Thymic stromal lymphopoietin activity is increased in nasal polyps of patients with chronic rhinosinusitis

Deepti R. Nagarkar; Julie A. Poposki; Bruce K. Tan; Michael R. Comeau; Anju T. Peters; Kathryn E. Hulse; Lydia A. Suh; James Norton; Kathleen E. Harris; Leslie C. Grammer; Rakesh K. Chandra; David B. Conley; Robert C. Kern; Robert P. Schleimer; Atsushi Kato

doi:10.1016/j.jaci.2013.04.005

Thymic stromal lymphopoietin activity is increased in nasal polyps of patients with chronic rhinosinusitis

Deepti R. Nagarkar, Julie A. Poposki, Bruce K. Tan, Michael R. Comeau, Anju T. Peters, Kathryn E. Hulse, Lydia A. Suh, James Norton, Kathleen E. Harris, Leslie C. Grammer, Rakesh K. Chandra, David B. Conley, Robert C. Kern, Robert P. Schleimer, Atsushi Kato^*

^*Corresponding author for this work

Research output: Contribution to journal › Article › peer-review

187 Scopus citations

Abstract

Background: Chronic rhinosinusitis with nasal polyps (CRSwNP) is associated with T_H2-dominant inflammation. Thymic stromal lymphopoietin (TSLP) is a cytokine that triggers dendritic cell-mediated T_H2 inflammatory responses and that enhances IL-1-dependent T_H2 cytokine production in mast cells. Although increased TSLP mRNA levels have been found in nasal polyps (NPs), expression of TSLP protein and its function in patients with chronic rhinosinusitis (CRS) have not been fully explored. Objectives: The objective of this study was to investigate the role of TSLP in patients with CRS. Methods: We investigated the presence and stability of TSLP protein in NPs using ELISA and Western blotting and investigated the function of TSLP in nasal tissue extracts with a bioassay based on activation of human mast cells. Results: Although TSLP mRNA levels were significantly increased in NP tissue from patients with CRSwNP compared with uncinate tissue from patients with CRS or control subjects, TSLP protein was significantly decreased in NP tissue, as detected by using the commercial ELISA kit. We found that recombinant TSLP was time-dependently degraded by NP extracts, and this degradation was completely inhibited by a protease inhibitor cocktail, suggesting that TSLP is sensitive to tissue proteases. Interestingly, NP extract-treated TSLP had higher activity in mast cells, although the amount of full-length TSLP was reduced up to 85%. NP extracts significantly enhanced IL-1β-dependent IL-5 production in mast cells compared with uncinate tissue homogenates, and responses were significantly inhibited by anti-TSLP, suggesting that NPs contain biologically relevant levels of TSLP activity. Conclusion: TSLP and its metabolic products might play an important role in the inflammation seen in patients with CRSwNP.

Original language	English (US)
Pages (from-to)	593-600.e12
Journal	Journal of Allergy and Clinical Immunology
Volume	132
Issue number	3
DOIs	https://doi.org/10.1016/j.jaci.2013.04.005
State	Published - Sep 2013

Keywords

Chronic rhinosinusitis
IL-5
epithelial cells
mast cells
nasal polyps
proteases
thymic stromal lymphopoietin

ASJC Scopus subject areas

Immunology and Allergy
Immunology

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10.1016/j.jaci.2013.04.005

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Nagarkar, D. R., Poposki, J. A., Tan, B. K., Comeau, M. R., Peters, A. T., Hulse, K. E., Suh, L. A., Norton, J., Harris, K. E., Grammer, L. C., Chandra, R. K., Conley, D. B., Kern, R. C., Schleimer, R. P., & Kato, A. (2013). Thymic stromal lymphopoietin activity is increased in nasal polyps of patients with chronic rhinosinusitis. Journal of Allergy and Clinical Immunology, 132(3), 593-600.e12. https://doi.org/10.1016/j.jaci.2013.04.005

@article{94de8ebe471241ae98b4f4ecab772928,

title = "Thymic stromal lymphopoietin activity is increased in nasal polyps of patients with chronic rhinosinusitis",

