Prostaglandin E2-induced interleukin-6
release by a human airway epithelial cell line
S.
Tavakoli,
M. J.
Cowan,
T.
Benfield,
C.
Logun, and
J. H.
Shelhamer
Critical Care Medicine Department, Clinical Center, National
Institutes of Health, Bethesda, Maryland 20892
 |
ABSTRACT |
Human airway epithelial cell
release of interleukin (IL)-6 in response to lipid mediators was
studied in an airway cell line (BEAS-2B). Prostaglandin (PG)
E2 (10
7 M) treatment caused an increase in
IL-6 release at 2, 4, 8, and 24 h. IL-6 release into the culture
medium at 24 h was 3,396 ± 306 vs. 1,051 ± 154 pg/ml
(PGE2-treated cells vs. control cells). PGE2
(10
7 to 10
10 M) induced a dose-related
increase in IL-6 release at 24 h. PGF2
(10
6 M) treatment caused a similar effect to that of
PGE2 (10
7 M). PGE2 analogs with
relative selectivity for PGE2 receptor subtypes were
studied. Sulprostone, a selective agonist for the EP-3 receptor subtype
had no effect on IL-6 release.
11-Deoxy-16,16-dimethyl-PGE2, an EP-2/4 agonist, and
17-phenyl trinor PGE2, an agonist selective for the
EP-1 > EP-3 receptor subtype (10
6 to
10
8 M), caused dose-dependent increases in IL-6 release.
8-Bromo-cAMP treatment resulted in dose-related increases in IL-6
release. RT-PCR of BEAS-2B cell mRNA demonstrated mRNA for EP-1, EP-2, and EP-4 receptors. After PGE2 treatment, increases in IL-6
mRNA were noted at 4 and 18 h. Therefore, PGE2
increases airway epithelial cell IL-6 production and release.
cytokines; eicosanoids; lung inflammation
 |
INTRODUCTION |
THE AIRWAY
EPITHELIUM is a first contact site for external stimuli such as
infectious agents, exogenous inhaled antigens, and noxious agents. It
may serve as a first line of defense against these stimuli by providing
mucus secretion and mucociliary clearance to remove the exogenous
materials, or it may initiate or amplify the local inflammatory
reaction in the airway (21). In the setting of the airway
inflammatory reaction, epithelial cells may function as both target and
effector cells. As target cells, their defense functions such as
mucociliary clearance, mucus secretion, and water and ion transport may
be altered by a number of proinflammatory lipid or cytokine mediators.
As effector cells, epithelial cells can produce a number of cytokine
products that may directly or indirectly participate in the
inflammatory cascade via the recruitment, activation, and alteration of
the survival of inflammatory cells within the airway. Human airway
epithelial cells also synthesize and release a variety of lipid
mediators including, primarily, prostaglandin (PG) E2,
15-hydroxyeicosatetraenoic acid (HETE), PGF2
, and
platelet-activating factor (PAF) (3, 13, 15, 35). In the
setting of airway inflammation, these same cells are exposed to other
lipid mediators produced locally by resident or recruited inflammatory
cells. These mediators include leukotriene (LT) B4, 5-HETE
and LTD4.
Airway epithelial cells produce a variety of cytokine products
including
- and
-chemokines, colony-stimulating factors, lymphocyte chemoattractant factor, and pleiotropic cytokines such as
interleukin (IL)-6, IL-11, tumor necrosis factor (TNF)-
, and IL-1
(23). Secretion of these cytokines by the airway
epithelium may be a primary response to external stimuli, or it may
serve as a secondary response to an inflammatory mediator. It is clear that some cytokines, such as TNF-
or IL-1, can stimulate epithelial cell cytokine production. Furthermore, lipid mediators such as PAF can
stimulate subsequent cellular production of lipid mediators (38). It has been reported that murine alveolar
macrophages respond to PAF, LTB4, and PGE2 with
the production of IL-6 (37). However, less is known of the
interaction of these networks of lipid and cytokine mediators in the
airway epithelium. Therefore, we studied whether PGE2 or
other lipid mediators present in significant quantities in inflamed
airways can modulate cytokine production by a human bronchial
epithelial cell line.
 |
MATERIALS AND METHODS |
Cell culture.
