Protective role of IL-6 in vascular remodeling in schistosoma pulmonary hypertension

Brian B. Graham, Jacob Chabon, Rahul Kumar, Ewa Kolosionek, Liya Gebreab, Elias Debella, Michael Edwards, Katrina Diener, Ted Shade, Gao Bifeng, Angela Bandeira, Ghazwan Butrous, Kenneth Jones, Mark Geraci, Rubin M. Tuder

Research output: Contribution to journalArticle

28 Scopus citations

Abstract

Schistosomiasis is one of the most common causes of pulmonary arterial hypertension worldwide, but the pathogenic mechanism by which the host inflammatory response contributes to vascular remodeling is unknown. We sought to identify signaling pathways thatplay protectiveorpathogenic rolesinexperimental Schistosomainduced pulmonary vascular disease via whole-lung transcriptome analysis. Wild-type mice were experimentally exposed to Schistosoma mansoni ova by intraperitoneal sensitization followed by tail-vein augmentation, and the phenotype was assessed by right ventricular catheterization and tissue histology,as wellas RNA and protein analysis. Whole-lung transcriptome analysis by microarray and RNA sequencing was performed, and RNA sequencing was analyzed according to two bioinformatics methods. Functional testing of the candidate IL-6 pathway was determined using IL-6 knockout mice and the signal transducers and activators of transcription protein-3 (STAT3) inhibitor S3I-201. Wild-type mice exposed to S. mansoni demonstrated increased right ventricular systolic pressure and thickness of the pulmonary vascular media. Whole-lung transcriptome analysis determined that the IL-6-STAT3-nuclear factor of activated T cells c2(NFATc2)pathwaywasup-regulated, asconfirmed by PCR and the immunostaining of lung tissue from S. mansoni-exposed mice and patients who died of the disease. Mice lacking IL-6 or treated with S3I-201 developed pulmonary hypertension, associated with significant intima remodeling after exposure to S. mansoni. Whole-lung transcriptome analysis identified the up-regulation of the IL-6-STAT3-NFATc2 pathway, and IL-6 signaling was found to be protective against Schistosomainduced intimal remodeling.

Original languageEnglish (US)
Pages (from-to)951-959
Number of pages9
JournalAmerican journal of respiratory cell and molecular biology
Volume49
Issue number6
DOIs
StatePublished - Dec 2013
Externally publishedYes

Keywords

  • Gene expression profiling
  • IL-6
  • Pulmonary hypertension
  • Schistosomiasis

ASJC Scopus subject areas

  • Molecular Biology
  • Pulmonary and Respiratory Medicine
  • Clinical Biochemistry
  • Cell Biology

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  • Cite this

    Graham, B. B., Chabon, J., Kumar, R., Kolosionek, E., Gebreab, L., Debella, E., Edwards, M., Diener, K., Shade, T., Bifeng, G., Bandeira, A., Butrous, G., Jones, K., Geraci, M., & Tuder, R. M. (2013). Protective role of IL-6 in vascular remodeling in schistosoma pulmonary hypertension. American journal of respiratory cell and molecular biology, 49(6), 951-959. https://doi.org/10.1165/rcmb.2012-0532OC