Regulation of Th9-Type Pulmonary Immune Responses
A New Role for COX-2
Prostaglandins (PGs) are ubiquitous products of arachidonic
acid metabolism by the cyclooxygenase (COX) enzymes. Five
structurally and functionally distinct PGs (PGE2, PGF2, PGI2,
PGD2, and thromboxane A2) form in a cell- and tissue-specific
manner from the COX-derived precursor, PGH2, which is con-
verted to end products by specific terminal synthases (1). Each
PG is implicated in a broad range of homeostatic functions,
including thrombosis, maintenance of vascular tone and blood
flow, and repair of epithelial surfaces. Most have also been
implicated in inflammation; indeed, COX inhibitors are one of
the oldest and most successful target-based treatments for in-
flammatory diseases, and are still used widely to control pain,
fever, and swelling. These drugs also impair the synthesis of PGs
needed for homeostatic functions of PGs, likely accounting for
some of their unwanted side effects.
Although PGs play proinflammatory roles in most organ sys-
tems, their role in the lungs is largely protective and antiinflamma-
tory. The most obvious example in humans is the approximately
5–10% of asthmatic individuals who develop bronchoconstriction
with the administration of nonselective COX inhibitors (aspirin-
exacerbated respiratory disease) (2). These individuals exhibit
marked eosinophilic inflammation of the sinonasal and bronchial
mucosal surfaces, along with impaired expression of the COX-2
isoenzyme in their sinonasal mucosa (3). In mice, pharmacologic
inhibition of COX-1 and/or COX-2 or genetic deletion of either
enzyme results in enhanced eosinophilia and bronchovascular pa-
thology after allergen sensitization and challenge (4–6). More re-
cently, the use of mice with targeted deletions in specific PG
synthases and receptors for PGs has implicated separate roles
for PGE2and PGI2in regulating pulmonary immune responses
to allergen, as well as end-organ responsiveness to the inflamma-
tory state (7, 8). The broad distribution of receptors for these and
other PGs on cells of the innate and adaptive immune systems
suggests multiple potential immunologic targets and effects of
PGs, most of which have not been defined.
T cells that generate IL-9 and IL-10 (previously thought to be
Th2-type cytokines) (Figure 1) (9). Th9 cells develop from naive
T cells as a result of stimulation by IL-4 and transforming
growth factor b, and express the type B IL-17 receptor (IL-
17RB). The IL-17RB ligand, IL-25, amplifies the production
of IL-9 (a potent inducer of mast cell expansion and airway
reactivity) (10) by Th9 cells. In this issue of the Journal, Li
and colleagues (pp. 812–822) demonstrate a marked homeo-
static function for COX-2–derived PGE2and PGD2in the con-
trol of Th9 development in vitro and in vivo (11). Using
a traditional model of ovalbumin sensitization and challenge,
the authors demonstrate that mice lacking COX-2, but not
those lacking COX-1, display increased numbers of Th9 cells
in the blood, lung, bronchoalveolar lavage fluid, and lung-
draining lymph nodes relative to wild-type controls. The absence
of endogenous COX-2 in naive CD41T cells amplifies their ex-
pression of IL-9 and other Th9 lineage markers when polarized
under Th9-favoring conditions in vitro. Using a combination of
complementary approaches, the authors demonstrated that two
PGs, PGE2(acting at E prostanoid [EP]2and EP4receptors) and
PGD2(acting at D prostanoid [DP]2receptors) could suppress
Th9-cell development in vitro and in vivo by suppressing the
expression of the IL-17RB (Figure 1). Finally, they showed that
PGE2and PGD2suppressed Th9 development from naive hu-
man T cells in vitro.
