Attenuation of Allergen-, IL-13-, and TGF-α-induced Lung Fibrosis after the Treatment of rIL-15 in Mice

Endogenous IL-15 deficiency promotes lung fibrosis; therefore, we examined the effect of induced IL-15 in restricting the progression of lung fibrosis. Our objective in this work was to establish a novel therapeutic molecule for pulmonary fibrosis. Western blot, qPCR, and ELISA were performed on the lung tissues of IL-15-deficient mice, and recombinant IL-15 (rIL-15)-treated CC10-IL-13 and CC10-TGF-α mice, and allergen-challenged CC10-IL-15 mice were examined to establish the antifibrotic effect of IL-15 in lung fibrosis. We show that endogenous IL-15 deficiency induces baseline profibrotic cytokine and collagen accumulation in the lung, and pharmacological delivery of rIL-15 downregulates Aspergillus antigen-induced lung collagen, the profibrotic cytokines IL-13 and TGF-β1, and α-SMA+ and FSP1+ cells in mice. To confirm that overexpression of IL-15 diminishes pulmonary fibrosis, we generated CC10-rtTA-tetO7-IL-15 transgenic mice and challenged them with Aspergillus antigen. Aspergillus antigen-challenged, doxycycline (DOX)-treated CC10-IL-15 transgenic mice exhibited decreased collagen accumulation, profibrotic cytokine (IL-13 and TGF-β1) expression, and α-SMA+ and FSP1+ cells compared with IL-15-overexpressing mice not treated with DOX. Additionally, to establish that the antifibrotic effect of IL-15 is not limited to allergen-induced fibrosis, we showed that rIL-15 or IL-15 agonist treatment restricted pulmonary fibrosis even in CC10-IL-13 and CC10-TGF-α mice. Mechanistically, we show that T-helper cell type 17 suppressor IL-15-responsive RORγ+ T regulatory cells are induced in DOX-treated, allergen-challenged IL-15-overexpressing mice, which may be a novel pathway for restricting progression of pulmonary fibrosis. Taken together, our data establishes antifibrotic activity of IL-15 that might be a novel therapeutic molecule to combat the development of pulmonary fibrosis.

Errataetall:

ErratumIn: Am J Respir Cell Mol Biol. 2021 Aug;65(2):229-230. - PMID 34328408

Medienart:

E-Artikel

Erscheinungsjahr:

2019

Erschienen:

2019

Enthalten in:

Zur Gesamtaufnahme - volume:61

Enthalten in:

American journal of respiratory cell and molecular biology - 61(2019), 1 vom: 01. Juli, Seite 97-109

Sprache:

Englisch

Beteiligte Personen:

Upparahalli Venkateshaiah, Sathisha [VerfasserIn]
Niranjan, Rituraj [VerfasserIn]
Manohar, Murli [VerfasserIn]
Verma, Alok K [VerfasserIn]
Kandikattu, Hemanth K [VerfasserIn]
Lasky, Joseph A [VerfasserIn]
Mishra, Anil [VerfasserIn]

Links:

Volltext

Themen:

9007-34-5
ALT-803
Allergen
Allergens
Collagen
Doxycycline
Fibrosis
IL-13
Interleukin-13
Interleukin-15
Journal Article
Lung
N12000U13O
Nuclear Receptor Subfamily 1, Group F, Member 3
Proteins
Recombinant Fusion Proteins
Recombinant Proteins
Research Support, N.I.H., Extramural
Research Support, Non-U.S. Gov't
Rorc protein, mouse
TGF-β
Transforming Growth Factor alpha

Anmerkungen:

Date Completed 17.02.2020

Date Revised 07.09.2021

published: Print

ErratumIn: Am J Respir Cell Mol Biol. 2021 Aug;65(2):229-230. - PMID 34328408

Citation Status MEDLINE

doi:

10.1165/rcmb.2018-0254OC

funding:

Förderinstitution / Projekttitel:

PPN (Katalog-ID):

NLM29329822X