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

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, relaxin-stimulated 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. 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, relaxin-stimulated 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 (1Coussens L.M. Werb Z. Nature. 2002; 420: 860-867Crossref PubMed Scopus (11050) Google Scholar). 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 (2Silvertown J.D. Summerlee A.J. Klonisch T. Int. J. Cancer. 2003; 107: 513-519Crossref PubMed Scopus (63) Google Scholar). In humans, relaxin is encoded by three genes designated H1, H2, and H3 (3Bathgate R.A. Samuel C.S. Burazin T.C. Gundlach A.L. Tregear G.W. Trends Endocrinol. Metab. 2003; 14: 207-213Abstract Full Text Full Text PDF PubMed Scopus (109) Google Scholar). