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Medical Specialities, Southampton General Hospital, Southampton, United Kingdom
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Abstract |
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 Top Abstract IntroductionMaterials and MethodsResultsDiscussionReferences |
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Introduction |
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TopAbstractIntroductionMaterials and MethodsResultsDiscussionReferences |
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and
provide protection against intracellular pathogens and viruses. Th2
cells, characterized by their secretion of IL-4, IL-5, and IL-13,
facilitate IgE production and eosinophilic inflammation, which
contribute to the elimination of extracellular parasites and the
pathogenesis of allergic disease such as asthma (2, 3, 4).
Allergic asthma is a chronic inflammatory disorder in which a type 2
response by CD4+ T cells in the airways takes
primacy in driving the inflammation (2, 3, 4). It has been
suggested that such chronic inflammation arises from the dysfunction of
events that normally lead to the resolution of the underlying T cell
response. T cells at mucosal sites are subject to immune regulation,
partly due to the actions of cyclooxygenase
(COX)4-derived
prostanoids (5) and cytokines such as IL-10 and TGF-
(6, 7). In addition, CD4+
CD25+ regulatory T cells that produce IL-10 have been shown
to suppress mucosal immune responses (6, 8). The events
that limit allergic Th2 responses in the lung are unclear, and
conceivably there are distinct mechanisms that differentially regulate
Th1 and Th2 effector functions. To this end we have used a mouse model
of T cell-mediated airway inflammation (9) to assess the
role of prostanoids in influencing T cell responses in the lung mucosa
following Ag inhalation.
Prostanoids are products of arachidonic acid metabolism synthesized via
the cyclooxygenase (COX4) pathway. The two
isoforms of this enzyme, COX-1 and COX-2, metabolize arachidonic acid
to PGH2, which is subsequently processed by
specific enzymes to generate a series of products, most notably
PGD2, PGE2,
PGF2
, prostacyclin
(PGI2), and thromboxanes (Tx). COX-1 is
constitutively expressed in most cell types, and is the predominant
form present in the gastrointestinal tract, kidney, and platelets
(10, 11, 12). COX-2 is an enzyme expressed at inflammatory
sites by macrophages, neutrophils, and activated mesenchymal cells and
is believed to produce prostanoids that contribute to inflammatory
swelling, pain, and fever (10, 11, 12). Nonsteroidal
anti-inflammatory drugs (NSAIDs), such as aspirin and indomethacin,
are nonselective COX inhibitors and suppress these inflammatory
processes. The inhibition of COX-1, however, underlies the
gastrointestinal toxicity of NSAIDs in humans, and this has prompted
the development of COX-2-selective inhibitors such as NS-398 and
celecoxib, which circumvent such damaging effects (13).
The spectrum of prostanoids elicited by COX-2 differs from that
synthesized by COX-1. Specifically, COX-2 is thought to be important
for the production of PGE2 and
PGI2 (14).
PGI2 has anti-thrombotic effects in vivo and
plays an important role in inflammation and pain perception
(15). Despite these potent actions, the effects of
PGI2 appear to be very localized, since the
prostanoid is highly unstable, with t1/2 of
30 s under physiological conditions (10).
Using DO11.10 mice, we have developed a model of T cell-mediated pulmonary inflammation to examine the role of PGs in influencing allergic airway responses. Our results show that selective inhibition of COX-2 in vivo specifically reduced PGI2 levels in the lung and led to a significant elevation in local Th2 inflammatory responses to inhaled OVA. Consistent with this observation, we found that the mRNA for the PGI2 receptor IP-R was expressed by Th2, but not Th1, cells, and transcripts for the IP-R were induced by IL-4 and OVA peptide stimulation. PGI2 acted on Th2 cells to elevate production of the anti-inflammatory cytokine, IL-10. Collectively, our findings demonstrate that PGI2 plays an important role in preferentially limiting lung mucosal Th2 responses by promoting IL-10 production at the site of allergic inflammation.
