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1 Medicine, UCDHSC, Denver, Colorado, United States
2 Medicine, Vanderbilt University, Nashville, Tennessee, United States
* To whom correspondence should be addressed. E-mail: james.west{at}uchsc.edu.
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 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 IL6, in the development of PAH. We thus hypothesized that the BMP pathway regulates IL6 in pulmonary tissues, and conversely that IL6 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 IL6-expressing virus, and in vitro using siRNA to BMPR2 in human pulmonary artery smooth muscle cells (PA SMC). Consistent with our hypothesis, we found upregulation of IL6 in both the transgenic mice and in cultured PA SMC with siRNA to BMPR2; this could be abolished with p38MAPK inhibitors. We also found that IL6 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 IL6 and BMP, suggesting that an important consequence of BMPR2 mutations may be poor regulation of cytokines and thus vulnerability to an inflammatory second hit.
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