Relaxin Stimulates Leukocyte Adhesion and Migration through a Relaxin Receptor LGR7-dependent Mechanism

Abstract

Leukocytes are critical effectors of inflammation and tumor biology. Chemokine-like factors produced by such inflammatory sites are key mediators of tumor growth that activate leukocytic recruitment and tumor infiltration and suppress immune surveillance. Here we report that the endocrine peptide hormone, relaxin, is a regulator of leukocyte biology with properties important in recruitment to sites of inflammation. This study uses the human monocytic cell line THP-1 and normal human peripheral blood mononuclear cells to define a novel role for relaxin in regulation of leukocyte adhesion and migration. Our studies indicate that relaxin promotes adenylate cyclase activation, substrate adhesion, and migratory capacity of mononuclear leukocytes through a relaxin receptor LGR7-dependent mechanism. Relaxin-stimulated cAMP accumulation was observed to occur primarily in non-adherent cells. Relaxin stimulation results in increased substrate adhesion and increased migratory activity of leukocytes. In addition, relaxinstimulated substrate adhesion resulted in enhanced chemotaxis to monocyte chemoattractant protein-1. These responses in THP-1 and peripheral blood mononuclear cells are relaxin dose-dependent and proportional to cAMP accumulation. We further demonstrate that LGR7 is critical for mediating these biological responses by use of RNA interference lentiviral short hairpin constructs. In summary, we provide evidence that relaxin is a novel leukocyte stimulatory agent with properties affecting adhesion and chemomigration.Complex interactions between tumor cells and the immune system regulate disease progression by stimulating cell proliferation, neovascularization, tissue remodeling, and metastasis or by inhibiting the host anti-tumor immune response (1). However, the factors produced by tumor cells that affect their immune surveillance remain to be fully elucidated. The insulin-related peptide hormone, relaxin, possesses key features required of a tumor-derived factor capable of affecting malignant progression, and its emerging role as a putative mediator of tumor progression has been recently reviewed (2). In humans, relaxin is encoded by three genes designated H1, H2, and H3 (3). Functionally, relaxin is classically described to improve blood supply to multiple organs including the uterus, mammary gland, lung, and heart (4). Relaxin is also known to increase matrix metalloproteinase expression, resulting in collagen turnover of reproductive tissues and in models of fibrosis, and is responsible for lengthening of the interpubic ligament during delivery (3-5).A role for relaxin in cancer progression was first suggested 38 years ago by studies indicating that carcinogen-fed rats experienced substantially enhanced mammary tumor growth when co-treated with relaxin several weeks later (6). More recently, relaxin has been shown to support growth and invasiveness of breast cancer cells (7,8), and elevated relaxin serum levels are positively correlated with breast cancer metastases (9). Relaxin immunostaining has been dem...

The hormonal induction of cervical remodeling in the common marmoset monkey (Callithrix jacchus)

“…It is possible that this cooperation of RLX and E2 due to the invasion of eosinophil cells could be related to the ability of E2 to increase the production of granulocyte/macrophage-colony stimulating factor (GM-CSF), which is acting chemotactically on the appropriate cells (Robertson et al 1996). Moreover, it has been suggested that RLX as a novel leukocyte stimulatory agent can affect adhesion and chemomigration (Figueiredo et al 2006). Furthermore, the polymorphonuclear leukocytes can increase the permeability of certain tissues by the formation of intercommunicating canals through the cervical ECM (Hibbs et al 1982, Milks et al 1986.…”

Prevention of Bleomycin-Induced Pulmonary Fibrosis by a Novel Antifibrotic Peptide with Relaxin-Like Activity

“…To further evaluate the biological activity of CGEN25009, we used THP-1 cells that natively express the RXFP1/LGR7 receptor. H2 relaxin was previously shown to promote adenylate cyclase activation in these cells in a RXFP1/LGR7-dependent manner (Nguyen et al, 2003;Figueiredo et al, 2006). Relaxin was also shown to concentration-dependently stimulate intracellular accumulation of cAMP and cGMP in THP-1 cells as well as NO generation (Parsell et al, 1996;Baccari and Bani, 2008).…”

Transcriptome Changes Associated with Protective Immunity in T and B Cell-Deficient <i>Rag1<sup>-/-</sup> </i> Mutant Zebrafish

“…Relaxins (RLN) are a pleotropic hormone group with a wide range of biological and pathological activities in various tissues and organs in various physiological and pathological conditions [70]. Relaxins are hormones that regulate the migration of leukocyte to sites of inflammation, and increases substrate adhesion [71].…”

“…Relaxins act on inactivation of contractile machinery leading to cell relaxation. It is also involved in vasodilation in several organs and tissues [70]. Dilation of the blood vessels is a result of the movement of tissue macrophage derived cytokines to the site of injection and/or bacterial presence, which in turn leads to the movement of leucocytes such as neutrophils and monocytes to the site of bacterial infection [75].…”