase
vascular permeability and thereby facilitate cell migration to inflammatory
area.10 Prostaglandins also complicate the
inflammatory reaction by modulating some important biological behavior of
the proinflammatory cytokines.9, 11
For example, PGE2 can enhance the stimulatory effect of IL-1 on
matrix metalloproteinase 1 or IL-6 synthesis in macrophages12
or synovial fibroblasts,13 respectively.
Interleukin 6 and COX-2 serve to modulate a complex of responses in
an inflammatory tissue.4-5 However,
these reactions tend to become overexpressed14-16
and subsequently lead to tissue destruction instead of wound healing. Recent
studies had identified increased levels of proinflammatory cytokines such
as IL-1 and tumor necrosis factor (TNF-) as well as IL-6 and
COX-2 in NP and proposed an association between the overexpression of these
mediators and disease propagation.16-19
However, most of these experiments concentrated primarily on detecting the
presence of these mediators, and the mechanisms responsible for the synthesis
of these molecules remained unclear. It is important to clarify these processes
in that this may lead to the development of new therapeutic strategy. Since
the resident stromal cells in addition to the infiltrating inflammatory cells
are also important contributors to the inflammatory cascade,4
we studied the stimulatory effects of IL-1 or TNF- on IL-6 and
COX-2 mRNAs production in nasal polyp fibroblasts (NPFs) to further understand
the pathogenesis of nasal polyposis. The modulating effects of COX-2 and PGs
in these cytokine-induced reactions were also investigated. The in vivo expressions
of IL-6 and COX-2 mRNAs were examined in surgical samples of NP. The results
suggest that IL-6 and COX-2 produced by NPFs may contribute to NP development.
To verify this proposal, we also compared the synthesis of IL-6 and COX-2
mRNAs between NPFs and fibroblasts derived from nasal turbinate where NP never
occurs.
PATIENTS, MATERIALS, AND METHODS
TISSUE SAMPLES
Nasal mucosal tissues were obtained from inferior turbinate of patients
receiving turbinectomy to relieve nasal obstruction. Prior to surgery, the
tissue appeared to be free of inflammation and had a normal appearance. Nasal
polyps were dissected by functional endoscopic sinus surgery for treatment
of chronic sinusitis with polyposis. The patients had no history of nasal
allergy, asthma, or aspirin sensitivity and had not taken regular topical
or oral medication within 3 weeks. Informed consent was obtained before surgical
procedure.
PRIMARY CELL CULTURES
Six primary cultures of fibroblasts, 3 from NP (NPFs) and 3 (including
1 from the patient with NP) from nasal turbinate (NFs) were established. Cultured
cells were subjected to 3 independent experiments. Consequently, each datum
presented in the Northern blot hybridization was the average value obtained
from the results of 9 independent experiments. The primary cell cultures were
established as described in our recent study.20
In brief, after removing the epithelial layer, the specimens were immersed
overnight in Dulbecco Modified Eagle Medium containing 10% fetal calf serum,
200 U/mL of penicillin, 200 µg/mL of streptomycin, and 1 mg/mL of amphotericin
B. The samples were placed in the 10-cm Petri dish, minced into 1-mm3 fragments, and covered with a sterilized glass coverslip. After fibroblasts
had migrated from tissue explants and became confluent, cells were trypsinized
and subcultured.
PROBE PREPARATION
For Northern blot, DNA plasmids of human IL-6 and COX-2 (Cayman Chemical,
Ann Arbor, Mich) were radiolabeled with [32P] deoxycytidine 5'-triphosphate
([32P]dCTP) by random prime labeling method (Amersham Biosciences,
Little Chalfont, England). For in situ hybridization, the probes were labeled
using digoxigenin-11-deoxyuridine triphosphate (DIG-11-dUTP) by random priming
(Boehringer Mannheim, Indianapolis, Ind).