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Materials and Methods |
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TopAbstractIntroductionMaterials and MethodsResultsDiscussionReferences |
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DO11.10 mice (originally developed by Dr. D. Y. Loh, Howard Hughes Medical Institute, St. Louis, MO) were bred under aseptic conditions in a barrier facility at Southampton University. These animals were provided by Dr. E. Shevach (National Institutes of Health, Bethesda, MD). BALB/c mice were obtained from Harlan (Loughborough, U.K.).
Adoptive transfer of DO11.10 T cells and OVA challenge of recipient animals
DO11.10 Th1 or Th2 cells were adoptively transferred into BALB/c
mice before exposure to OVA aerosols. To drive T cell differentiation
into a Th1 or Th2 effector phenotype, peripheral lymph node (PLN) cells
were incubated (5 x 105/ml) in the presence
of OVA323–339 peptide (1 µg/ml), and either
mouse IL-12 (1 ng/ml; R&D Systems, Abingdon, U.K.) and anti-IL-4 Ab
(5 µg/ml 11B11; American Type Culture Collection, Manassas, VA), or
murine IL-4 (2 ng/ml; R&D Systems) and anti-IFN- Ab (5 µg/ml;
R4-6A2; American Type Culture Collection), respectively. After 4 days
of culture, cells were restimulated as previously, but in the presence
of IL-2 (100 U/ml; Cetus, Emeryville, CA). Cells were routinely
depleted of both CD8+ T cells (using YTS169.4;
Serotec, Oxford, U.K.) and APC (using anti-class II Ab M5/114;
American Type Culture Collection) by panning before injection. On day
8, polarized effector CD4+ cells were injected
i.v. into BALB/c mice (107/mouse). Mice were
intranasally challenged by exposure to aerosolized solutions of either
PBS or OVA (grade V; Sigma, Poole, U.K.) for 20 min/day over 6
consecutive days using a Wright’s nebulizer. Mice were killed on day
7, and bronchoalveolar lavage (BAL) fluid (BALF) was collected for
analysis. Experimental groups comprised animals (four per group)
treated daily (over the duration of aerosol challenge) with the
COX-2-specific inhibitor NS-398 (10 mg/kg daily, i.p. injection every
8 h; Calbiochem, Nottingham, U.K.), the nonselective COX inhibitor
indomethacin (INDO; a daily i.p. injection of 5 mg/kg; Sigma), and a
control group not treated with NSAIDS (vehicle-treated only). Identical
data were produced from control mice regardless of whether these
animals were exposed to aerosolized PBS, not exposed to any aerosol, or
treated with NSAIDS alone. Airway hyperreactivity (AHR) was measured in
response to methacholine inhalation by whole-body plethysmography
(Buxco Europe, Petersfield, U.K.). Animals were placed in chambers and
exposed to aerosols of PBS (baseline), followed by increasing
concentrations of methacholine. The enhanced pause (Penh) was measured
after each 3-min exposure. Values were taken from the highest average
over a 1-min period. For preparation of tissue for histopathologic
analysis, lung tissue was fixed in formalin and embedded in paraffin.
Tissue sections were prepared and stained with H&E.
Level of airway inflammation
BAL was performed by cannulating the trachea of each animal and
washing the airways with 0.5 ml PBS to collect BALF. BALF from three or
four animals were pooled, and eosinophil peroxide (EPO) levels present
in BAL cells or BALF (soluble EPO) were determined by colorimetric
analysis as previously described (9). Cell differential
percentages were determined by light microscopic evaluation of cytospin
preparations and expressed as absolute cell numbers. Levels of IL-4,
IL-5, IL-10, IL-13, and IFN- in the BALF were measured using
sensitive commercially available ELISA kits (all from BioSource,
Camarillo, CA; except IL-4 from R&D Systems), according to the
manufacturer’s instructions. To measure mucus production in the
airways, the amount of mucin in the BAL fluid (from Th2 recipients
exposed to OVA aerosols that were treated with NS-398 or from untreated
controls) was determined by ELISA using the mucin-binding lectin
jacalin (Calbiochem, Nottingham, U.K.) as described previously
(16). Values were expressed as the percent increase in
measurements obtained from untreated control groups.
