Disparate effects of relaxin and TGF 1: relaxin increases, but TGF 1 inhibits, the relaxin receptor and the production of IGFBP-1 in human endometrial stromal/decidual cells

Mazella, James; Tang, Meiyi; Tseng, Linda

doi:10.1093/humrep/deh274

Cited by 55 publications

(47 citation statements)

References 23 publications

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“…We found that RXFP1 expression was reduced in IPF fibroblasts and that expression was reduced even further in the presence of TGF-b. These data support previous observations that TGF-b is associated with reduced expression of RXFP1 (30). In our hands, supraphysiologic in vitro concentrations of TGF-b were observed to decrease RXFP1 in IPF fibroblasts.…”

Section: Discussionsupporting

confidence: 93%

Expression of RXFP1 Is Decreased in Idiopathic Pulmonary Fibrosis. Implications for Relaxin-based Therapies

Tan

Tedrow

Dutta

et al. 2016

Am J Respir Crit Care Med

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Rationale: Relaxin is a hormone that has been considered as a potential therapy for patients with fibrotic diseases.Objectives: To gauge the potential efficacy of relaxin-based therapies in idiopathic pulmonary fibrosis (IPF), we studied gene expression for relaxin/insulin-like family peptide receptor 1 (RXFP1) in IPF lungs and controls.Methods: We analyzed gene expression data obtained from the Lung Tissue Research Consortium and correlated RXFP1 gene expression data with cross-sectional clinical and demographic data. We also employed ex vivo donor and IPF lung fibroblasts to test RXFP1 expression in vitro. We tested CGEN25009, a relaxin-like peptide, in lung fibroblasts and in bleomycin injury. Measurements and Main Results:We found that RXFP1 is significantly decreased in IPF. In patients with IPF, the magnitude of RXFP1 gene expression correlated directly with diffusing capacity of the lung for carbon monoxide (P , 0.0001). Significantly less RXFP1 was detected in vitro in IPF fibroblasts than in donor controls. Transforming growth factor-b decreased RXFP1 in both donor and IPF lung fibroblasts. CGEN25009 was effective at decreasing bleomycin-induced, acid-soluble collagen deposition in vivo. The relaxin-like actions of CGEN25009 were abrogated by RXFP1 silencing in vitro, and, in comparison with donor lung fibroblasts, IPF lung fibroblasts exhibited decreased sensitivity to the relaxin-like effects of CGEN25009.Conclusions: IPF is characterized by the loss of RXFP1 expression. RXFP1 expression is directly associated with pulmonary function in patients with IPF. The relaxin-like effects of CGEN25009 in vitro are dependent on expression of RXFP1. Our data suggest that patients with IPF with the highest RXFP1 expression would be predicted to be most sensitive to relaxin-based therapies.Keywords: relaxin; pulmonary fibrosis; transforming growth factor-b; RXFP1 At a Glance CommentaryScientific Knowledge on the Subject: Relaxin and relaxinbased therapies have been considered as potential therapies for pulmonary fibrosis.What This Study Adds to the Field: We found that expression of the relaxin receptor, RXFP1, is decreased in idiopathic pulmonary fibrosis and is associated with impaired pulmonary function. Understanding how RXFP1 is regulated is critical to the success of relaxin-based therapies in idiopathic pulmonary fibrosis.

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Section: Discussionsupporting

confidence: 93%

Expression of RXFP1 Is Decreased in Idiopathic Pulmonary Fibrosis. Implications for Relaxin-based Therapies

Tan

Tedrow

Dutta

et al. 2016

Am J Respir Crit Care Med

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“…This occurred constitutively and was significantly increased in the presence of ligand. Relaxin treatment of human endometrial (52) and decidual cells (23) increases RXFP1 mRNA, but the data presented here suggest that relaxin action in the fetal membranes is also controlled by the level of its receptors expressed on the cell surface of its target cells.…”

Section: Discussionmentioning

confidence: 55%

Characterization of Relaxin Receptor (RXFP1) Desensitization and Internalization in Primary Human Decidual Cells and RXFP1-Transfected HEK293 Cells

