Role of IL‐4 and IL‐13 in Schistosoma‐induced pulmonary hypertension (LB780)

• Published in: The FASEB journal 2014-04, Vol.28 (S1), p.n/a
• Main Authors: Kumar, Rahul, Chabon, Jacob, Gebreab, Liya, Rodriguez Garcia, Alexandra, Koyanangi, Dan, Sanders, Linda, Tuder, Rubin, Graham, Brian
• Format: Article
• Language: English
• ISSN: 0892-6638; 1530-6860
• DOI: 10.1096/fasebj.28.1_supplement.lb780

Background: Schistosomiasis‐associated pulmonary arterial hypertension (PAH) occurs in the context of Th2 inflammation, which is induced by IL‐4 and IL‐13. We had previously observed that TGF‐β signaling is necessary for Schistosoma‐induced pulmonary hypertension (PH) in the mouse. We hypothesized that IL‐4 and IL‐13 were necessary for the TGF‐β‐induced pulmonary vascular disease induced by Schistosoma. Methods: Wild type, IL‐13YFP, IL‐4GFP, IL‐4‐/‐, IL‐13‐/‐ and IL‐4‐/‐IL‐13‐/‐ mice (N=5‐17 per group) were intraperitoneally (IP) sensitized with 175 S. mansoni eggs/gram body weight, two weeks later intravenously (IV) challenged via tail vein with the same dose of eggs, and one week thereafter underwent right ventricular catheterization followed by quantitative histologic and protein analysis, or lung digestion and flow cytometry. Lung tissue from patients who died of schistosomiasis‐associated PAH was studied by immunostaining. Results: The lungs of patients with schistosomiasis‐associated PAH and mice with experimental disease had an increase in IL‐13, IL‐4Rα, phospho‐STAT6 and periostin, a target of IL‐13 signaling. Flow cytometry with IL‐13YFP and IL‐4GFP mice identified both of these cytokines were produced by CD4+ T‐cells. IL‐4‐/‐IL‐13‐/‐ mice, but not IL‐4‐/‐IL13+/+ or IL4+/+IL‐13‐/‐ mice, were protected from Schistosoma‐induced vascular remodeling, although the elevated right ventricular pressure persisted. Immunostaining of Schistosoma‐exposed mice demonstrated decreased phospho‐STAT6, perivascular TGF‐β ligand, and intravascular nuclear phospho‐Smad2/3 in IL4/IL13 double‐deficient mice only. Conclusions: Combined IL‐4 and IL‐13 deficiency are required for protection against Schistosoma‐induced pulmonary vascular remodeling.