BEAS-2B cells, a human bronchial epithelial cell line transformed by an
adenovirus 12-SV40 hybrid virus, were supplied by J. E. Lechner
(National Cancer Institute, National Institutes of Health, Bethesda,
MD) (19). The cells were cultured in the serum-free,
hormonally defined culture medium LHC-8 (Biofluids, Rockville, MD) and
grown on 175-cm2 tissue culture flasks (Falcon, Becton
Dickinson, Oxnard, CA) that were coated with a thin layer of type I rat
tail collagen (Collaborative Research, Bedford, MA). For passage, cells
were detached from the collagen film with 0.02% trypsin, 1%
polyvinylpyrrolidine, and 0.02% ethylene glycol bis (E-PET, Biofluids)
that was subsequently neutralized with soybean trypsin inhibitor
(Biofluids). Replicate cultures were made by passing cells into either
6-well, 35-mm plates precoated with a thin layer of type I rat tail
collagen (Collaborative Research) for secretion studies or into
175-cm2 tissue culture flasks coated with a thin layer of
type I rat tail collagen for gene expression studies. Experiments were
performed when the cells were near confluence.
Reagents.
PGE2, PGF2
, 5-HETE, LTB4,
LTD4, and PAF were purchased from Calbiochem (San Diego,
CA). 17-Phenyl trinor PGE2, a selective EP-1 > EP-3
receptor agonist (2),
11-deoxy-16,16-dimethyl-PGE2, a relatively selective EP-2
receptor agonist (16, 28, 31), and sulprostone, a
selective EP-3 receptor agonist were purchased from Cayman Chemical
(Ann Arbor, MI). 8-Bromo-cAMP was purchased from Sigma (St. Louis, Mo).
Experimental design.
At the start of each experiment, medium (LHC-8) was replaced by
fresh medium. For IL-6 time-course experiments, PGE2
(10
7 M), 5-HETE (10
7 M), LTB4
(10
7 M), LTD4 (10
7 M), or PAF
(10
7 M) was added to cell cultures in six-well plates,
and supernatants were collected 2, 4, 8, or 24 h later. For
subsequent dose-response experiments, PGE2 was added in
concentrations ranging from 10
7 to 10
10 M,
and supernatants were collected at 24 h. Similar designs were used
for dose-response experiments with PGE2 receptor-specific agonists, with doses ranging from 10
6 to
10
9 M. DNA was measured with benzimidazole (Hoechst
33258, Janssen Chimica, Geel, Belgium) (18), and
cytotoxicity was determined by lactate dehydrogenase (LDH) assay (Sigma).
ELISA for secreted IL-6.
Immunoreactive levels of IL-6 in culture medium were determined with a
sandwich-type ELISA (R&D Systems, Minneapolis, MN). The microtiter
plates were coated with specific murine monoclonal antibodies directed
against human IL-6. One hundred microliters of cell-free culture medium
diluted 1:20 were plated in duplicate for the IL-6 assay. The assay was
developed by the addition of horseradish peroxidase-linked goat
polyclonal antibody directed against human IL-6.
Ribonuclease protection assay.
Total cellular RNA was extracted from BEAS-2B cells in
175-cm2 flasks with TRI Reagent (Molecular Research,
Cincinnati, OH) for both PGE2 (10
7
M)-stimulated and control cultures for 4 and 16 h. One hundred micrograms of total RNA were used for IL-6 assays, and 10 µg of total
RNA were used for glyceraldehyde-3-phosphate dehydrogenase (GAPDH)
assays. 32P-labeled riboprobes were made from a plasmid
containing an IL-6 cDNA insert labeled to a specific activity ranging
from 108 to 109
counts · minute
1
(cpm) · µg
1. GAPDH riboprobes were made from a
commercially available template (Ambion, Austin, TX) and were labeled
to a specific activity of 107 to 108 cpm/µg.