Kern

Bryant‐Greenwood

2008

Endocrinology

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We report here the desensitization and internalization of the relaxin receptor (RXFP1) after agonist activation in both primary human decidual cells and HEK293 cells stably transfected with RXFP1. The importance of ␤-arrestin 2 in these processes has also been demonstrated. Thus, in HEK-RXFP1 cells the desensitization of RXFP1 was significantly increased when ␤-arrestin 2 was overexpressed. After relaxin activation, ␤-arrestin 2 was translocated to the cell membrane and RXFP1 underwent rapid internalization. We have previously shown that RXFP1 forms dimers/oligomers during its biosynthesis and trafficking to the plasma membrane, we now show that internalization of RXFP1 occurs through this dimerization/oligomerization. In nonagonist stimulated cells, it is known that the majority of the RXFP1 is located intracellularly and was confirmed in the cells used here. Constitutive internalization of RXFP1 could account for this and indeed, slow but robust constitutive internalization, which was increased after agonist stimulation was demonstrated. A carboxyl-terminal deleted RXFP1 variant had a similar level of constitutive agonist-independent internalization as the wild-type RXFP1 but lost sensitivity to agonist stimulation. This demonstrated the importance of the carboxyl terminus in agonist-stimulated receptor internalization. These data suggest that the autocrine/paracrine actions of relaxin in the decidua are under additional controls at the level of expression of its receptor on the surface of its target cells. (Endocrinology 150: 2419 -2428, 2009) R elaxin is structurally related to insulin (1), and its main systemic source in pregnant women is the corpus luteum (2). Recent work has expanded its role to several important nonreproductive tissues: cardiovascular, renal, and lung tissues and in prostate and thyroid cancers (3-7). We have shown that human relaxin is produced by the maternal decidua during pregnancy and acts locally within the decidua and the apposed chorion (8, 9) by binding to these cells (10).The relaxin receptor, relaxin family peptide receptor (RXFP)-1, belongs to the G protein-coupled receptor (GPCR) superfamily and was originally named the leucine-rich repeat-containing G proteincoupled receptor (LGR)-7 (11) and most recently RXFP1. RXFP1 and the closely related RXFP2 are mosaic proteins containing an extracellular region with 10 leucine-rich repeats and seven-transmembrane helix domains. RXFP1 and RXFP2 are activated by their endogenous ligands, relaxin, and insulin-like peptide 3 (INSL3), respectively. Among the members of the LGR subfamily are the glycoprotein hormone receptors such as LH receptor (LHR), FSH receptor (FSHR), and TSH receptor (TSHR) (12). RXFP1 and RXFP2 belong to the LGR C subfamily distinguished by a unique low-density lipoprotein class A module (LDL-A) at their N termini. We demonstrated that the LDL-A module of RXFP1 has a role in receptor maturation, cell surface delivery, and ligand-induced receptor signaling (13). Mutations in the LDL-A module of RXFP2 affects the prop...

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“…In mouse, RXFP2 mRNA is present in testis and gubernaculum (Overbeek et al, 2001). In human, RXFP2 mRNA is found in uterus and testis Mazella et al, 2004). By immunohistochemistry, RXFP2 epitopes have been identified in spermatocytes, spermatids, and Leydig cells within the human testis, and in the epididymal epithelium (R. Ivell, unpublished data).…”

Section: Table 3 Agonists and Antagonists At Receptors For Relaxin Anmentioning

confidence: 99%

“…Rats treated with monoclonal relaxin antibody during the second half of pregnancy display a lack of nipple devel- ; e mRNA by RT-PCR ; f mRNA by RT-PCR (Kubota et al, 2002); g mRNA by RT-PCR (Samuel et al, 2003b); h mRNA by RT-PCR, protein by immunohistochemical analysis (Luna et al, 2004); i mRNA by RT-PCR (Samuel et al, 2004a); j mRNA by RT-PCR (Mazella et al, 2004); k mRNA by RT-PCR (Overbeek et al, 2001); l mRNA by Northern blot analysis ; m mRNA by RT-PCR (Nguyen et al, 2003); n mRNA by RT-PCR (Siebel et al, 2003); o mRNA by RT-PCR (Samuel et al, 2003b); p mRNA by RT-PCR (Hombach- Klonisch et al, 2003); q mRNA by Northern blot analysis and in situ hybridization (Kawamura et al, 2004); r mRNA by RT-PCR (Liu et al, 2003b); s mRNA by RT-PCR (Liu et al, 2003a); t protein by receptor autoradiography (Osheroff et al, 1990); u protein by receptor autoradiography ; v protein by immunohistochemistry ; w protein by receptor autoradiography ;…”

Section: Table 3 Agonists and Antagonists At Receptors For Relaxin Anmentioning

confidence: 99%

International Union of Pharmacology LVII: Recommendations for the Nomenclature of Receptors for Relaxin Family Peptides

Bathgate

Ivell²,

Sanborn³

et al. 2006

Pharmacol Rev

291

256

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Disparate effects of relaxin and TGF 1: relaxin increases, but TGF 1 inhibits, the relaxin receptor and the production of IGFBP-1 in human endometrial stromal/decidual cells

Cited by 55 publications

References 23 publications

Expression of RXFP1 Is Decreased in Idiopathic Pulmonary Fibrosis. Implications for Relaxin-based Therapies

Expression of RXFP1 Is Decreased in Idiopathic Pulmonary Fibrosis. Implications for Relaxin-based Therapies

Characterization of Relaxin Receptor (RXFP1) Desensitization and Internalization in Primary Human Decidual Cells and RXFP1-Transfected HEK293 Cells

International Union of Pharmacology LVII: Recommendations for the Nomenclature of Receptors for Relaxin Family Peptides

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