abstract = "Background: Chronic rhinosinusitis with nasal polyps (CRSwNP) is associated with TH2-dominant inflammation. Thymic stromal lymphopoietin (TSLP) is a cytokine that triggers dendritic cell-mediated TH2 inflammatory responses and that enhances IL-1-dependent TH2 cytokine production in mast cells. Although increased TSLP mRNA levels have been found in nasal polyps (NPs), expression of TSLP protein and its function in patients with chronic rhinosinusitis (CRS) have not been fully explored. Objectives: The objective of this study was to investigate the role of TSLP in patients with CRS. Methods: We investigated the presence and stability of TSLP protein in NPs using ELISA and Western blotting and investigated the function of TSLP in nasal tissue extracts with a bioassay based on activation of human mast cells. Results: Although TSLP mRNA levels were significantly increased in NP tissue from patients with CRSwNP compared with uncinate tissue from patients with CRS or control subjects, TSLP protein was significantly decreased in NP tissue, as detected by using the commercial ELISA kit. We found that recombinant TSLP was time-dependently degraded by NP extracts, and this degradation was completely inhibited by a protease inhibitor cocktail, suggesting that TSLP is sensitive to tissue proteases. Interestingly, NP extract-treated TSLP had higher activity in mast cells, although the amount of full-length TSLP was reduced up to 85%. NP extracts significantly enhanced IL-1β-dependent IL-5 production in mast cells compared with uncinate tissue homogenates, and responses were significantly inhibited by anti-TSLP, suggesting that NPs contain biologically relevant levels of TSLP activity. Conclusion: TSLP and its metabolic products might play an important role in the inflammation seen in patients with CRSwNP.",

keywords = "Chronic rhinosinusitis, IL-5, epithelial cells, mast cells, nasal polyps, proteases, thymic stromal lymphopoietin",

author = "Nagarkar, {Deepti R.} and Poposki, {Julie A.} and Tan, {Bruce K.} and Comeau, {Michael R.} and Peters, {Anju T.} and Hulse, {Kathryn E.} and Suh, {Lydia A.} and James Norton and Harris, {Kathleen E.} and Grammer, {Leslie C.} and Chandra, {Rakesh K.} and Conley, {David B.} and Kern, {Robert C.} and Schleimer, {Robert P.} and Atsushi Kato",

note = "Funding Information: Disclosure of potential conflict of interest: J. A. Poposki and B. K. Tan have received research support from the National Institutes of Health (NIH) . M. R. Comeau is employed by and has stock/stock options in Amgen and has patents related to TSLP. A. T. Peters has provided expert testimony on SJS/TEN and has received lecture fees from Baxter . L. C. Grammer has received research and travel support from the NIH ; has received research support from the Food Allergy Network and S&C Electric and a Bazley Foundation grant; has received consultancy fees from Astellas Pharmaceuticals ; is employed by Northwestern University and Northwestern Medical Faculty Foundation; has received lecture fees from the American Academy of Allergy, Asthma & Immunology ; and receives royalties from Lippincott, UpToDate, BMU, and Elsevier . R. P. Schleimer has received research support from the NIH ; has received consultancy fees from Intersect ENT, GlaxoSmithKline, Allakos, and Aurasense ; and has stock/stock options in Allakos. A. Kato has received research support from the NIH . The rest of the authors declare that they have no relevant conflicts of interest. Funding Information: Supported in part by National Institutes of Health grants R01 HL078860 , R01 AI072570 , and R37 HL068546 and by a grant from the Ernest S. Bazley Trust . ",

year = "2013",

month = sep,

doi = "10.1016/j.jaci.2013.04.005",

language = "English (US)",

volume = "132",

pages = "593--600.e12",

journal = "Journal of Allergy and Clinical Immunology",

issn = "0091-6749",

publisher = "Mosby Inc.",

number = "3",

}

Nagarkar, DR, Poposki, JA, Tan, BK, Comeau, MR, Peters, AT, Hulse, KE, Suh, LA, Norton, J, Harris, KE, Grammer, LC, Chandra, RK, Conley, DB , Kern, RC , Schleimer, RP & Kato, A 2013, 'Thymic stromal lymphopoietin activity is increased in nasal polyps of patients with chronic rhinosinusitis', Journal of Allergy and Clinical Immunology, vol. 132, no. 3, pp. 593-600.e12. https://doi.org/10.1016/j.jaci.2013.04.005

TY - JOUR

T1 - Thymic stromal lymphopoietin activity is increased in nasal polyps of patients with chronic rhinosinusitis

AU - Nagarkar, Deepti R.

AU - Poposki, Julie A.

AU - Tan, Bruce K.

AU - Comeau, Michael R.

AU - Peters, Anju T.

AU - Hulse, Kathryn E.

AU - Suh, Lydia A.

AU - Norton, James

AU - Harris, Kathleen E.

AU - Grammer, Leslie C.

AU - Chandra, Rakesh K.

AU - Conley, David B.

AU - Kern, Robert C.

AU - Schleimer, Robert P.