Ribonuclease protection assay (RPA) products were separated under
denaturing conditions on 6% Tris-borate-EDTA (TBE)-urea polyacrylamide
gels (Novex, San Diego, CA) and detected by autoradiography. Labeled
RNA markers (RNA Century Marker template set; Ambion) were employed to
determine the size of protected fragments. Both the IL-6 and GAPDH
probe concentrations used were in excess of target. The plasmid
containing the IL-6 sequence was made by RT-PCR of total RNA from
BEAS-2B cells. Total RNA was reverse transcribed into cDNA with Moloney
murine leukemia virus reverse transcriptase and random hexamer primers
during a 1-h incubation at 42°C (GeneAmp RNA PCR kit, PerkinElmer
Cetus, Norwalk, CT). The primer pair for IL-6 amplified a 628-bp
product and was composed of the following sequences: 5' primer, ATG AAC
TCC TTC TCC ACA AGC GC and 3' primer, GAA GAG CCC TCA GGC TGG ACT G
(GenBank accession no. M18403). Denaturation, annealing, and extension
temperatures for PCR were 94°C, 55°C, and 72°C, respectively, for
1 min each for 35 cycles. This PCR product was cloned into the pCRII
vector with the TA cloning kit (Invitrogen, San Diego, CA). The
orientation and sequence of the insert were confirmed by automated
fluorescence sequencing. The plasmid was linearized before riboprobe
generation with Xba I, resulting in a 147-bp protected
sequence, and cRNA transcripts were prepared with Sp6 RNA polymerase
and radiolabeled with [32P]CTP (Lofstrand Laboratories,
Gaithersburg, MD). The vector containing the GAPDH sequence was
linearized with Hind III and cRNA labeled as outlined above.
RT-PCR amplification of PGE
receptor mRNA.
PCR was performed with specific primers for the amplification of mRNA
for PGE receptor subtypes 1, 2, and 4. A 274-base sequence of EP-1 mRNA
was amplified with the 5' primer, 5'-TGTCCAACCTGCTGGCGCTG-3' and the 3'
primer, 5'-ACGCCCACGCAGCGCTCCAC-3', corresponding to bases 216-235
and 471-490, respectively, of the published sequence (GenBank
accession no. L22647). A 326-bp sequence of the EP-2 receptor subtype
mRNA was amplified with a 5' primer, 5'-ATGGGCAATGCCTCCAATGACTCC-3' and
a 3' primer, 5'-GCACGCGCGGCTCTCGGGCGCCAG-3' (bases 157-180 and
460-483, respectively, of GenBank accession no. U19487) (31). A 446-bp sequence of EP-2/4 mRNA was amplified with
the 5' primer, 5'-CGCTGTCCTCCCGCAGACGA-3' and a 3' primer,
5'-CCACCCCGAAGATGAACATC-3' corresponding to bases 236-255 and
663-682, respectively, of the published sequence (GenBank
accession no. L25124) (1). An 838-base sequence of
-actin was amplified with a human
-actin control amplimer set
(CLONTECH Laboratories, Palo Alto, CA). HeLa cells and BEAS-2B cells
were grown in culture, and total RNA was extracted with TRI Reagent
(Molecular Research Center). Human lung total RNA and human kidney
total RNA were obtained from CLONTECH. One microgram of RNA from each
source was used as a template for reverse transcriptase (GeneAmp,
PerkinElmer, Branchburg, NJ). PCR was performed with 50 ng of cDNA and
1 µM primers with 30 cycles with the following conditions:
denaturation at 94°C for 1 min, annealing at 50°C for 30 s,
and elongation at 72°C for 30 s. Amplified DNA was separated on
a TBE-polyacrylamide gel (Novex) and visualized with SYBR Green I
(Molecular Probes, Eugene, OR).
Statistical analysis.
Data are shown as means ± SE. Statistical analysis was carried
out on a Macintosh G3 with Microsoft Excel. P < 0.05 was considered significant. Increases in IL-6 secretion were analyzed
by unpaired t-test. Concentration-dependent effects were
evaluated by one-way ANOVA.
 |
RESULTS |
Effect of PGE2 on IL-6
secretion by BEAS-2B cells.
Cell-free culture supernatants were assayed with an ELISA for IL-6.
Unstimulated cells produced detectable amounts of IL-6 in medium at 2 or 4 h of culture. LTB4, 5-HETE, LTD4, and
PAF, all at 10
7 M, had no effect on IL-6 release at 2, 4, 8, or 24 h (Fig. 1). Significant
increases in IL-6 secretion in response to PGE2
(10
7 M) were observed at 2, 4, 8, and 24 h
(P < 0.001 for each time point; Fig.
2). Maximal cumulative increases in IL-6
secretion were detected at 24 h. Concentration-dependent increases
in PGE2-induced IL-6 secretion were studied at 24 h
after stimulation with PGE2 (10
7 to
10
10 M; P < 0.001 by ANOVA; Fig.
3). In a separate experiment, the effect
of PGE2 at 10
6 M was tested. PGE2
at 10
6 M resulted in an IL-6 concentration of 3,345 ± 331 pg/ml at 24 h vs. 1,129 ± 52 pg/ml for control
cultures (n = 12; P < 0.001), an
effect not greater than the effect of PGE2 at
10
7 M. Therefore, treatment with PGE2 at
10
7 M appeared to induce a peak effect. No evidence of
PGE2-mediated toxicity was apparent by LDH determination
when compared with control cultures at 24 h. In addition, no
differences in cell number were present between
PGE2-stimulated and control cultures at 24 h as
determined by cellular DNA quantification.

