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

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.