Level of prostanoid synthesis in the BALF
Levels of PGE2,
PGD2, TxA2, and
PGF2 in the BALF were measured by sensitive
commercial enzyme immunoassay kits (all from Cayman Chemical, Ann
Arbor, MI; except PGE2 kits supplied by R&D
Systems) according to the manufacturer’s instructions. For
determination of PGI2 synthesis, the
concentration of the stable metabolite of prostacyclin,
6-keto-PGF1, was measured using an immunoassay
kit (R&D Systems).
In vitro effect of prostanoids on cytokine production by Th1 and Th2 cells
PLN cells were stimulated with OVA peptide (1 µg/ml) and
either IL-4 (2 ng/ml) or IL-12 (1 ng/ml) to polarize Th2 or Th1 cells,
as described above. Either PGI2 (5 µM/ml daily;
Cayman) or its stable analog carbaprostacyclin (0.5 µM/ml; Cayman)
was added to the cultures together with indomethacin (2 µg/ml), which
was used to inhibit all endogenous prostanoid biosynthesis. After 8
days cells were harvested and restimulated with anti-CD3 (2
µg/ml) for 48 h, and the supernatant was analyzed for IL-4,
IL-5, IL-10, and IFN- production by ELISA, as described previously
(9). For IL-10 measurement JES5-2A5 (BD PharMingen, San
Diego, CA) was used as capture Ab, and biotinylated polyclonal
anti-IL-10 Ab was used for detection (PeproTech, Rockyhill, NJ).
Cells were routinely depleted of CD8+ (using
YTS169.4) and class II+ cells (using M5/114) by
panning before in vitro analysis. Flow cytometry was used to determine
the purity of CD4+ T cells, which was >95%.
Real-time RT-PCR
Using the TRIzol technique (9), RNA was extracted
from purified CD4+ T cells obtained from 8-day
polarized Th1 and Th2 cells or from PLN cells before (naive) and after
culture for 3 days with type 2 cytokines (2 ng/ml; except IL-10, 10
ng/ml) or specific Abs (5 µg/ml 11B11 (anti-IL-4) or 5 µg/ml
anti-IL-13). Total RNA (2 µg) was then reverse transcribed using
Omniscript II (Qiagen, Crawley, U.K.) at 37°C for 1 h using
oligo(dT)15 as a primer, and the cDNA was PCR
amplified and quantified using the TaqMan technique.
Real-time detection of PCR was performed using the Perkin-Elmer AB1
PRISM 7700 Sequence Detection System (PE Applied Biosystems,
Warrington, U.K.). The expressions of IP-R (using forward primer,
5'-TTTTCCGAAAGGCTGTCTTCC-3'; reverse primer,
5'-ATCCCCATGGACAGAACGG-3'; and FAM-TAMRA probe,
5'-ACGCCTCAAGTTCTGG TTGTGTTGCC-3'), GAPDH (housekeeping gene),
IL-4, IL-5, and IFN- were determined in this way (for sequences, see
Ref. 17). Equal amounts of cDNA were used in triplicate
and amplified with the TaqMan master mix according to the
manufacturer’s instructions (PE Applied Biosystems). Thermal cycling
conditions were 2 min at 50°C and 10 min at 95°C, followed by 40
cycles of two-step PCR consisting of 15 s at 95°C and 1 min at
60°C. The threshold cycle was measured as the cycle number at which
the reporter fluorescent emission increased above the threshold level.