NORTHERN BLOT ANALYSIS
Following stimulation, total RNAs were isolated by acid guanidinium
thiocyanate-phenol-chloroform method (Zol-B; Biotecx Laboratories Inc, Houston,
Tex), electrophoresed, and transferred to a nylon membrane. The RNAs were
immobilized by UV cross-linking. The membrane was hybridized with radiolabeled
complementary DNA probes for IL-6, COX-2, and glyceraldehyde-3-phosphate dehydrogenase
(GAPDH, as internal standard), washed under high stringency conditions, and
autoradiographed at –80°C. The intensity of each band, after normalization
with GAPDH mRNA abundance, was quantified by scanning video densitometer and
software (Image Reader V1.8; Biomed Instruments Inc, Fullerton, Calif). As
described above in "Primary Cell Cultures", each densitometric value, expressed
as mean ± SD, was obtained from 9 independent experiments.
IN SITU HYBRIDIZATION
Thirty-four surgical specimens of NP and 15 cases of nasal mucosa were
collected. They were fixed in 4% paraformaldehyde and embedded in paraffin.
Serial sections of 5 µm were cut and mounted on Superfrost/Plus slides
(Fisher Scientific International, Pittsburgh, Pa). In situ hybridization was
performed as described in our recent article.20
In brief, sections were treated with 0.1% pepsin/0.2N hydrochloric acid, postfixed
with 0.4% paraformaldehyde, and acetylated with acetic anhydride. After prehybridization
with hybridization buffer (4x sodium chloride and sodium citrate, 50%
deionized formamide, 1x Denhardt solution, 5% dextran sulfate, 0.5 mg/mL
of salmon sperm DNA, and 0.25 mg/mL of yeast transfer RNA), hybridization
was carried out overnight with hybridization buffer containing 0.5 to 1.0
µg/mL of digoxigenin-labeled probes at 42°C. After a series of stringent
washings, slides were incubated with alkaline phosphatase-conjugated sheep
antidigoxigenin antibody overnight at 4°C. The sections were incubated
in a chromogen solution (0.1M Tris hydrochloride [pH, 9.5], 0.1M sodium chloride,
0.05M magnesium chloride, 0.45% 4-nitroblue tetrazolium, and 0.35% 5-bromo-4-chloro-3-indolylphosphate),
counterstained with methyl green, and examined by light microscopy. Sections
digested with ribonuclease A before hybridization served as negative controls.
STATISTICAL ANALYSIS
The difference between the relative mRNA level in each experimental
group was analyzed by 1-way analysis of variance for multiple comparisons
and then by the Fisher protected least significant difference test. P<.05 was considered statistically significant.
RESULTS
All the NPFs exhibited similar and reproducible responses concerning
the expressions of IL-6 and COX-2 genes following stimulation (data not shown).
The problem of heterogeneity derived from using primary fibroblast cultures
does not exist in this experiment.
IL-6 GENE EXPRESSIONS IN NPFs FOLLOWING IL-1, TNF- STIMULATION
After exposure to various stimuli, total RNAs in NPFs were subjected
to Northern blot hybridization. A prominent amount of constitutive IL-6 mRNA
was found. Exposure to IL-1 and TNF- resulted in further elevated
levels of IL-6 mRNA (2.0-fold to 1.9-fold) compared with the control groups
(Figure 1A and B).
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Figure 1. Induction of interleukin (IL)
6 messenger RNA (mRNA) transcripts in nasal turbinate fibroblasts and nasal
polyp fibroblasts (NPFs) of a patient with nasal polyp. After incubating in
serum-free medium for 8 hours, cells were untreated (C) or treated for 24
hours with 10 ng/mL of IL-1 (I), 10 ng/mL of tumor necrosis factor
(TNF-) (T), 1 µg/mL of prostaglandin E2(PGE2) (P), 10 ng/mL of IL-1 + 1 µg/mL of PGE2 (P
+ I), and 10 ng/mL of TNF- + 1 µg/mL of PGE2 (P +
T). In addition, some cells were preincubated with 10 -6M
meloxicam for 2 hours (M) prior to subsequent stimulation by IL-1 (M
+ I), TNF- (M + T), IL-1 + PGE2 (M + I + P), TNF-
+ PGE2 (M + T + P) for 24 hours. A, Total RNAs were subjected to
IL-6 mRNA analysis by Northern blot hybridization, quantified by densitometric
analysis after glyceraldehyde-3-phosphate dehydrogenase (GAPDH) mRNA standardization,
and expressed as relative optical density to control group. B, Relative IL-6
mRNA level following PGE2 treatment. C, Relative IL-6 mRNA level
following meloxicam treatment. Data of NPFs were analyzed by 1-way analysis
of variance for multiple comparisons and then by the Fisher protected least
significant difference test. Each bar represents mean ± SD of 9 individual
experiments. B and C, The asterisk indicates P<.05
vs control.
