Thymic stromal lymphopoietin (TSLP), an interleukin 7-like cytokine, can trigger dendritic cell (DC)-mediated T-helper type 2 (Th2) inflammatory responses. Recent evidence demonstrates that cytokines TSLP and OX40 (CD134)/OX40 ligand seem to be important players in the maintenance of Th2 memory pool in the pathogenesis of asthma. Accumulating data reveal that the pathogenic T cells involved in asthma are likely to be inflammatory Th2 cells. TSLP is involved in the development of asthma through crosstalk with nuclear factor NF-ĸB. Progression of skin fibrosis in atopic dermatitis occurs via TSLP/TSLP receptor. TSLP-mediated dermal inflammation aggravates experimental allergic asthma. Also, TSLP polymorphisms are associated with susceptibility to asthma, atopic dermatitis, and eczema herpeticum. These findings suggest a master switch of TSLP in the initiation of allergic and adaptive inflammation through innate pathways at the epithelial cell-DC interface. The TSLP pathway is therefore a promising target for immunotherapy of allergic diseases.

Keywords:
Allergy, Asthma, Dendritic cells, Inflammatory Th2 cells, NF-ĸB, Regulatory T cells, Thymic stromal lymphopoietin
1.
Liu YJ, Soumelis V, Watanabe N, Ito T, Wang YH, Malefyt Rde W, Omori M, Zhou B, Ziegler SF: TSLP: an epithelial cell cytokine that regulates T cell differentiation by conditioning dendritic cell maturation. Annu Rev Immunol 2007;5:193–219.
2.
Zhou LF, Zhu Y, Cui XF, Xie WP, Hu AH, Yin KS: Arsenic trioxide, a potent inhibitor of NF-ĸB, abrogates allergen-induced airway hyper-responsiveness and inflammation. Respir Res 2006;7:146.
3.
Sims JE, Williams DE, Morrissey PJ, Garka K, Foxworthe D, Price V, Friend SL, Farr A, Bedell MA, Jenkins NA, Copeland NG, Grabstein K, Paxton RJ: Molecular cloning and biological characterization of a novel murine lymphoid growth factor. J Exp Med 2000;192:671–680.
4.
He R, Geha RS: Thymic stromal lymphopoietin. Ann NY Acad Sci 2010;1183:13–24.
5.
Ziegler SF: The role of thymic stromal lymphopoietin (TSLP) in allergic disorders. Curr Opin Immunol 2010;22:795–799.
6.
Kashyap M, Rochman Y, Spolski R, Samsel L, Leonard WJ: Thymic stromal lymphopoietin is produced by dendritic cells. J Immunol 2011;187:1207–1211.
7.
Reche PA, Soumelis V, Gorman DM, Clifford T, Liu Mr, Travis M, Zurawski SM, Johnston J, Liu YJ, Spits H, de Waal Malefyt R, Kastelein RA, Bazan JF: Human thymic stromal lymphopoietin preferentially stimulates myeloid cells. J Immunol 2001;167:336–343.
8.
Quentmeier H, Drexler HG, Fleckenstein D, Zaborski M, Armstrong A, Sims JE, Lyman SD: Cloning of human thymic stromal lymphopoietin (TSLP) and signaling mechanisms leading to proliferation. Leukemia 2001;15:1286–1292.
9.
Park LS, Martin U, Garka K, Gliniak B, Di Santo JP, Muller W, Largaespada DA, Copeland NG, Jenkins NA, Farr AG, Ziegler SF, Morrissey PJ, Paxton R, Sims JE: Cloning of the murine thymic stromal lymphopoietin (TSLP) receptor: formation of a functional heteromeric complex requires interleukin 7 receptor. J Exp Med 2000;192:659–670.
10.
Pandey A, Ozaki K, Baumann H, Levin SD, Puel A, Farr AG, Ziegler SF, Leonard WJ, Lodish HF: Cloning of a receptor subunit required for signaling by thymic stromal lymphopoietin. Nat Immunol 2000;1:59–64.
11.
He SH, Liu ZQ, Chen X, Song CH, Zhou LF, Ma WJ, Cheng L, Du Y, Tang SG, Yang PC: IL-9+IL-10+ T cells link immediate allergic response to late phase reaction. Clin Exp Immunol 2011;165:29–37.
12.