The study by Li and colleagues demonstrates a completely
novel role for endogenous COX-2 products in regulating
T-helper cell polarization in vivo, and translates the findings in mice
to human cells. Given the implied role for IL-9 in several allergic
diseases, including asthma (12), atopic dermatitis (13), and food
allergy (14), the discovery that two COX products control Th9
development has exciting potential implications for pathobiology
and treatment of human disease. Inhaled PGE2blocks pulmo-
nary late-phase reactions in allergen-challenged atopic individu-
als (15) and aspirin-challenged subjects with aspirin-exacerbated
respiratory disease (16), and it is tempting to speculate that EP2
and EP4receptors on Th9 cells are among the targets responsible
for these effects. Like Th9 cells, the recently identified innate
helper cell type 2 (ILC2) population (which generates large quan-
tities of IL-5, IL-13, and, interestingly, IL-9 in allergic inflamma-
tion) requires expression of IL-17RB and the presence of IL-25,
and also expresses DP2receptors (17). Whether EP and/or DP
receptor signaling controls ILC2 functions by regulating IL-17RB
expression as it does in Th9 cells remains to be determined. Lastly,
the study further complicates the functions of PGD2, which is
either inductive (18) or suppressive (19) of allergen-induced pul-
monary inflammation depending on the model used and the recep-
tor involved. Understanding the full range of relevant receptors
and targets of PGs is a necessary step before the application of
targeted agonists and antagonists to human allergic disease.
Author disclosures are available with the text of this article at www.atsjournals.org.
Joshua A. Boyce, M.D.
Harvard Medical School
Division of Rheumatology, Immunology and Allergy
Brigham and Women’s Hospital
R. Stokes Peebles, M.D.
Division of Allergy, Pulmonary, and Critical Care Medicine
Vanderbilt University School of Medicine
1. Smyth EM, Grosser T, Wang M, Yu Y, FitzGerald GA. Prostanoids in
health and disease. J Lipid Res 2009;50:S423–S428.
2. Pleskow WW, Stevenson DD, Mathison DA, Simon RA, Schatz M,
Zeiger RS. Aspirin desensitization in aspirin-sensitive asthmatic patients:
clinical manifestations and characterization of the refractory period.
J Allergy Clin Immunol 1982;69:11–19.
3. Picado C, Fernandez-Morata JC, Juan M, Roca-Ferrer J, Fuentes M,
Xaubet A, Mullol J. Cyclooxygenase-2 mRNA is downexpressed in
nasal polyps from aspirin-sensitive asthmatics. Am J Respir Crit Care
Am J Respir Crit Care Med
Internet address: www.atsjournals.org
Vol 187, Iss. 8, pp 785–797, Apr 15, 2013
4. Peebles RS Jr, Dworski R, Collins RD, Jarzecka K, Mitchell DB, Graham Download full-text
BS, Sheller JR. Cyclooxygenase inhibition increases interleukin 5
and interleukin 13 production and airway hyperresponsiveness in
allergic mice. Am J Respir Crit Care Med 2000;162:676–681.
5. Peebles RS Jr, Hashimoto K, Morrow JD, Dworski R, Collins RD,
Hashimoto Y, Christman JW, Kang KH, Jarzecka K, Furlong J, et al.
Selective cyclooxygenase-1 and -2 inhibitors each increase allergic in-
flammation and airway hyperresponsiveness in mice. Am J Respir Crit
Care Med 2002;165:1154–1160.
6. Gavett SH, Madison SL, Chulada PC, Scarborough PE, Qu W, Boyle JE,
Tiano HF, Lee CA, Langenbach R, Roggli VL, et al. Allergic lung
responses are increased in prostaglandin H synthase-deficient mice.
J Clin Invest 1999;104:721–732.
7. Zhou W, Blackwell TS, Goleniewska K, O’Neal JF, FitzGerald GA,
Lucitt M, Breyer RM, Peebles RS Jr. Prostaglandin I2 analogs inhibit
Th1 and Th2 effector cytokine production by CD4 T cells. J Leukoc
8. Liu T, Laidlaw TM, Feng C, Xing W, Shen S, Milne GL, Boyce JA.
Prostaglandin E2 deficiency uncovers a dominant role for thrombox-
ane A2 in house dust mite-induced allergic pulmonary inflammation.
Proc Natl Acad Sci USA 2012;109:12692–12697.
9. Veldhoen M,Uyttenhove C, van Snick J, Helmby H, Westendorf A, Buer J,
Martin B, Wilhelm C, Stockinger B. Transforming growth factor-beta
‘reprograms’ the differentiation of T helper 2 cells and promotes an in-
terleukin 9-producing subset. Nat Immunol 2008;9:1341–1346.