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EFFECTS OF PGE2 AND MELOXICAM ON CYTOKINE-STIMULATED IL-6
GENE EXPRESSION
Although cytokines in combination with PGE2 also triggered
pronounced IL-6 gene expressions, PGE2 did not change statistically
the induction of IL-6 mRNA by cytokines in NPFs (Figure 1A-B). Approximately 40% of the cytokine-stimulated IL-6
mRNA production in NPFs was suppressed by the COX-2–specific inhibitor
meloxicam.21 Exogenous PGE2 restored
the inhibitory effects of meloxicam. Furthermore, 34% of the endogenous IL-6
mRNA level in NPFs was diminished by meloxicam (Figure 1A and C).
COX-2 GENE EXPRESSIONS IN NPFs
Similar to IL-6, significant amount of constitutive COX-2 mRNA was also
found in NPFs. Interleukin 1 and TNF- also induced COX-2 gene
expressions (2.1-fold to 1.8-fold) compared with the control groups. Although
cytokines plus PGE2 also stimulated significant COX-2 gene expressions,
the cytokine-induced COX-2 mRNA production in NPFs was not affected by PGE2 (Figure 2A and B).
PRODUCTION OF IL-6 AND COX-2 mRNAs: COMPARISON BETWEEN NPFs AND NFs
Total RNAs in NPFs and NFs, quiescent or treated with meloxicam, were
subjected to Northern blot analysis. Similar to NPFs, all the NFs exhibited
similar and reproducible responses with regard to the expressions of IL-6
and COX-2 genes. Substantially high amounts of constitutive IL-6 and COX-2
mRNAs were detected in NPFs compared with NFs. Meloxicam abolished significantly
the IL-6 mRNA levels in NPFs but not in NFs (Figure 3A and B).
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Figure 3. Production of interleukin (IL)
6 (A) and inducible cyclooxygenase (COX-2) (B) messenger RNA (mRNAs): comparison
between nasal polyp fibroblasts (NPFs) and nasal turbinate fibroblasts (NFs).
After incubating in serum-free medium for 8 hours, cells were untreated (C)
or treated for 24 hours with 10 -6M meloxicam (M). Total
RNAs were subjected to IL-6 and COX-2 mRNA analysis by Northern blot hybridization.
The level of glyceraldehyde-3-phosphate dehydrogenase (GAPDH) mRNA was also
analyzed and served as an internal standard. The effects of meloxicam on the
endogenous IL-6 mRNA levels in NPFs and NFs were also investigated.
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IN VIVO EXPRESSIONS OF IL-6 AND COX-2 GENES IN NPS
Microscopically, NPs were lined by a layer of ciliated respiratory epithelium.
Abundant IL-6 mRNAs were identified in the subepithelial resident fibroblasts
as well as the infiltrating plasma cells and mononuclear round cells in contrast
to the faint, weak signal in the lining epithelium. An intimate alignment
between the IL-6 mRNA–producing fibroblasts and plasma cells was frequently
found (Figure 4A). The ECM around
some IL-6-mRNA+ fibroblasts showed a certain degree of collagen
deposition in contrast to the commonly seen loose, edematous stroma (Figure 4C). Interestingly, these IL-6 mRNA+ fibroblasts as well as their associated collagen were located in close
vicinity to the lining epithelium (Figure
4B). Pronounced COX-2 mRNAs were detected primarily in plasma cells,
fibroblasts, and mononuclear round cells (Figure 4E), whereas only a weak signal appeared in some of the lining
epithelium. Furthermore, examination of the adjacent sections revealed that
the ECM around some COX-2 mRNA+ NPFs also contained rich vascular
supply (Figure 4D). However, expressions
of COX-2 and IL-6 mRNAs were insignificant in nasal mucosa from inferior turbinate
(data not shown). Little or no signal was found in the negative control groups.
