Interaction of interleukin-6 and the BMP pathway in pulmonary smooth muscle

Am J Physiol Lung Cell Mol Physiol. 2007 Jun;292(6):L1473-9. doi: 10.1152/ajplung.00197.2006. Epub 2007 Feb 23.

Abstract

The majority of familial pulmonary arterial hypertension (PAH) cases are caused by mutations in the type 2 bone morphogenetic protein receptor (BMPR2). However, less than one-half of BMPR2 mutation carriers develop PAH, suggesting that the most important function of BMPR2 mutation is to cause susceptibility to a "second hit." There is substantial evidence from the literature implicating dysregulated inflammation, in particular the cytokine IL-6, in the development of PAH. We thus hypothesized that the BMP pathway regulates IL-6 in pulmonary tissues and conversely that IL-6 regulates the BMP pathway. We tested this in vivo using transgenic mice expressing an inducible dominant negative BMPR2 in smooth muscle, using mice injected with an IL-6-expressing virus, and in vitro using small interfering RNA (siRNA) to BMPR2 in human pulmonary artery smooth muscle cells (PA SMC). Consistent with our hypothesis, we found upregulation of IL-6 in both the transgenic mice and in cultured PA SMC with siRNA to BMPR2; this could be abolished with p38(MAPK) inhibitors. We also found that IL-6 in vivo caused a twofold increase in expression of the BMP signaling target Id1 and caused increased BMP activity in a luciferase-reporter assay in PA SMC. Thus we have shown both in vitro and in vivo a complete negative feedback loop between IL-6 and BMP, suggesting that an important consequence of BMPR2 mutations may be poor regulation of cytokines and thus vulnerability to an inflammatory second hit.

Publication types

  • Research Support, N.I.H., Extramural
  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animals
  • Bone Morphogenetic Protein Receptors, Type II / genetics
  • Bone Morphogenetic Protein Receptors, Type II / metabolism*
  • Cells, Cultured
  • Chemokine CCL2 / genetics
  • Chemokine CCL2 / metabolism
  • Humans
  • Hypertension, Pulmonary / metabolism*
  • Hypertension, Pulmonary / physiopathology
  • Inhibitor of Differentiation Protein 1 / genetics
  • Interleukin-6 / genetics
  • Interleukin-6 / metabolism*
  • Mice
  • Mice, Transgenic
  • Muscle, Smooth, Vascular / cytology
  • Muscle, Smooth, Vascular / immunology
  • Muscle, Smooth, Vascular / metabolism*
  • Pulmonary Artery / cytology
  • Pulmonary Artery / immunology
  • Pulmonary Artery / metabolism*
  • RNA, Small Interfering
  • Signal Transduction / immunology
  • Transcription, Genetic / physiology
  • Transforming Growth Factor beta / genetics
  • Transforming Growth Factor beta / metabolism

Substances

  • Ccl2 protein, mouse
  • Chemokine CCL2
  • Idb1 protein, mouse
  • Inhibitor of Differentiation Protein 1
  • Interleukin-6
  • RNA, Small Interfering
  • Transforming Growth Factor beta
  • Bmpr2 protein, mouse
  • Bone Morphogenetic Protein Receptors, Type II