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Fig. 1.
Effect of the lipid mediators leukotriene (LT)
B4, platelet-activating factor (PAF), and
5-hydroxyeicosatetraenoic acid (5-HETE) (A) and
LTD4 (B) on interleukin (IL)-6 release into
culture medium by BEAS-2B cells (n = 6 experimental
points, each determined in duplicate). Cells were treated with each
mediator (10 6 M) for 2, 4, or 8 h. Media were then
harvested and assayed (see MATERIALS AND METHODS).
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Fig. 2.
Time course of IL-6 secretion by BEAS-2B cells both
unstimulated and in response to PGE2 (10 7 M).
Significant rises in IL-6 secretion in response to PGE2
were observed at 2, 4, 8, and 24 h. At each point, treated samples
differed from control samples (n = 9-21
experimental points, each determined in duplicate). P < 0.001 by unpaired t-test.
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Fig. 3.
Effect of indicated doses of PGE2 on IL-6
secretion from BEAS-2B cells. Cells were stimulated for 24 h with
PGE2; n = 6 separate experimental points,
each determined in duplicate. The dose effect was significant,
P < 0.001, by ANOVA.
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The effect of PGF2
on IL-6 production was also studied.
PGF2
in a log higher concentration (10
6 M)
also stimulated cellular IL-6 production over 2-24 h (Fig. 4A). Figure 4B
presents the dose effect of PGF2
on IL-6 production from
BEAS-2B cells. This effect was dose dependent but at higher concentrations than required for PGE2 stimulation.

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Fig. 4.
A: time course of IL-6 secretion by BEAS-2B
cells both unstimulated and in response to PGF2
(10 6 M). Significant increases in IL-6 secretion in
response to PGF2 were noted at each time point;
n = 9 experimental points, each determined in
duplicate. At each time point, treated samples were different from
control samples, P < 0.001 by unpaired
t-test. B: effect of indicated doses of
PGF2 on IL-6 secretion from BEAS-2B cells. Cells
(n = 6 experimental points) were stimulated for 24 h with PGF2 . The dose effect was significant,
P < 0.001, by ANOVA.
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PGE2 analogs with some PGE2 receptor subtype
specificity were used to determine their effect on IL-6 secretion by
epithelial cells. Sulprostone, an EP-3 > EP-1 receptor subtype
agonist, in concentrations as high as 10
6 M had no effect
on IL-6 production. An agonist with relative specificity for the EP-2/4
receptor subtypes, 11-deoxy-16,16-dimethyl-PGE2, stimulated
IL-6 production in a dose-dependent manner, whereas 17-phenyl trinor
PGE2, an EP-1 receptor subtype agonist, also stimulated
IL-6 production in a dose-dependent manner at concentrations ranging
from 10
6 to 10
8 M (Fig.
5).

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Fig. 5.
Concentration-dependent effect on IL-6 secretion in
response to relatively selective PGE2 agonists [17-phenyl
trinor PGE2, 11-deoxy-16,16-dimethyl (11-deoxy
DM)-PGE2, and sulprostone]. Cells were incubated for
24 h with 1 of the PGE receptor agonists (n = 6 experimental points, each determined in duplicate).
Concentration-dependent increases in IL-6 secretion were observed with
treatment with the EP-1 receptor agonist 17-phenyl trinor
PGE2 (P < 0.001 by ANOVA) and the EP-2/4
receptor agonist 11-deoxy-16,16-dimethyl- PGE2.
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Effect of 8-bromo-cAMP on IL-6
release.
Ligand binding and activation of the EP-2 or EP-4 receptor subtypes
resulted in the activation of adenylate cyclase and an increase in
intracellular cAMP. Therefore, 8-bromo-cAMP was added to cells to
determine if this cAMP analog was capable of inducing changes in IL-6
production. As demonstrated in Fig. 6,
the addition of 8-bromo-cAMP to cell cultures induced dose-related
increases in IL-6 release, suggesting that the PGE2
induction of IL-6 release was, at least in part, mediated via EP-2/4
receptor activation.

