Evidence that oncostatin M synergizes with IL-4 signaling to induce TSLP expression in chronic rhinosinusitis with nasal polyps - 04/05/23
, James E. Norton, MS a, Julie A. Poposki, MS a, Aiko I. Klingler, PhD a, Lydia A. Suh, BS a, Roderick Carter, BS a, Julia H. Huang, MS a, Junqin Bai, PhD a, Whitney W. Stevens, MD, PhD a, Bruce K. Tan, MD d, Anju T. Peters, MD a, d, Leslie C. Grammer, MD a, David B. Conley, MD d, Kevin C. Welch, MD d, Zheng Liu, MD, PhD b, Robert C. Kern, MD d, Atsushi Kato, PhD a, Robert P. Schleimer, PhD a, d, ⁎ Abstract |
Background |
Oncostatin M (OSM) may promote type 2 inflammation in chronic rhinosinusitis with nasal polyps (CRSwNP) by inducing thymic stromal lymphopoietin (TSLP).
Objective |
We sought to study the impact of OSM on TSLP synthesis and release from nasal epithelial cells (NECs).
Methods |
OSM receptors, IL-4 receptors (IL-4R), and TSLP were evaluated in mucosal tissue and primary NECs from patients with CRSwNP by quantitative PCR and immunofluorescence. Air-liquid interface–cultured NECs were stimulated with cytokines, including OSM, and quantitative PCR, ELISA, Western blot, and flow cytometry were used to assess the expression of OSM receptors, IL-4R, and TSLP.
Results |
Increased levels of OSM receptor β chain (OSMRβ), IL-4Rα, and TSLP were observed in nasal polyp tissues and primary epithelial cells from nasal polyps of patients with CRSwNP compared with control tissues or cells from control subjects. The level of expression of OSMRβ in tissue was correlated with levels of both IL-4Rα and TSLP. OSM stimulation of NECs increased the expression of OSMRβ and IL-4Rα. Stimulation with IL-4 plus OSM augmented the production of TSLP; the response was suppressed by a signal transducer and activator of transcription 6 inhibitor. Stimulation of NECs with IL-4 plus OSM increased the expression of proprotein convertase subtilisin/kexin 3, an enzyme that truncates and activates TSLP.
Conclusions |
OSM increases the expression of IL-4Rα and synergizes with IL-4 to induce the synthesis and release of TSLP in NECs. Because the combination of IL-4 and OSM also augmented the expression of proprotein convertase subtilisin/kexin 3, these results suggest that OSM can induce both synthesis and posttranslational processing/activation of TSLP, promoting type 2 inflammation.
Il testo completo di questo articolo è disponibile in PDF.Key words : OSM, OSMRβ, IL-4Rα, TSLP, chronic rhinosinusitis, nasal polyps, nasal epithelial cells, type 2–dominant inflammation
Abbreviations used : ALI, BMEM, CRS, CRSsNP, CRSwNP, DMSO, EREG, IL-4Rα, IL-13Rα1, IL-13Rα2, LIFR, NEC, NHBEC, NP, OSM, OSMRβ, PCSK3, STAT6, TSLP, UT
Mappa
| The first 2 authors contributed equally to the manuscript as co-first authors. |
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| This research was supported in part by grants from the National Institutes of Health (grant nos. KL2 TR001424, K23 AI141694, R01 AI104733, 24 U19 AI106683, and P01 145818), by grants from the Parker B. Francis Fellowship Foundation 25, by a HOPE American Partnership For Eosinophilic Disorders (APFED)/American Academy of Allergy, Asthma & Immunology Pilot Grant Award, by the Ernest S. Bazley Foundation, and by the National Natural Science Foundation of China (grant nos. 81800888 and 82171113). |
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| Disclosure of potential conflict of interest: W. W. Stevens served on an advisory board for GlaxoSmithKline. B. K. Tan reports personal fees from Sanofi Regeneron/Genzyme and OptiNose. A. T. Peters reports personal fees from Sanofi Regeneron and personal fees and grants from AstraZeneca. L. C. Grammer reports personal fees from Astellas Pharmaceuticals. R. C. Kern reports personal fees from Sanofi Regeneron, Novartis, Lyra Pharmaceutical, and Neurent. A. Kato reports consultant fees from Astellas Pharmaceuticals and a gift for his research from Lyra Therapeutics. R. P. Schleimer reports personal fees from Intersect ENT, Merck, GlaxoSmithKline, Sanofi Regeneron, AstraZeneca/Medimmune, Genentech, Actobio Therapeutics, Lyra Therapeutics, Astellas Pharmaceuticals, Allakos, Inc, and Otsuka, Inc, and receives royalties from Siglec-8 and Siglec-8 ligand–related patents licensed by Johns Hopkins to Allakos. The rest of the authors declare that they have no relevant conflicts of interest. |
Vol 151 - N° 5
P. 1379 - Maggio 2023 Ritorno al numero
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