The amount of mRNA was expressed as the fold difference relative to the
amount obtained from unstimulated control cells. Amplification
efficiencies were validated and normalized against GAPDH. For all
samples, total RNA that was not reverse transcribed was also analyzed
to determine genomic DNA contamination, which was negligible.
Statistical analysis
Cell number and cytokine and prostanoid levels in the BALF of Th1 and Th2 recipient mice before and after Ag inhalation or treatment with COX inhibitors were compared using the Wilcoxon test for paired data or the Mann-Whitney test. Values of p < 0.05 were accepted as statistically significant.
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Results |
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TopAbstractIntroductionMaterials and MethodsResultsDiscussionReferences |
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We have used a murine model of pulmonary inflammation to
investigate whether prostanoids influence lung mucosal Th2 responses.
DO11.10 CD4+ Th1 or Th2 effector cells, which
constitutively express a TCR specific for an
OVA323–339 peptide, were adoptively transferred
(107 cells/mouse) into BALB/c mice, which were
then exposed to aerosolized OVA for 6 consecutive days. Histological
examination of lungs from Th2 recipient mice exposed to OVA aerosols
displayed marked peribronchiolar and perivascular eosinophilic
inflammation (Fig. 1
A).
Treatment of mice with the COX-2-selective inhibitor, NS-398, resulted
in a dramatic increase in pulmonary eosinophilic inflammation. Analysis
of BALF also revealed that following Ag inhalation, recipients of Th2
cells developed pronounced inflammation in the airways, with a marked
infiltration by eosinophils and lymphocytes (Fig. 1B).
However, no infiltration was observed in control mice not exposed to
OVA aerosols. Treatment of recipient mice with NS-398 or indomethacin
(the latter of which blocks both COX-1 and COX-2) markedly augmented
the intensity of the eosinophilia (Fig. 1B). In contrast,
Th1 recipients developed an airway neutrophilia that was not
significantly affected by treatment with NS-398 or indomethacin (Fig. 1C). A striking increase in the total number of eosinophils
was reflected by elevated levels of cell-associated EPO activity in the
BALF of NS-398- and indomethacin-treated animals (Fig. 1D).
Soluble EPO activity was also increased in the BALF from treated mice,
suggesting that not only does COX inhibition augment eosinophil numbers
in the airways, but it may also facilitate their activation and
subsequent release of mediators. In addition, NS-398 treatment of Th2
recipients resulted in an increase in the amount of mucus present in
the BALF (41% rise compared with mucus production by untreated mice).
The number of macrophages in the BALF of Th1 and Th2 recipients was
unchanged following OVA inhalation or treatment with the inhibitors
(data not shown). Exposure of Th2 recipients to OVA aerosols resulted
in AHR, as measured by exaggerated increases in Penh in response to
inhaled methacholine. Coincident with the increase in inflammation,
NS-398 treatment of Th2 recipients resulted in enhanced AHR (Fig. 1E).
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,
PGD2 (Fig. 3), and
TxB2, but negligible amounts of the stable
metabolite of PGI2,
6-keto-PGF1 (Fig. 3). The levels of these
prostanoids, particularly the PGI2 metabolite,
were markedly increased following OVA inhalation. Treatment of Th1 and
Th2 recipient mice with NS-398 inhibited production of the metabolite
of PGI2 (54.2 and 52.9% inhibition,
respectively), but did not affect the levels of other prostanoids (Fig. 3). However, indomethacin (which irreversibly inactivates both COX-1
and COX-2) blocked the biosynthesis of all prostanoids examined. These
results demonstrate that in the lung, NS-398 treatment selectively
inhibits PGI2 synthesis, in contrast to
indomethacin, which blocked all prostanoid production. Consequently,
the increase in airway eosinophilia and Th2 cytokines induced by NS-398
treatment was associated with a reduction in PGI2
synthesis.
