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.
Hagen
Moira
M
Division of Pulmonary Sciences and Critical Care Medicine, University of Colorado Health Sciences Center, Denver, Colorado 80262, USA.
Fagan
Karen
K
Steudel
Wolfgang
W
Carr
Michelle
M
Lane
Kirk
K
Rodman
David M
DM
West
James
J
D000818:Animals; D052006:Bone Morphogenetic Protein Receptors, Type II / Q000235:genetics / Q000378:metabolism*; D002478:Cells, Cultured; D018932:Chemokine CCL2 / Q000235:genetics / Q000378:metabolism; D006801:Humans; D006976:Hypertension, Pulmonary / Q000378:metabolism* / Q000503:physiopathology; D051798:Inhibitor of Differentiation Protein 1 / Q000235:genetics; D015850:Interleukin-6 / Q000235:genetics / Q000378:metabolism*; D051379:Mice; D008822:Mice, Transgenic; D009131:Muscle, Smooth, Vascular / Q000166:cytology / Q000276:immunology / Q000378:metabolism*; D011651:Pulmonary Artery / Q000166:cytology / Q000276:immunology / Q000378:metabolism*; D034741:RNA, Small Interfering; D015398:Signal Transduction / Q000276:immunology; D014158:Transcription, Genetic / Q000502:physiology; D016212:Transforming Growth Factor beta / Q000235:genetics / Q000378:metabolism
C491768:Ccl2 protein, mouse; D018932:Chemokine CCL2; C497455:Idb1 protein, mouse; D051798:Inhibitor of Differentiation Protein 1; D015850:Interleukin-6; D034741:RNA, Small Interfering; D016212:Transforming Growth Factor beta; C498219:Bmpr2 protein, mouse; D052006:Bone Morphogenetic Protein Receptors, Type II