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

Hagen, Moira; Fagan, Karen A.; Steudel, Wolfgang; Carr, Michelle; Lane, Kirk B.; Rodman, David M.; West, James

doi:10.1152/ajplung.00197.2006

Cited by 145 publications

(134 citation statements)

References 36 publications

Supporting

Mentioning

129

Contrasting

Unclassified

Order By: Relevance

“…We did observe an increase in Id1 expression, which is sensitive to increased iron stores 46 and IL-6. 47 IL-6 is the primary mediator of increased Hepc expression in response to inflammation, 27 but we were not able to detect a significant decrease in Hepc in our aged IL-6 KO mice (Figure 1 and Online Supplementary Table S6).…”

Section: Anemia In Aged Mice Is Not Iron-restrictedmentioning

confidence: 74%

Investigation of the role of interleukin-6 and hepcidin antimicrobial peptide in the development of anemia with age

et al. 2013

View full text Add to dashboard Cite

Anemia is common in older adults and associated with adverse health outcomes in epidemiological studies. A thorough understanding of the complex pathophysiological mechanisms driving anemia in the elderly is lacking; but inflammation, iron restriction, and impaired erythroid maturation are thought to influence the phenotype. We hypothesized that interleukin-6 contributes to this anemia, given its pro-inflammatory activities, its ability to induce hepcidin antimicrobial peptide, and its negative impact on several tissues in older adults. We tested this hypothesis by comparing changes in indices of inflammation, iron metabolism and erythropoiesis in aged C57BL/6 mice to aged mice with targeted deletions of interleukin-6 or hepcidin antimicrobial peptide. Circulating neutrophil and monocyte numbers and inflammatory cytokines increased with age. Decline in hemoglobin concentration and red blood cell number indicated that C57BL/6, interleukin-6 knockout mice, and hepcidin antimicrobial peptide knockout mice all demonstrated impaired erythropoiesis by 24 months. However, the interleukin-6 knock out genotype and the hepcidin antimicrobial peptide knock out genotype resulted in improved erythropoiesis in aged mice. Increased erythropoietic activity in the spleen suggested that the erythroid compartment was stressed in aged C57BL/6 mice compared to aged interleukin-6 knockout mice. Our data suggest C57BL/6 mice are an appropriate mammalian model for the study of anemia with age. Furthermore, although interleukin-6 and hepcidin antimicrobial peptide are not required, they can participate in the development of anemia in aging mice, and could be targeted, pre-clinically, with existing interventions to determine the feasibility of such agents for the treatment of anemia in older adults. ABSTRACTsuch as IL-1α or β.33 Thus, IL-6 and Hepc may have inde

show abstract

Section: Anemia In Aged Mice Is Not Iron-restrictedmentioning

confidence: 74%

Investigation of the role of interleukin-6 and hepcidin antimicrobial peptide in the development of anemia with age

et al. 2013

View full text Add to dashboard Cite

show abstract

“…These mutations disrupt bone morphogenetic protein (BMP)/Smad-mediated signalling [29], potentiate BMP/mitogen-activated protein kinase signalling [30] and could underlie the abnormal vascular cell proliferation observed in FPAH [31]. Interestingly, several studies suggest that dysregulation of the BMP pathway leads to vulnerability to an inflammatory second hit [32][33][34].…”

mentioning

confidence: 99%

Dexamethasone reverses monocrotaline-induced pulmonary arterial hypertension in rats

Lc¹,

Montani²,

Tchérakian³

et al. 2010

Eur Respir J

View full text Add to dashboard Cite

Pulmonary arterial hypertension (PAH) is associated with dysregulated bone morphogenetic protein receptor (BMPR)-II signaling and pulmonary vascular inflammation. We evaluated the effects of dexamethasone on monocrotaline (MCT)-induced PAH in rats for potential reversal of PAH at late time-points.Saline-treated control, MCT-exposed, MCT-exposed and dexamethasone-treated rats (5 mg?kg ) were evaluated at day 28 and day 35 following MCT for haemodynamic parameters, right ventricular hypertrophy, morphometry, immunohistochemistry, and IL6 and BMPR2 expression.Dexamethasone improved haemodynamics and pulmonary vascular remodelling, preventing PAH development at early (day 1-14 and 1-28) and reversing PAH at late (day 14-28 and 21-35) time-points following MCT, as well as improving survival in MCT-exposed rats compared with controls. Both MCT-induced pulmonary IL6 overexpression and interleukin (IL)-6-expressing adventitial inflammatory cell infiltration were reduced with dexamethasone. This was associated with pulmonary BMPR2 downregulation following MCT, which was increased with dexamethasone, in whole lung and control pulmonary artery smooth muscle cells. Dexamethasone also reduced proliferation of rat pulmonary artery smooth muscle cells in vitro.Experimental PAH can be prevented and reversed by dexamethasone, and survival is improved. In this model, mechanisms may involve reduction of IL-6-expressing inflammatory cells, restoration of pulmonary BMPR2 expression and reduced proliferation of vascular smooth muscle cells.