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Since a reduction of PGI2 production is
associated with an increase in lung Th2 inflammation, but does not
influence Th1 responses, we next determined whether there was
differential expression of IP-R on Th1 vs Th2 cells. Using real-time
RT-PCR, the expression of IP-R mRNA was found to be restricted to
CD4+ Th2, but not Th1, cells (Fig. 4A). IP-R mRNA was not
expressed by naive (unstimulated) CD4+ T cells
purified from PLN cells or by whole PLN cells that had not been
polarized. In contrast, the P815 (mastocytoma) cell line, which was
analyzed for comparison, constitutively expressed this receptor (Fig. 4A). Both polarized Th1 and Th2 cells expressed mRNA for the
appropriate cytokines (Th1 cells expressed IFN-, whereas Th2 cells
expressed IL-4 and IL-5 mRNA), confirming their effector phenotype
(Fig. 4B). To identify whether the expression of the
receptor was regulated by cytokines, PLN cells from DO11.10 mice were
stimulated for 3 days with OVA peptide in the presence of Th2 cytokines
IL-4, IL-5, IL-6, IL-9, IL-10, and IL-13. IP-R mRNA expression by
CD4+ T cells was evoked in the presence of IL-4
only (Fig. 4C). IL-4 was unique in this respect, as although
IL-13 marginally increased this expression, the effect was lost on the
inclusion of a neutralizing Ab to IL-4. Moreover, basal expression of
the IP-R mRNA was lost when anti-IL-4 (Fig. 4C), but not
anti-IL-13, Ab was added to the cultures.
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). In
contrast, the prostanoid and its analog did not affect the levels of
IL-4 and IL-5 produced by Th2 cells or of IFN- by Th1 cells (Fig. 5). Indeed, in the absence of indomethacin in the culture, Th2 cells
produced high levels of IL-10 compared with cells cultured in the
presence of indomethacin, which inhibits PGI2
production (data not shown). This implies that endogenous
PGI2 synthesis plays an important role in
elevating IL-10 production by Th2 cells.
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), which is consistent with the
elevated inflammatory response. In marked contrast, the amount of IL-10
present in the BALF was markedly reduced following treatment with
NS-398 (Fig. 6). The reciprocal
relationship between IL-10 levels and the Th2 cytokines in the airways
is consistent with the possibility that the actions of the
COX-2-specific inhibitor are mediated at least in part by modulating
IL-10 production. Only negligible amounts of IL-10 were present in the
BALF from mice that received Th1 cells.
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Discussion |
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TopAbstractIntroductionMaterials and MethodsResultsDiscussionReferences |
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, IL-10, and prostanoids produced locally (5, 6, 7).
Whether the nature of such regulatory mechanisms changes following the
onset of an inflammatory response remains unclear. It is possible that
distinct mechanisms may serve to differentially regulate Th1 and Th2
effector function. In addition, a role for IL-12 and IFN- has been
proposed in limiting pulmonary Th2 responses (18).
However, IL-12 is most effective during the early stages of T cell
polarization, since polarized Th2 effector cells do not express the
2-chain of the IL-12R. We propose that
specific mechanisms exist by which COX-2-derived mediators, generated
during allergic inflammation, inhibit the responses of
CD4+ Th2 cells. During an inflammatory response multiple prostanoids are generated from the oxidative metabolism of arachidonic acid by COX-1 and COX-2 that act on a range of cell types (11, 12). It has been previously proposed that COX-2 plays an important role in limiting inflammatory processes (5, 19). The inhibition of COX-2 is known to augment proliferative responses in the intestine to dietary Ag (5). This may result from COX-2 facilitating the synthesis of anti-inflammatory cyclopentenone PGs, which are thought to play a role in the resolution of inflammation (19).