10. Kearley J, Erjefalt JS, Andersson C, Benjamin E, Jones CP, Robichaud
A, Pegorier S, Brewah Y, Burwell TJ, Bjermer L, et al. IL-9 governs
allergen-induced mast cell numbers in the lung and chronic remod-
eling of the airways. Am J Respir Crit Care Med 2011;183:865–875.
11. Li H, Edin ML, Bradbury JA, Graves JP, DeGraff LM, Gruzdev A,
Cheng J, Dackor RT, Wang PM, Bortner CD, et al. Cyclooxygenase-2
inhibits T helper cell type 9 differentiation during allergic lung
inflammation via down-regulation of IL-17RB. Am J Respir Crit Care
12. Oh CK, Raible D, Geba GP, Molfino NA. Biology of the interleukin-9
pathway and its therapeutic potential for the treatment of asthma.
Inflamm Allergy Drug Targets 2011;10:180–186.
13. Ciprandi G, De Amici M, Giunta V, Marseglia A, Marseglia G. Serum
interleukin-9 levels are associated with clinical severity in children
with atopic dermatitis. Pediatr Dermatol 2012;30:222–225.
14. Xie J, Lotoski LC, Chooniedass R, Su RC, Simons FE, Liem J, Becker
AB, Uzonna J, HayGlass KT. Elevated antigen-driven IL-9 responses
are prominent in peanut allergic humans. PLoS ONE 2012;7:e45377.
15. Gauvreau GM, Watson RM, O’Byrne PM. Protective effects of inhaled
PGE2 on allergen-induced airway responses and airway inflammation.
Am J Respir Crit Care Med 1999;159:31–36.
16. Sestini P, Armetti L, Gambaro G, Pieroni MG, Refini RM, Sala A, Vaghi
A, Folco GC, Bianco S, Robuschi M. Inhaled PGE2 prevents aspirin-
induced bronchoconstriction and urinary LTE4 excretion in aspirin-
sensitive asthma. Am J Respir Crit Care Med 1996;153:572–575.
17. Mjosberg J, Bernink J, Golebski K, Karrich JJ, Peters CP, Blom B, Te
Velde AA, Fokkens WJ, van Drunen CM, Spits H. The transcription
factor GATA3 is essential for the function of human type 2 innate
lymphoid cells. Immunity 2012;37:649–659.
18. Uller L, Mathiesen JM, Alenmyr L, Korsgren M, Ulven T, Hogberg T,
Andersson G, Persson CG, Kostenis E. Antagonism of the prosta-
glandin D2 receptor CRTH2 attenuates asthma pathology in mouse
eosinophilic airway inflammation. Respir Res 2007;8:16.
19. Hammad H, Kool M, Soullie T, Narumiya S, Trottein F, Hoogsteden
HC, Lambrecht BN. Activation of the D prostanoid 1 receptor sup-
presses asthma by modulation of lung dendritic cell function and in-
duction of regulatory T cells. J Exp Med 2007;204:357–367.
Copyright ª 2013 by the American Thoracic Society
Bronchiectasis with Chronic Obstructive
Association or a Further Phenotype?
When reviewing articles for the Journal, one of the questions
asked is, “Should an editorial accompany this article?” and
a second, “If so, would you be willing to write it?” In general
my response is no, but occasionally an article allows a moment’s
reflection or in some cases (with age) a 35-year reflection. If you
look up Chronic Obstructive Pulmonary Disease (COPD) on
PubMed, there are 110 papers identified for 1975. By 1995, it
had risen to 433, and by 2012 to 3,196 (Figure 1), and ECLIPSE
Figure 1. Naive CD4 cells differentiate into Th9 cells when
activated in the presence of TGF-b and IL-4. (A) Th9 cells
produce IL-9. (B) IL-25, signaling through its heterodi-
meric receptor consisting of IL-17 receptor type A (IL-
17RA) and IL-17RB, augments IL-9 production by Th9
cells. (C) Prostaglandin D2(PGD2) and PGE2produced
by the COX-2 pathway of arachidonic acid metabolism
inhibit expression of IL-17RB, thus preventing the IL-25–
driven augmentation of IL-9 protein expression by Th9
cells. COX ¼ cyclooxygenase; TGF-b ¼ transforming growth
786AMERICAN JOURNAL OF RESPIRATORY AND CRITICAL CARE MEDICINE VOL 1872013