show abstract

“…Additionally, IL-6 levels were dramatically increased by more than 15-fold in transgenic mice expressing a mutant isoform of BMPR2 that spontaneously developed PAH (15). A negative feedback loop in which IL-6 inhibits bone morphogenetic protein receptor 2 (BMPR2) signaling has been proposed in this model (15).In 2004, working with the rat/MCT model of PAH, we reported the reciprocal relationship between the loss of caveolin-1 (cav-1) in plasma membrane rafts/caveolae in PAECs and hyperactivation of the pro-proliferative, IL-6-activated transcription factor STAT3 [increase in tyrosine-phosphorylated STAT3 (PY-STAT3); Ref. 24].…”

mentioning

confidence: 99%

mentioning

confidence: 99%

Cytoplasmic provenance of STAT3 and PY-STAT3 in the endolysosomal compartments in pulmonary arterial endothelial and smooth muscle cells: implications in pulmonary arterial hypertension

Mukhopadhyay

Shah

et al. 2008

American Journal of Physiology-Lung Cellular and Molecular Phys

View full text Add to dashboard Cite

PB. Cytoplasmic provenance of STAT3 and PY-STAT3 in the endolysosomal compartments in pulmonary arterial endothelial and smooth muscle cells: implications in pulmonary arterial hypertension. Am J Physiol Lung Cell Mol Physiol 294: L449-L468, 2008. First published December 14, 2007 doi:10.1152/ajplung.00377.2007.-Lung vascular lesions in pulmonary arterial hypertension (PAH) are characterized by enlarged, vacuolated ("megalocytotic") pulmonary arterial endothelial (PAEC) and smooth muscle cells (PASMC). We have recently proposed that dysfunction of vesicle tethers, soluble N-ethylmaleimide-sensitive factor attachment proteins (SNAPs), and SNAP receptors (SNAREs), leading to disruptions of intracellular trafficking in the Golgi to plasma membrane (centrifugal) and the plasma membrane to cell interior (centripetal) directions is a key causal mechanism in this disease. In PAH, there was a reciprocal relationship between loss of caveolin-1 (cav-1) in PAECs and increased expression of "activated" tyrosine-phosphorylated STAT3 (PY-STAT3) associated with a block in centrifugal trafficking to/through the Golgi organelle. In the present study, we investigated 1) whether centripetal trafficking of STAT3 and PY-STAT3 in PAECs and PASMCs was membrane-associated, and 2) whether this might be affected in PAH. Immunofluorescence and live cell imaging studies showed that, in both PAEC and PASMC, STAT3 was associated with cytoplasmic vesicles partially colocalizing with markers of the endolysosomal compartments (clathrin, EEA1, Rab5, Rab11, and LAMP1). Overexpression of cav-1 increased the targeting of STAT3 to lysosomes and inhibited STAT3 transcriptional activity. Exposure of PAECs to monocrotaline (MCT) pyrrole, which causes PAH in the rat, led to a loss of caveolar STAT3 with increased sequestration of STAT3 and PY-STAT3 in endosomes. In vivo, marked cytoplasmic sequestration of activated PY-STAT3 was a common feature in PAEC in the rat/MCT model and in cells in the proliferative arterial and plexiform lesions in PAH in humans. These data highlight the epigenetic regulation of centripetal cytokine and growth-factor signaling pathways and its modulation in PAH.caveolin-1; signaling endosome; monocrotaline PULMONARY ARTERIAL HYPERTENSION (PAH) is characterized by the reduction of the lumen of medium-sized pulmonary arteries by proliferating, enlarged, vacuolated, and apoptosis-resistant ("megalocytotic") pulmonary arterial endothelial (PAEC) and smooth muscle (PASMC) cells (42,43). We (24, 26 -28, 41-43, 47) recently proposed that dysfunction of vesicle tethers, soluble N-ethylmaleimide-sensitive factor attachment proteins (SNAPs), and SNAP receptors (SNAREs), leading to disruptions of intracellular trafficking from the Golgi to plasma membrane (centrifugal) and the plasma membrane to cell interior (centripetal) directions might represent a key subcellular mechanism leading to the changes observed in endothelial and vascular smooth muscle cells in PAH. We (24, 26 -28, 41-43, 47) have previously provided evidence for disrupt...

show abstract

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

Cited by 145 publications

References 36 publications

Investigation of the role of interleukin-6 and hepcidin antimicrobial peptide in the development of anemia with age

Investigation of the role of interleukin-6 and hepcidin antimicrobial peptide in the development of anemia with age

Dexamethasone reverses monocrotaline-induced pulmonary arterial hypertension in rats

Cytoplasmic provenance of STAT3 and PY-STAT3 in the endolysosomal compartments in pulmonary arterial endothelial and smooth muscle cells: implications in pulmonary arterial hypertension

Contact Info

Product

Resources

About