Using a mouse model of pulmonary inflammation, we have shown that
following OVA inhalation, animals that received Th2 DO11.10 cells
developed pronounced airway inflammation with infiltration of
eosinophils and lymphocytes, whereas recipients of Th1 cells developed
pulmonary neutrophilia. Treatment with NS-398, a COX-2-selective
inhibitor, markedly augmented the intensity of the eosinophilia and AHR
in the Th2 recipient mice, but did not affect the level of
inflammation in the Th1 recipients. Consistently, IL-4, IL-5, and IL-13
production was elevated in the airways of Th2 recipients following
treatment with a COX-2 inhibitor. We found that the BALF of
resting animals contained significant amounts of prostanoids, including
PGF2, PGE2,
PGD2, and TxB2, which are
thought to play an important role in maintaining homeostasis. Before
OVA inhalation the BALF contained negligible levels of the stable
metabolite of PGI2. However, the concentration of
this prostanoid was markedly elevated in Th1 and Th2 recipient mice
following Ag inhalation. The inhibition of COX-2 by NS-398 treatment
resulted in a selective reduction in PGI2
synthesis in the airways. Although the levels of other prostanoids were
also increased following challenge, their synthesis was not affected by
the COX-2 inhibitor. This implies that COX-1 is responsible for the
majority of PGs present in the BALF, which is in agreement with
previous observations using COX-1- and COX-2-deficient mice
(20). Moreover, the selective inhibition of
PGI2 synthesis by NS-398 in the lung is in
accordance with recent reports that treatment of healthy
individuals with a COX-2-specific inhibitor resulted in marked
reduction of systemic prostacyclin biosynthesis (21) and
that the production of PGI2 by activated
macrophages is COX-2 dependent (14).
In the present study the increase in airway Th2, but not Th1, inflammation following treatment with the COX-2 inhibitor was invariably associated with a reduction in PGI2 synthesis. This suggests that COX-2-specific generation of PGI2 may form a mechanism by which inflammatory processes in the lung limit the underlying Th2, but not Th1, responses. Consistent with this observation, the PGI2 receptor mRNA was found to be expressed by CD4+ Th2, but not by Th1 cells or unstimulated T cells. Moreover, IP-R mRNA was induced in these T cells by IL-4 following OVA stimulation. No other Th2 cytokine was effective at inducing IP-R mRNA transcripts. The rapid induction of the IP-R mRNA by IL-4 suggests that this is a direct effect of the cytokine, rather than a consequence of the Th2 polarization process. These observations extend the functional attributes of IL-4 and highlight this cytokine not only as essential for the differentiation of CD4+ Th2 cells, but also in promoting a mechanism that limits the progression of allergic inflammation. Although it is well documented that the IP-R is abundantly expressed on platelets and medullary thymocytes (22, 23), this is the first demonstration that activated T cells express this receptor. Collectively these findings suggest that PGI2 plays an important immunoregulatory function by limiting lung mucosal Th2, but not Th1, responses.
We found that in vitro PGI2 evoked a marked
increase in the production of IL-10 by Th2 cells, but did not affect
IL-4 and IL-5 levels or the production of IFN- by Th1 cells.
Conversely, treatment of mice with the COX-2-specific inhibitor reduced
IL-10 production in the airways of Th2 recipients. It is likely that
the Th2 cells were the source of IL-10, as this cytokine was not
detected in the BALF of Th1 recipients. Since the expression of IL-10
is increased by agents that raise cAMP levels (24), it is
possible that this is the mode by which the IP-R mediates its
anti-inflammatory effects. In this context both
PGI2 and PGE2 have been
shown to elevate IL-10 production by murine peritoneal macrophages
(25). IL-10 is known to exert multiple immunosuppressive
effects, including inhibition of eosinophil migration, decreased CD80
expression and IL-5 production, and the consequent reduction
in pulmonary eosinophilic inflammation (26, 27). As such,
PGI2 provides a negative feedback mechanism that
limits the severity of the Th2-mediated inflammatory response. This
form of immune regulation may act solely via IL-10 or in combination
with a direct effect of PGI2 on Th2 function in
vivo, for example, by inhibiting T cell chemotaxis. Certainly, other
prostanoids, such as PGE2, have been shown to
exert multiple immunomodulatory effects on T cells, including
inhibition of T cell proliferation, chemotaxis, and Fas-mediated
apoptosis (28, 29, 30). The source of
PGI2 in the lungs of OVA-challenged animals is
unclear; however, endothelial cells and macrophages are known to
produce large amounts of the prostanoid (31, 32). Since
PGI2 is highly labile, its immunomodulatory
action is likely to be restricted to the site of inflammation.