Al-Shami A, Spolski R, Kelly J, Fry T, Schwartzberg PL, Pandey A, Mackall CL, Leonard WJ: A role for thymic stromal lymphopoietin in CD4+ T cell development. J Exp Med 2004;200:159–168.
13.
Wu WH, Park CO, Oh SH, Kim HJ, Kwon YS, Bae BG, Noh JY, Lee KH: Thymic stromal lymphopoietin-activated invariant natural killer T cells trigger an innate allergic immune response in atopic dermatitis. J Allergy Clin Immunol 2010;126:290–299, 299.e1–e4.
14.
Soumelis V, Reche PA, Kanzler H, Yuan W, Edward G, Homey B, Gilliet M, Ho S, Antonenko S, Lauerma A, Smith K, Gorman D, Zurawski S, Abrams J, Menon S, McClanahan T, de Waal-Malefyt Rd R, Bazan F, Kastelein RA, Liu YJ: Human epithelial cells trigger dendritic cell mediated allergic inflammation by producing TSLP. Nat Immunol 2002;3:673–680.
15.
Liu YJ: Thymic stromal lymphopoietin: master switch for allergic inflammation. J Exp Med 2006;203:269–273.
16.
Isaksen DE, Baumann H, Zhou B, Nivollet S, Farr AG, Levin SD, Ziegler SF: Uncoupling of proliferation and Stat5 activation in thymic stromal lymphopoietin-mediated signal transduction. J Immunol 2002;168:3288–3294.
17.
Allakhverdi Z, Comeau MR, Jessup HK, Yoon BR, Brewer A, Chartier S, Paquette N, Ziegler SF, Sarfati M, Delespesse G: Thymic stromal lymphopoietin is released by human epithelial cells in response to microbes, trauma, or inflammation and potently activates mast cells. J Exp Med 2007;204:253–258.
18.
Lee HC, Ziegler SF: Inducible expression of the proallergic cytokine thymic stromal lymphopoietin in airway epithelial cells is controlled by NF-ĸB. Proc Natl Acad Sci USA 2007;104:914–919.
19.
Nagata Y, Kamijuku H, Taniguchi M, Ziegler S, Seino K: Differential role of thymic stromal lymphopoietin in the induction of airway hyperreactivity and Th2 immune response in antigen-induced asthma with respect to natural killer T cell function. Int Arch Allergy Immunol 2007;144:305–314.
20.
Huston DP, Liu YJ: Thymic stromal lymphopoietin: a potential therapeutic target for allergy and asthma. Curr Allergy Asthma Rep 2006;6:372–376.
21.
Willart MA, Hammad H: Alarming dendritic cells for allergic sensitization. Allergol Int 2010;59:95–103.
22.
Lee do I, Huh YJ, Hwang KW, Choi Y, Choi JS, Han SY, Gyoung YS, Joo SS: Alternative therapeutic advantages of catfish bile on atopic dermatitis: protection of T cell-mediated skin disease via antioxidant activities. J Pharm Pharmacol 2011;63:1327–1335.
23.
Blumenthal MN: Genetic, epigenetic, and environmental factors in asthma and allergy. Ann Allergy Asthma Immunol 2012;108:69–73.
24.
Moffatt MF, James A, Ryan G, Musk AW, Cookson WO: Extended tumour necrosis factor/HLA-DR haplotypes and asthma in an Australian population sample. Thorax 1999;54:757–761.
25.
Guo PF, Du MR, Wu HX, Lin Y, Jin LP, Li DJ: Thymic stromal lymphopoietin from trophoblasts induces dendritic cell-mediated regulatory TH2 bias in the decidua during early gestation in humans. Blood 2010;116:2061–2069.
26.
Hunninghake GM, Soto-Quirós ME, Avila L, Kim HP, Lasky-Su J, Rafaels N, Ruczinski I, Beaty TH, Mathias RA, Barnes KC, Wilk JB, O’Connor GT, Gauderman WJ, Vora H, Baurley JW, Gilliland F, Liang C, Sylvia JS, Klanderman BJ, Sharma SS, Himes BE, Bossley CJ, Israel E, Raby BA, Bush A, Choi AM, Weiss ST, Celedón JC: TSLP polymorphisms are associated with asthma in a sex-specific fashion. Allergy 2010;65:1566–1575.
