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Interaction of interleukin-6 and the BMP pathway in pulmonary smooth muscle
Moira Hagen1, Karen Fagan, Wolfgang Steudel
1Division of Pulmonary Sciences and Critical Care Medicine, University of Colorado Health Sciences Center, Denver, Colorado 80262, USA.
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.
Insights
Mutations in BMPR2 cause susceptibility to pulmonary arterial hypertension (PAH). This study reveals a negative feedback loop between BMP signaling and IL-6, suggesting inflammation is a critical "second hit" in PAH development.
Area of Science:
- Cardiovascular Biology
- Molecular Medicine
- Genetic Diseases
Background:
- Familial pulmonary arterial hypertension (PAH) is often linked to bone morphogenetic protein receptor type 2 (BMPR2) mutations.
- However, BMPR2 mutation carriers have incomplete penetrance, indicating a need for additional factors (a "second hit") for PAH development.
- Inflammation, particularly involving the cytokine IL-6, is implicated in PAH pathogenesis.
Purpose of the Study:
- To investigate the reciprocal regulatory relationship between the BMP pathway and IL-6 in pulmonary arterial hypertension.
- To determine if BMPR2 dysfunction leads to altered IL-6 levels and if IL-6 influences BMP pathway activity.
Main Methods:
- In vivo studies using transgenic mice with inducible dominant-negative BMPR2 and viral IL-6 delivery.
- In vitro studies using small interfering RNA (siRNA) targeting BMPR2 in human pulmonary artery smooth muscle cells (PA SMC).
- Assays included measuring IL-6 levels, p38(MAPK) inhibition, BMP signaling target Id1 expression, and BMP activity via luciferase reporter assays.
Main Results:
- BMPR2 dysfunction (via genetic manipulation or siRNA) led to increased IL-6 expression in pulmonary tissues and PA SMC.
- This IL-6 upregulation was mitigated by p38(MAPK) inhibitors.
- IL-6 administration in vivo increased the expression of the BMP signaling target Id1 and enhanced BMP activity in PA SMC.
Conclusions:
- A complete negative feedback loop exists between the BMP pathway and IL-6 in pulmonary artery smooth muscle cells.
- BMPR2 mutations may impair cytokine regulation, increasing susceptibility to inflammatory "second hits" that contribute to PAH.
- This finding highlights the interplay between genetic predisposition and inflammatory triggers in PAH.
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