PGE2 synthesis at tissue sites is thought to favor the development of Th2 responses by inhibiting IL-12 production by dendritic cells (33). Our data extend this observation, and we propose that local prostanoid production strongly influences the subsequent progression of the T cell response (i.e., whether a Th1 or Th2 response is favored). Although we found that PGI2 is produced during both Th1- and Th2-mediated lung inflammation, the IL-4-dependent nature of the IP-R expression on T cells implies that the immunomodulatory action of this prostanoid is limited to a Th2 inflammatory response. PGI2, by acting on Th2 cells activated in the presence of IL-4, would serve to limit the Th2 response. It is possible that such regulatory mechanisms are not restricted to allergic inflammation. For example, infection with the filarial helminth Brugia malayi typically elicits a potent Th2-type host immune response. This response is followed by the development of a profound T cell hyporesponsiveness whose onset is dependent on IL-4 generated by the host (34). Interestingly, the filarial parasite is also capable of using arachidonic acid to generate both PGI2 and PGE2 (35). Conceivably, the immune evasion displayed by this parasite may involve the cooperation of IL-4 and COX-derived prostanoids to elicit immune regulation.
COX-2-specific inhibitors are a new class of drugs that have the same anti-inflammatory and analgesic properties as aspirin and reduce inflammation without affecting the housekeeping function of the COX-1 products (11). In 10–15% of patients with asthma the ingestion of aspirin precipitates a life-threatening exacerbation of the disease. Such aspirin intolerance is associated with the release of cysteinyl leukotrienes that mediate the bronchial obstruction (36). It has been proposed that drugs that selectively inhibit COX-2, such as celexocib and rofexocib, may be used safely by aspirin-intolerant asthmatics (37); however, the effect of administering these drugs to other cohorts of asthmatics has not been examined. Moreover, it has recently been reported that treatment with celecoxib has been associated with the onset of fatal allergic vasculitis (38). Our data imply that during chronic allergic inflammation in the lung, inhibition of COX-2 increases the inflammatory reaction by ablating the immunoregulatory effects of PGI2. These findings thus highlight a potential risk in the use of COX-specific inhibitors by allergic asthmatics. Alternatively, a defect in this novel form of immune regulation may contribute to the chronic inflammation evident in this disease.
In summary, our observations reveal a key role for PGI2 in regulating allergic responses in the lung mucosa, possibly by acting on Th2 cells to promote IL-10 production. This study provides important insight into the regulatory processes that limit the severity of Th2-mediated inflammatory reactions. There is increasing evidence that PGs are important modulators of immunity (30), and thus a better understanding of the multifarious activities of these mediators is crucial for the design of novel approaches aimed at immune intervention/modulation.
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Acknowledgments |
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Footnotes |
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2 Z.J. and K.-S.W. contributed equally to this study.
3 Address correspondence and reprint requests to Dr. Kevan Roberts, Medical Specialties (Mailpoint 810), Level D, Center Block, Southampton General Hospital, Southampton, U.K. SO16 6YD. E-mail address: kroberts{at}soton.ac.uk
4 Abbreviations used in this paper: COX, cyclooxygenase; AHR, airway hyperreactivity; BALF, bronchoalveolar lavage fluid; EPO, eosinophil peroxidase; INDO, indomethacin; IP-R, PGI2 receptor; Penh, enhanced pause; NSAIDS, nonsteroidal anti-inflammatory drugs; PGI2, prostacyclin; PLN, peripheral lymph node; Tx, thromboxane.