27.
Akbari O, DeKruyff RH, Umetsu DT: Pulmonary dendritic cells producing IL-10 mediate tolerance induced by respiratory exposure to antigen. Nat Immunol 2001;2:725–731.
28.
Oh JW, Seroogy CM, Meyer EH, Akbari O, Berry G, Fathman CG, Dekruyff RH, Umetsu DT: CD4 T-helper cells engineered to produce IL-10 prevent allergen-induced airway hyperreactivity and inflammation. J Allergy Clin Immunol 2002;110:460–468.
29.
Ito T, Wang YH, Duramad O, Hori T, Delespesse GJ, Watanabe N, Qin FX, Yao Z, Cao W, Liu YJ: TSLP-activated dendritic cells induce an inflammatory T helper type 2 cell response through OX40 ligand. J Exp Med 2005;202:1213–1223.
30.
Liu YJ: Thymic stromal lymphopoietin and OX40 ligand pathway in the initiation of dendritic cell-mediated allergic inflammation. J Allergy Clin Immunol 2007;120:238–244.
31.
Eisenbarth SC, Piggott DA, Bottomly K: The master regulators of allergic inflammation: dendritic cells in Th2 sensitization. Curr Opin Immunol 2003;15:620–626.
32.
Kapsenberg ML: Dendritic-cell control of pathogen-driven T-cell polarization. Nat Rev Immunol 2003;3:984–993.
33.
Sher A, Pearce E, Kaye P: Shaping the immune response to parasites: role of dendritic cells. Curr Opin Immunol 2003;15:421–429.
34.
Moser M, Murphy KM: Dendritic cell regulation of TH1-TH2 development. Nat Immunol 2000;1:199–205.
35.
So T, Song J, Sugie K, Altman A, Croft M: Signals from OX40 regulate nuclear factor of activated T cells c1 and T cell helper 2 lineage commitment. Proc Natl Acad Sci USA 2006;103:3740–3745.
36.
He SH, Chen X, Song CH, Liu ZQ, Zhou LF, Ma WE, Zhao LD, Li TL, Tang SG, Xing Z, Yang PC: Interferon-λ mediates oral tolerance and inhibits antigen-specific, T-helper 2 cell-mediated inflammation in mouse intestine. Gastroenterology 2011;141:249–258.
37.
Ziegler SF, Artis D: Sensing the outside world: TSLP regulates barrier immunity. Nat Immunol 2010;11:289–293.
38.
Watanabe N, Wang YH, Lee HK, Ito T, Wang YH, Cao W, Liu YJ: Hassall’s corpuscles instruct dendritic cells to induce CD4+CD25+ regulatory T cells in human thymus. Nature 2005;436:1181–1185.
39.
Akdis CA, Akdis M: Mechanisms and treatment of allergic disease in the big picture of regulatory T cells. J Allergy Clin Immunol 2009;123:735–746; quiz 747–748.
40.
Herrick CA, Bottomly K: To respond or not to respond: T cells in allergic asthma. Nat Rev Immunol 2003;3:405–412.
41.
Zhu Z, Zheng T, Homer RJ, Kim YK, Chen NY, Cohn L, Hamid Q, Elias JA: Acidic mammalian chitinase in asthmatic Th2 inflammation and IL-13 pathway activation. Science 2004;304:1678–1682.
42.
Watanabe N, Hanabuchi S, Soumelis V, Yuan W, Ho S, de Waal Malefyt R, Liu YJ: Human thymic stromal lymphopoietin promotes dendritic cell-mediated CD4+ T cell homeostatic expansion. Nat Immunol 2004;5:426–434.
43.
Kearley J, Robinson DS, Lloyd CM: CD4+CD25+ regulatory T cells reverse established allergic airway inflammation and prevent airway remodeling. J Allergy Clin Immunol 2008;122:617–624.e6.
44.
Presser K, Schwinge D, Wegmann M, Huber S, Schmitt S, Quaas A, Maxeiner JH, Finotto S, Lohse AW, Blessing M, Schramm C: Coexpression of TGF-β1 and IL-10 enables regulatory T cells to completely suppress airway hyperreactivity. J Immunol 2008;181:7751–7758.
45.
