IL-6 trans-signaling increases expression of airways disease genes in airway smooth muscle

Mac B. Robinson, Deepak A. Deshpande, Jeffery Chou, Wei Cui, Shelly Smith, Carl Langefeld, Annette T. Hastie, Eugene R. Bleecker, Gregory A. Hawkins

Research output: Contribution to journalArticlepeer-review

39 Scopus citations


Genetic data suggest that IL-6 trans-signaling may have a pathogenic role in the lung; however, the effects of IL-6 trans-signaling on lung effector cells have not been investigated. In this study, human airway smooth muscle (HASM) cells were treated with IL-6 (classical) or IL-6+sIL6R (trans-signaling) for 24 h and gene expression was measured by RNAseq. Intracellular signaling and transcription factor activation were assessed by Western blotting and luciferase assay, respectively. The functional effect of IL-6 trans-signaling was determined by proliferation assay. IL-6 trans-signaling had no effect on phosphoinositide-3 kinase and Erk MAP kinase pathways in HASM cells. Both classical and IL-6 trans-signaling in HASM involves activation of Stat3. However, the kinetics of Stat3 phosphorylation by IL-6 trans-signaling was different than classical IL-6 signaling. This was further reflected in the differential gene expression profile by IL-6 trans-signaling in HASM cells. Under IL-6 trans-signaling conditions 36 genes were upregulated, including PLA2G2A, IL13RA1, MUC1, and SOD2. Four genes, including CCL11, were downregulated at least twofold. The expression of 112 genes was divergent between IL-6 classical and trans-signaling, including the genes HILPDA, NNMT, DAB2, MUC1, WWC1, and VEGFA. Pathway analysis revealed that IL-6 trans-signaling induced expression of genes involved in regulation of airway remodeling, immune response, hypoxia, and glucose metabolism. Treatment of HASM cells with IL-6+sIL6R induced proliferation in a dose-dependent fashion, suggesting a role for IL-6 trans-signaling in asthma pathogenesis. These novel findings demonstrate differential effect of IL-6 trans-signaling on airway cells and identify IL-6 trans-signaling as a potential modifier of airway inflammation and remodeling.

Original languageEnglish (US)
Pages (from-to)L129-L138
JournalAmerican Journal of Physiology - Lung Cellular and Molecular Physiology
Issue number2
StatePublished - Jul 15 2015
Externally publishedYes


  • Airway disease
  • Gene expression
  • Human airway smooth muscle
  • IL-6
  • IL-6 trans-signaling

ASJC Scopus subject areas

  • Physiology
  • Pulmonary and Respiratory Medicine
  • Physiology (medical)
  • Cell Biology


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