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Fig. 6.
Effect of 8-bromo-cAMP on IL-6 release from BEAS-2B
cells. Cells (n = 6 experimental points) were exposed
to 8-bromo-cAMP at indicated concentrations for 24 h. Cell-free
supernatant was assayed for IL-6. 8-Bromo-cAMP induced a dose-related
increase in IL-6 production. P < 0.001 by ANOVA.
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Detection of PGE2 receptor subtype
mRNAs.
Because a PGE2 receptor agonist with some specificity for
the EP-1 receptor and an agonist with some specificity for the EP-2 receptor caused an increase in epithelial cell release of IL-6, studies
were performed to determine whether these cells expressed mRNA for
these receptors. RT-PCR was performed on total cellular RNA from
BEAS-2B cells and, as controls, on total cellular RNA from HeLa cells
and RNAs from lung and kidney. As can be seen in Fig.
7, RT-PCR with primers specific for mRNA
for the EP-1 receptor subtype revealed an appropriately sized band of
RNA from BEAS-2B cells, from lung tissue, and from kidney tissue (Fig. 7A). Similarly RT-PCR with primers specific for the EP-2
receptor subtype produced an appropriately sized band of RNA from
BEAS-2B cells and from lung and kidney but not from HeLa cells (Fig.
7B). In addition, RT-PCR with primers specific for the EP-4
receptor subtype resulted in the production of an appropriately sized
band (Fig. 7C). Figure 7D presents the results of
RT-PCR for
-actin and demonstrates undegraded mRNA in all samples.
Therefore, BEAS-2B cells express mRNA for the EP-1, the EP-2, and the
EP-4 receptor subtypes.

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Fig. 7.
Detection of mRNA for PGE receptor subtypes by RT-PCR.
Total cellular mRNA from BEAS-2B cells, HeLa cells, and lung and kidney
was reverse transcribed. The resultant DNA was used as substrate.
Oligonucleotide probes for sequences of the coding sequence for EP-1,
EP-2, and EP-4 receptor subtypes were used for PCR (see MATERIALS
AND METHODS for details). Amplified DNA was separated on a
Tris-borate-EDTA polyacrylamide gel and visualized with SYBR Green I. A: results of PCR performed with the EP-1 primers to amplify
a 274-bp sequence of EP-1 cDNA. B: results of PCR performed
with EP-2 primers to amplify a 326-bp sequence of EP-2 cDNA.
C: results of PCR performed with EP-4 primers to amplify a
446-bp sequence of EP-4 cDNA. D: results of PCR with probes
specific for -actin to amplify an 838-bp sequence of -actin cDNA
(positive control).
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Effect of PGE2 on IL-6
mRNA levels.
PGE2 treatment of these airway epithelial cells resulted in
an increase in IL-6 production over a prolonged period of time. Therefore, experiments were performed to determine whether the PGE2 treatment resulted in an increase in the cellular
steady-state levels of IL-6 mRNA during this time. BEAS-2B cells were
stimulated with PGE2 (10
7 M) for 4 or 16 h. Total cellular RNA was extracted, and RPAs were performed. As
demonstrated in Fig. 8, PGE2
treatment increased the steady-state levels of IL-6 mRNA at both times,
suggesting that PGE2 modulates IL-6 gene expression and
therefore augments IL-6 protein synthesis in the BEAS-2B cells.

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Fig. 8.
Effect of PGE2 on IL-6 mRNA levels. BEAS-2B
cells were stimulated with PGE2 (10 7 M) for 4 or 16 h. Total cellular mRNA was extracted, and ribonuclease
protection assays (RPAs) were performed (see MATERIALS AND
METHODS). PGE2 treatment increased steady-state
levels of IL-6 mRNA at both time points. RPA for
glyceraldehyde-3-phosphate dehydrogenase (GAPDH) was performed as a
control. The RPA shown is representative of 3 different RPAs, each
demonstrating the same result.
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|
Therefore, PGE2 and, to a lesser degree,
PGF2
stimulation of airway epithelial cells result in an
increase in IL-6 synthesis and release by these cells.
 |
DISCUSSION |
The airway epithelium has the ability to synthesize or release a
variety of inflammatory mediators such as metabolites of arachidonic
acid, PAF, and cytokines as well as products that may downregulate the
inflammatory response, including eicosanoid metabolites, cytokine
receptor antagonists such as IL-1 receptor antagonist, and solubilized
cytokine receptors such as soluble TNF receptor (20, 22).