Nguyen KD, Vanichsarn C, Nadeau KC: TSLP directly impairs pulmonary Treg function: association with aberrant tolerogenic immunity in asthmatic airway. Allergy Asthma Clin Immunol 2010;6:4.
46.
Shi L, Leu SW, Xu F, Zhou X, Yin H, Cai L, Zhang L: Local blockade of TSLP receptor alleviated allergic disease by regulating airway dendritic cells. Clin Immunol 2008;129:202–210.
47.
Headley MB, Zhou B, Shih WX, Aye T, Comeau MR, Ziegler SF: TSLP conditions the lung immune environment for the generation of pathogenic innate and antigen-specific adaptive immune responses. J Immunol 2009;182:1641–1647.
48.
Yoo J, Omori M, Gyarmati D, Zhou B, Aye T, Brewer A, Comeau MR, Campbell DJ, Ziegler SF: Spontaneous atopic dermatitis in mice expressing an inducible thymic stromal lymphopoietin transgene specifically in the skin. J Exp Med 2005;202:541–549.
49.
Oh MH, Oh SY, Yu J, Myers AC, Leonard WJ, Liu YJ, Zhu Z, Zheng T: IL-13 induces skin fibrosis in atopic dermatitis by thymic stromal lymphopoietin. J Immunol 2011;186:7232–7242.
50.
Zhou B, Comeau MR, De Smedt T, Liggitt HD, Dahl ME, Lewis DB, Gyarmati D, Aye T, Campbell DJ, Ziegler SF: Thymic stromal lymphopoietin as a key initiator of allergic airway inflammation in mice. Nat Immunol 2005;6:1047–1053.
51.
Li M, Hener P, Zhang Z, Kato S, Metzger D, Chambon P: Topical vitamin D3 and low-calcemic analogs induce thymic stromal lymphopoietin in mouse keratinocytes and trigger an atopic dermatitis. Proc Natl Acad Sci USA 2006;103:11736–11741.
52.
Zaph C, Troy AE, Taylor BC, Berman-Booty LD, Guild KJ, Du Y, Yost EA, Gruber AD, May MJ, Greten FR, Eckmann L, Karin M, Artis D: Epithelial-cell-intrinsic IKK-β expression regulates intestinal immune homeostasis. Nature 2007;446:552–556.
53.
Zhang Z, Hener P, Frossard N, Kato S, Metzger D, Li M, Chambon P: Thymic stromal lymphopoietin overproduced by keratinocytes in mouse skin aggravates experimental asthma. Proc Natl Acad Sci USA 2009;106:1536–1541.
54.
Demehri S, Morimoto M, Holtzman MJ, Kopan R: Skin-derived TSLP triggers progression from epidermal-barrier defects to asthma. PLoS Biol 2009;7:e1000067.
55.
Han H, Xu W, Headley MB, Jessup HK, Lee KS, Omori M, Comeau MR, Marshak-Rothstein A, Ziegler SF: Thymic stromal lymphopoietin (TSLP)-mediated dermal inflammation aggravates experimental asthma. Mucosal Immunol 2012;5:342–351.
56.
Kato A, Favoreto S Jr, Avila PC, Schleimer RP: TLR3- and Th2 cytokine-dependent production of thymic stromal lymphopoietin in human airway epithelial cells. J Immunol 2007;179:1080–1087.
57.
Bogiatzi SI, Fernandez I, Bichet JC, Marloie-Provost MA, Volpe E, Sastre X, Soumelis V: Cutting Edge: Proinflammatory and Th2 cytokines synergize to induce thymic stromal lymphopoietin production by human skin keratinocytes. J Immunol 2007;178:3373–3377.
58.
Oh SW, Cha JY, Jung JE, Chang BC, Kwon HJ, Lee BR, Kim DY: Curcumin attenuates allergic airway inflammation and hyper-responsiveness in mice through NF-ĸB inhibition. J Ethnopharmacol 2011;136:414–421.
59.
Bonizzi G, Karin M: The two NF-ĸB activation pathways and their role in innate and adaptive immunity. Trends Immunol 2004;25:280–288.
60.
Wan F, Lenardo MJ: The nuclear signaling of NF-ĸB: current knowledge, new insights, and future perspectives. Cell Res 2010;20:24–33.
61.