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Figure 4. Detection of inducible cyclooxygenase
(COX-2) and interleukin (IL) 6 messenger RNA (mRNAs) in nasal polyps by in
situ hybridization. A, Interleukin 6 was identified in the cytoplasm of plasma
cells (arrows) and macrophages and fibroblasts (arrowheads). B, A close spatial
orientation between these collagen bundle and lining epithelium, even in direct
contact. C, Collagen deposition in vicinity to some IL-6 mRNA+
fibroblasts (arrowheads) was found. D, The extracellular matrix around these
COX-2 mRNA+ cells was well vascularized. E, Expression of COX-2
mRNA in plasma cells (arrows), fibroblasts (arrowheads), and mononuclear round
cells was rather pronounced, whereas only weak signals were found in some
lining epithelium (A, C, and E, in situ hybridization; B and D, hematoxylin-eosin;
original magnification: A, x300; B-E, x150).
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COMMENT
Elevated levels of IL-6 have been demonstrated in NP compared with the
normal controls sampled from inferior turbinate.18
Immunohistochemical staining and in situ hybridization also indicated that
macrophages, eosinophils, and lining epithelium were the main cellular sources
of IL-6.18 In the present study, the significant
IL-6 mRNA levels (constitutive or stimulated) synthesized in NPFs suggest
that sources other than inflammatory cells or lining epithelium also contribute
to the pronounced levels of IL-6 detected in NP. To further confirm the data
from our in vitro assay, in situ hybridization in surgical specimens was performed,
and the results revealed the presence of abundant IL-6 mRNAs in NPFs. In addition,
an intimate spatial orientation between the IL-6 mRNA-producing fibroblasts
and plasma cells was found. These observations suggest that NPFs may modulate
the immune responses in NP through synthesizing IL-6 to induce plasma cell
formation.
Studies on the biological behavior of respiratory cells have clearly
demonstrated the influence of stroma or ECM on the attachment and proliferation
and differentiation of lung epithelium.21-22
In these studies, collagen gel is necessary for the cultured tracheal epithelium
to maintain their mucociliary phenotype. In addition, the number of ciliated
cell is obviously reduced when collagen gel is depleted from the culture dishes.22 Larsen et al23-24
also propose that a rapid ECM remodeling is necessary to support the growth
and elongation of mucoserous glands and subsequently, polyp proliferation.
Although the significance of ECM on the biological behavior of NP has been
widely accepted, the regulatory mechanism(s) accounting for ECM remodeling
in NP is still not clearly understood. In the present study, pronounced endogenous
as well as cytokine-stimulated IL-6 mRNAs were produced in NPFs. Surgical
specimens also revealed significant collagen deposition around the IL-6 mRNA+ fibroblasts. Since IL-6 has also been proposed to be fibrogenic6-7 in addition to its modulating role
in inflammatory reaction, these results suggest that the IL-6 released from
NPFs may promote collagen deposition in NP. Furthermore, IL-6-mRNA+
fibroblasts and their associated collagen were also located in close vicinity
to the lining epithelium, or even in direct contact. This observation further
implies that IL-6 may mediate the interactions between NPFs and the lining
epithelium. Our recent experiment also reveals substantially high amounts
of matrix metalloproteinase 1 mRNAs (constitutive or cytokine stimulated)
in NPFs.20 Since matrix metalloproteinase 1
is an essential enzyme for degrading collagen fiber, data from our present
and previous studies highlight the significance of NPFs in NP progression.
Namely, this cell may promote active ECM remodeling through producing IL-6
and matrix metalloproteinase 1 to modulate collagen deposition and breakdown,
respectively.
In the present study, obvious COX-2 mRNAs were located primarily in
fibroblasts, plasma cells, mononuclear round cells, and to a less extent,
lining epithelium in NP in contrast to the trivial signal in nasal mucosa
from inferior turbinate. Since PGE2 and epoprostenol are potent
vasodilators and COX-2 is the rate-limiting enzyme for PG synthesis during
inflammation,9-10 our findings
of the well-vascularized and edematous stroma around the COX-2 mRNA-producing
NPFs may be due to an excessive release of PGs.