AU - Kato, Atsushi

N1 - Funding Information: Disclosure of potential conflict of interest: J. A. Poposki and B. K. Tan have received research support from the National Institutes of Health (NIH) . M. R. Comeau is employed by and has stock/stock options in Amgen and has patents related to TSLP. A. T. Peters has provided expert testimony on SJS/TEN and has received lecture fees from Baxter . L. C. Grammer has received research and travel support from the NIH ; has received research support from the Food Allergy Network and S&C Electric and a Bazley Foundation grant; has received consultancy fees from Astellas Pharmaceuticals ; is employed by Northwestern University and Northwestern Medical Faculty Foundation; has received lecture fees from the American Academy of Allergy, Asthma & Immunology ; and receives royalties from Lippincott, UpToDate, BMU, and Elsevier . R. P. Schleimer has received research support from the NIH ; has received consultancy fees from Intersect ENT, GlaxoSmithKline, Allakos, and Aurasense ; and has stock/stock options in Allakos. A. Kato has received research support from the NIH . The rest of the authors declare that they have no relevant conflicts of interest. Funding Information: Supported in part by National Institutes of Health grants R01 HL078860 , R01 AI072570 , and R37 HL068546 and by a grant from the Ernest S. Bazley Trust .

PY - 2013/9

Y1 - 2013/9

N2 - Background: Chronic rhinosinusitis with nasal polyps (CRSwNP) is associated with TH2-dominant inflammation. Thymic stromal lymphopoietin (TSLP) is a cytokine that triggers dendritic cell-mediated TH2 inflammatory responses and that enhances IL-1-dependent TH2 cytokine production in mast cells. Although increased TSLP mRNA levels have been found in nasal polyps (NPs), expression of TSLP protein and its function in patients with chronic rhinosinusitis (CRS) have not been fully explored. Objectives: The objective of this study was to investigate the role of TSLP in patients with CRS. Methods: We investigated the presence and stability of TSLP protein in NPs using ELISA and Western blotting and investigated the function of TSLP in nasal tissue extracts with a bioassay based on activation of human mast cells. Results: Although TSLP mRNA levels were significantly increased in NP tissue from patients with CRSwNP compared with uncinate tissue from patients with CRS or control subjects, TSLP protein was significantly decreased in NP tissue, as detected by using the commercial ELISA kit. We found that recombinant TSLP was time-dependently degraded by NP extracts, and this degradation was completely inhibited by a protease inhibitor cocktail, suggesting that TSLP is sensitive to tissue proteases. Interestingly, NP extract-treated TSLP had higher activity in mast cells, although the amount of full-length TSLP was reduced up to 85%. NP extracts significantly enhanced IL-1β-dependent IL-5 production in mast cells compared with uncinate tissue homogenates, and responses were significantly inhibited by anti-TSLP, suggesting that NPs contain biologically relevant levels of TSLP activity. Conclusion: TSLP and its metabolic products might play an important role in the inflammation seen in patients with CRSwNP.

AB - Background: Chronic rhinosinusitis with nasal polyps (CRSwNP) is associated with TH2-dominant inflammation. Thymic stromal lymphopoietin (TSLP) is a cytokine that triggers dendritic cell-mediated TH2 inflammatory responses and that enhances IL-1-dependent TH2 cytokine production in mast cells. Although increased TSLP mRNA levels have been found in nasal polyps (NPs), expression of TSLP protein and its function in patients with chronic rhinosinusitis (CRS) have not been fully explored. Objectives: The objective of this study was to investigate the role of TSLP in patients with CRS. Methods: We investigated the presence and stability of TSLP protein in NPs using ELISA and Western blotting and investigated the function of TSLP in nasal tissue extracts with a bioassay based on activation of human mast cells. Results: Although TSLP mRNA levels were significantly increased in NP tissue from patients with CRSwNP compared with uncinate tissue from patients with CRS or control subjects, TSLP protein was significantly decreased in NP tissue, as detected by using the commercial ELISA kit. We found that recombinant TSLP was time-dependently degraded by NP extracts, and this degradation was completely inhibited by a protease inhibitor cocktail, suggesting that TSLP is sensitive to tissue proteases. Interestingly, NP extract-treated TSLP had higher activity in mast cells, although the amount of full-length TSLP was reduced up to 85%. NP extracts significantly enhanced IL-1β-dependent IL-5 production in mast cells compared with uncinate tissue homogenates, and responses were significantly inhibited by anti-TSLP, suggesting that NPs contain biologically relevant levels of TSLP activity. Conclusion: TSLP and its metabolic products might play an important role in the inflammation seen in patients with CRSwNP.

KW - Chronic rhinosinusitis

KW - IL-5

KW - epithelial cells

KW - mast cells

KW - nasal polyps

KW - proteases

KW - thymic stromal lymphopoietin

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DO - 10.1016/j.jaci.2013.04.005

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VL - 132

SP - 593-600.e12

JO - Journal of Allergy and Clinical Immunology

JF - Journal of Allergy and Clinical Immunology

IS - 3

ER -

Thymic stromal lymphopoietin activity is increased in nasal polyps of patients with chronic rhinosinusitis

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