Zhou LF, Chen L, Zhu Q, Wang C, Xu H, Cui XF, Jiang LF, He SH, Huang M, Yin KS: Unusual life-threatening Rosai-Dorfman disease of the trachea: role of NF-ĸB. Thorax 2010;65:927–929.
62.
Zhou LF, Zhang MS, Hu AH, Zhu Z, Yin KS: Selective blockade of NF-ĸB by novel mutated IĸBα suppresses CD3/CD28-induced activation of memory CD4+ T cells in asthma. Allergy 2008;63:509–517.
63.
Gu XY, Zhou LF, Zhang MS, Dai WJ, Chen SY, He SH, Ji XH, Yin KS: Targeted NF-ĸB inhibition of asthmatic serum-mediated human monocyte-derived dendritic cell differentiation in a transendothelial trafficking model. Cell Immunol 2009;260:14–20.
64.
Lee HC, Headley MB, Iseki M, Ikuta K, Ziegler SF: Cutting Edge: Inhibition of NF-ĸB-mediated TSLP expression by retinoid X receptor. J Immunol 2008;181:5189–5193.
65.
Li M, Messaddeq N, Teletin M, Pasquali JL, Metzger D, Chambon P: Retinoid X receptor ablation in adult mouse keratinocytes generates an atopic dermatitis triggered by thymic stromal lymphopoietin. Proc Natl Acad Sci USA 2005;102:14795–14800.
66.
Li M, Hener P, Zhang Z, Kato S, Metzger D, Chambon P: Topical vitamin D3 and low-calcemic analogs induce thymic stromal lymphopoietin in mouse keratinocytes and trigger an atopic dermatitis. Proc Natl Acad Sci USA 2006;103:11736–11741.
67.
Harada M, Hirota T, Jodo AI, Hitomi Y, Sakashita M, Tsunoda T, Miyagawa T, Doi S, Kameda M, Fujita K, Miyatake A, Enomoto T, Noguchi E, Masuko H, Sakamoto T, Hizawa N, Suzuki Y, Yoshihara S, Adachi M, Ebisawa M, Saito H, Matsumoto K, Nakajima T, Mathias RA, Rafaels N, Barnes KC, Himes BE, Duan QL, Tantisira KG, Weiss ST, Nakamura Y, Ziegler SF, Tamari M: Thymic stromal lymphopoietin gene promoter polymorphisms are associated with susceptibility to bronchial asthma. Am J Respir Cell Mol Biol 2011;44:787–793.
68.
Hunninghake GM, Lasky-Su J, Soto-Quirós ME, Avila L, Liang C, Lake SL, Hudson TJ, Spesny M, Fournier E, Sylvia JS, Freimer NB, Klanderman BJ, Raby BA, Celedón JC: Sex-stratified linkage analysis identifies a female-specific locus for IgE to cockroach in Costa Ricans. Am J Respir Crit Care Med 2008;177:830–836.
69.
Harada M, Hirota T, Jodo AI, Doi S, Kameda M, Fujita K, Miyatake A, Enomoto T, Noguchi E, Yoshihara S, Ebisawa M, Saito H, Matsumoto K, Nakamura Y, Ziegler SF, Tamari M: Functional analysis of the thymic stromal lymphopoietin variants in human bronchial epithelial cells. Am J Respir Cell Mol Biol 2009;40:368–374.
70.
Gao PS, Rafaels NM, Mu D, Hand T, Murray T, Boguniewicz M, Hata T, Schneider L, Hanifin JM, Gallo RL, Gao L, Beaty TH, Beck LA, Leung DY, Barnes KC: Genetic variants in thymic stromal lymphopoietin are associated with atopic dermatitis and eczema herpeticum. J Allergy Clin Immunol 2010;125:1403–1407.e4.
71.
Redhu NS, Gounni AS: Function and mechanisms of TSLP/TSLPR complex in asthma and COPD. Clin Exp Allergy 2012;42:994–1005.
72.
Wang YH, Liu YJ: Thymic stromal lymphopoietin, OX40-ligand, and interleukin-25 in allergic responses. Clin Exp Allergy 2009;39:798–806.
73.
Zhang Y, Zhou B: Functions of thymic stromal lymphopoietin in immunity and disease. Immunol Res 2012;52:211–223.
74.