These inflammatory mediators can participate in modulating the local
inflammatory process in neighboring cells and tissues. Lipid mediators
present in the airway may be produced by resident airway cells and by
inflammatory cells resident in or recruited to the lung. Lipid
mediators such as PAF, LTB4, and PGE2 may
regulate cytokine expression in inflammatory cells such as alveolar
macrophages and peripheral blood mononuclear cells (33, 34,
37).
IL-6 is a multifunctional cytokine important in the production of
acute-phase proteins, the immune response to viruses and bacteria,
immunoglobulin production, the differentiation of T cells, and,
perhaps, for tissue regeneration as well as in a variety of endocrine
effects (10, 29, 32). In the airway and alveolar spaces,
IL-6 is produced by alveolar macrophages and airway epithelial cells
(11). In experimental animals, intratracheal
administration of IL-6 induces an infiltration of neutrophils into the
interstitial space and into the alveolar space (11).
Increased IL-6 has been demonstrated in bronchoalveolar lavage fluid
from patients with asthma (25). Furthermore,
increased IL-6 production has been reported in airway epithelial cells
from patients with asthma (24) and from alveolar
macrophages harvested in the setting of the late asthmatic reaction
(9).
In this study, we report that PGE2 treatment of a human
bronchial epithelial cell line increased the cellular production of IL-6 over a 2- to 24-h period and that this effect is associated with
an increase in steady-state levels of IL-6 mRNA. This effect was not
produced by treatment of cells with other lipid mediators such as PAF,
LTB4, and LTD4. Although PGE2 may
have anti-inflammatory properties including suppression of cellular
production of IL-1, inhibition of leukocyte migration, inhibition of
superoxide and LT release from polymorphonuclear leukocytes, and
inhibition of T lymphocyte proliferation (8),
PGE2 may have important proinflammatory effects as well.
These may include vasodilator properties and an increase in vascular
permeability in synergy with bradykinin and LTs. In an experimental
animal model, carrageenan-induced tissue inflammation, edema, and
hyperalgesia were prevented by the administration of an
anti-PGE2 antibody, and this treatment also reduced tissue
levels of IL-6, which suggests that PGE2 can contribute to
local inflammatory responses that have been initiated by exogenous
stimuli or inflammatory cell products (12, 30). Furthermore, PGE2 has been reported to stimulate IL-6
release from murine macrophages, murine and rat osteoblasts (17,
26), and human lymphocytes (HSB.2 cells) and astrocytoma cells
(7, 40). The IL-6 produced by BEAS-2B cells after
PGE2 stimulation is roughly similar to stimulated IL-6
production by other cells: 500 pg · ml
1 · 3 h
1 from rat
osteoblasts (26), 400-600
pg · ml
1 · 24 h
1 from mouse
osteoblasts (17), and 200-1,000
pg · ml
1 · 12 h
1 from human
lung fibroblasts stimulated by transforming growth factor-
(6).
PGE receptors are pharmacologically and molecularly characterized into
at least four subtypes (28). Each subtype may have distinct signal transduction pathways. The EP-1 receptor signals through activation of phosopholipase C. The EP-2 receptor signals via
activation of adenyl cyclase and increases in cAMP as does the subtype
designated EP-4 (1, 14, 27, 28). Activation of the EP-3
subtype signals via a reduction in cAMP (4, 28, 36). The
results of the EP receptor agonist studies and the effect of
8-bromo-cAMP on IL-6 release suggest that the effect of
PGE2 on IL-6 release from BEAS-2B cells may be mediated, at least in part, through an EP-2/4 receptor linked to adenylate cyclase.
Given the ability of cytokines, including IL-6, to activate
arachidonate metabolism in some tissues (5, 21), these
findings suggest that there is a complex regulatory network that may be significant in the modulation of inflammatory responses in the airway
mucosa and lumen. These pathways may have an important role in the
pathogenesis of inflammatory airway disorders.
 |
FOOTNOTES |
Address for reprint requests and other correspondence: J. H. Shelhamer, Bldg. 10, Rm. 7-D-43, Natl. Institutes of Health, Bethesda, MD 20892.
The costs of publication of this
article were defrayed in part by the
payment of page charges. The article
must therefore be hereby marked
"advertisement"
in accordance with 18 U.S.C. Section 1734 solely to indicate this fact.
Received 6 August 1999; accepted in final form 21 July 2000.
 |
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