Northern blot hybridization revealed obvious synthesis of COX-2 mRNAs
in NPFs either constitutively or following the stimulation of IL-1
or TNF-. In addition to the originally reported 4.1-kilobase (kb) COX-2
complementary DNA, a smaller band (approximately 2.5 kb) of mRNA was also
presented. This smaller band probably reflects a different site of polyadenylation
as reported previously for murine COX-2.25-26
In NPFs, 34% of the constitutive and 40% of the cytokine-induced IL-6 mRNA
levels were suppressed by the COX-2 specific inhibitor meloxicam.27 These abolishing effects could be reversed by exogenous
PGE2. This implies the regulatory role of endogenous COX-2 and
PG on IL-6 synthesis in NPFs. Taken together, these data suggest that the
COX-2 produced by NPFs may contribute to NP propagation in the following 2
ways: (1) to promote vascular dilatation and proliferation through synthesizing
PGs and (2) to promote collagen synthesis by modulating IL-6 synthesis. In
their clinical investigations, Patriarca et al,28-29
found that intranasal treatment of lysine acetylsalicylate (nonspecific COX
inhibitor) effectively prevents or reduces the relapse of nasal polyps, which
supports our proposal indirectly.
To further elucidate the experimental proposal that the IL-6 and COX-2
produced by NPFs contribute to NP development, the levels of these molecules
in fibroblasts (NFs) from nasal turbinate where NP never occurs was also analyzed.
The results showed that substantially high amounts of constitutive IL-6 and
COX-2 mRNAs were produced in NPFs compared with NFs. In addition, meloxicam
diminished significantly the endogenous IL-6 mRNA level in NPFs but did not
exert any influence in NFs. Mullol et al30
compared the amounts of 5 different cytokines produced by cultured epithelial
cells from NP and nasal turbinate. A statistically significant difference
between these 2 cell types was found in only 2 of the 5 cytokines examined.30 Hicks et al31 examined
the expressions of cytokeratins in the epithelial cells of NP and nasal turbinate.
The results also showed an identical profile of cytokeratin production in
these 2 cell types.31 Accordingly, these authors,
together with others, suggest that local stroma disorder may play a more notable
role than lining epithelium in NP development.30-32
In our experiment, the data demonstrating an obviously altered biological
behavior between NPFs and NFs seem to provide further support for this hypothesis.
CONCLUSIONS
The experimental data suggest the involvement of NPFs in the pathogenesis
of nasal polyposis through synthesizing IL-6 to modulate the immune responses
(formation of plasma cells) and ECM synthesis. Inducible cyclooxygenase also
contributes to the development of NP by promoting vascular dilatation/proliferation
and modulating the cytokine-triggered IL-6 mRNA synthesis in NPFs. Furthermore,
the stimulatory effects of proinflammatory cytokines (IL-1 or TNF-)
on IL-6 and COX-2 gene expressions in NPFs support the pathogenic mechanism
of inflammation on nasal polyposis.
AUTHOR INFORMATION
Accepted for publication January 8, 2002.
This study was supported in part by grants NSC 89-2314-B-002-437 (Dr
Liu), 90-2314-B-002-366 (Dr Lin), and 90-2314-B-002-348 (Dr Hong) from the
National Science Council, Taipei, Taiwan, and DOH89-TD-1134, DOH90-TD-1041
(Dr Hong) from the National Health Research Institute, Taipei.
Corresponding author and reprints: Sze-Kwan Lin, BDS, MS, PhD, School
of Dentistry, National Taiwan University Hospital, 1 Chang-Teh St, Taipei
10016, Taiwan (e-mail: sklin{at}ha.mc.ntu.edu.tw).
From the Departments of Otolaryngology (Drs Liu and Hsiao), Dentistry
(Drs Hong, Wang, and Lin), and Forensic Medicine (Dr Shun), and the Graduate
Institute of Clinical Medicine (Mr Wang), National Taiwan University Hospital,
Taipei, Taiwan; and the Department of Medical Education and Research, Kaohsiung-Veterans
General Hospital, Kaohsiung (Dr Hsiao).
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