Uller L, Leino M, Bedke N, Sammut D, Green B, Lau L, Howarth PH, Holgate ST, Davies DE: Double-stranded RNA induces disproportionate expression of thymic stromal lymphopoietin versus interferon-β in bronchial epithelial cells from donors with asthma. Thorax 2010;65:626–632.
75.
Kaur D, Doe C, Woodman L, Wan H, Sutcliffe A, Hollins F, Brightling C: Mast cell-airway smooth muscle crosstalk: the role of thymic stromal lymphopoietin. Chest 2011; [Epub ahead of print].
76.
Shikotra A, Choy DF, Ohri CM, Doran E, Butler C, Hargadon B, Shelley M, Abbas AR, Austin CD, Jackman J, Wu LC, Heaney LG, Arron JR, Bradding P: Increased expression of immunoreactive thymic stromal lymphopoietin in patients with severe asthma. J Allergy Clin Immunol 2011;129:104–111.e1–e9.
77.
Liu M, Rogers L, Cheng Q, Shao Y, Fernandez-Beros ME, Hirschhorn JN, Lyon HN, Gajdos ZK, Vedantam S, Gregersen P, Seldin MF, Bleck B, Ramasamy A, Hartikainen AL, Jarvelin MR, Kuokkanen M, Laitinen T, Eriksson J, Lehtimäki T, Raitakari OT, Reibman J: Genetic variants of TSLP and asthma in an admixed urban population. PLoS One 2011;6:e25099.
78.
Zhang F, Huang G, Hu B, Song Y, Shi Y: A soluble thymic stromal lymphopoietin (TSLP) antagonist, TSLPR-immunoglobulin, reduces the severity of allergic disease by regulating pulmonary dendritic cells. Clin Exp Immunol 2011;164:256–264.
79.
Siracusa MC, Saenz SA, Hill DA, Kim BS, Headley MB, Doering TA, Wherry EJ, Jessup HK, Siegel LA, Kambayashi T, Dudek EC, Kubo M, Cianferoni A, Spergel JM, Ziegler SF, Comeau MR, Artis D: TSLP promotes interleukin-3-independent basophil haematopoiesis and type 2 inflammation. Nature 2011;477:229–233.
80.
Moon PD, Choi IH, Kim HM: Naringenin suppresses the production of thymic stromal lymphopoietin through the blockade of RIP2 and caspase-1 signal cascade in mast cells. Eur J Pharmacol 2011;671:128–132.
81.
Yokoi T, Amakawa R, Tanijiri T, Sugimoto H, Torii Y, Amuro H, Son Y, Tajima K, Liu YJ, Ito T, Fukuhara S: Mycobacterium bovis bacillus Calmette-Guérin suppresses inflammatory Th2 responses by inducing functional alteration of TSLP-activated dendritic cells. Int Immunol 2008;20:1321–1329.
82.
Li DQ, Zhang L, Pflugfelder SC, De Paiva CS, Zhang X, Zhao G, Zheng X, Su Z, Qu Y: Short ragweed pollen triggers allergic inflammation through Toll-like receptor 4-dependent thymic stromal lymphopoietin/OX40 ligand/OX40 signaling pathways. J Allergy Clin Immunol 2011;128:1318–1325.e2.
© 2012 S. Karger AG, Basel
2012
Copyright / Drug Dosage / Disclaimer
Copyright: All rights reserved. No part of this publication may be translated into other languages, reproduced or utilized in any form or by any means, electronic or mechanical, including photocopying, recording, microcopying, or by any information storage and retrieval system, without permission in writing from the publisher.
Drug Dosage: The authors and the publisher have exerted every effort to ensure that drug selection and dosage set forth in this text are in accord with current recommendations and practice at the time of publication. However, in view of ongoing research, changes in government regulations, and the constant flow of information relating to drug therapy and drug reactions, the reader is urged to check the package insert for each drug for any changes in indications and dosage and for added warnings and precautions. This is particularly important when the recommended agent is a new and/or infrequently employed drug.
Disclaimer: The statements, opinions and data contained in this publication are solely those of the individual authors and contributors and not of the publishers and the editor(s). The appearance of advertisements or/and product references in the publication is not a warranty, endorsement, or approval of the products or services advertised or of their effectiveness, quality or safety. The publisher and the editor(s) disclaim responsibility for any injury to persons or property resulting from any ideas, methods, instructions or products referred to in the content or advertisements.
You do not currently have access to this content.