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...