Received for publication June 14, 2002. Accepted for publication September 16, 2002.
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References |
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TopAbstractIntroductionMaterials and MethodsResultsDiscussionReferences |
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but not 
T cells. J. Immunol. 163:6283. and IL-10 production by prostaglandins I2 and E2: studies with prostaglandin receptor-deficient mice and prostaglandin E-receptor subtype-selective synthetic agonists. Biochem. Pharmacol. 61:1153.[Medline]
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W. Zhou, K. Hashimoto, K. Goleniewska, J. F. O'Neal, S. Ji, T. S. Blackwell, G. A. FitzGerald, K. M. Egan, M. W. Geraci, and R. S. Peebles Jr. Prostaglandin I2 Analogs Inhibit Proinflammatory Cytokine Production and T Cell Stimulatory Function of Dendritic Cells J. Immunol., January 15, 2007; 178(2): 702 - 710. [Abstract] [Full Text] [PDF]
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G. Y. Park and J. W. Christman Involvement of cyclooxygenase-2 and prostaglandins in the molecular pathogenesis of inflammatory lung diseases Am J Physiol Lung Cell Mol Physiol, May 1, 2006; 290(5): L797 - L805. [Abstract] [Full Text] [PDF]
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R. S. Peebles Jr, K. Hashimoto, J. R. Sheller, M. L. Moore, J. D. Morrow, S. Ji, J. A. Elias, K. Goleniewska, J. O'Neal, D. B. Mitchell, et al. Allergen-Induced Airway Hyperresponsiveness Mediated by Cyclooxygenase Inhibition Is Not Dependent on 5-Lipoxygenase or IL-5, but Is IL-13 Dependent J. Immunol., December 15, 2005; 175(12): 8253 - 8259. [Abstract] [Full Text] [PDF]
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 M. Joo, Y. S. Hahn, M. Kwon, R. T. Sadikot, T. S. Blackwell, and J. W. Christman Hepatitis C Virus Core Protein Suppresses NF-{kappa}B Activation and Cyclooxygenase-2 Expression by Direct Interaction with I{kappa}B Kinase {beta} J. Virol., June 15, 2005; 79(12): 7648 - 7657. [Abstract] [Full Text] [PDF]
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K. Hashimoto, B. S. Graham, M. W. Geraci, G. A. FitzGerald, K. Egan, W. Zhou, K. Goleniewska, J. F. O'Neal, J. D. Morrow, R. K. Durbin, et al. Signaling through the Prostaglandin I2 Receptor IP Protects against Respiratory Syncytial Virus-Induced Illness J. Virol., October 1, 2004; 78(19): 10303 - 10309. [Abstract] [Full Text] [PDF]
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V. Angeli, D. Staumont, A.-S. Charbonnier, H. Hammad, P. Gosset, M. Pichavant, B. N. Lambrecht, M. Capron, D. Dombrowicz, and F. Trottein Activation of the D Prostanoid Receptor 1 Regulates Immune and Skin Allergic Responses J. Immunol., March 15, 2004; 172(6): 3822 - 3829. [Abstract] [Full Text] [PDF]
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Z. Jaffar, T. Sivakuru, and K. Roberts CD4+CD25+ T Cells Regulate Airway Eosinophilic Inflammation by Modulating the Th2 Cell Phenotype J. Immunol., March 15, 2004; 172(6): 3842 - 3849. [Abstract] [Full Text] [PDF]
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 K. Nagao, H. Tanaka, M. Komai, T. Masuda, S. Narumiya, and H. Nagai Role of Prostaglandin I2 in Airway Remodeling Induced by Repeated Allergen Challenge in Mice Am. J. Respir. Cell Mol. Biol., September 1, 2003; 29(3): 314 - 320. [Abstract] [Full Text] [PDF]
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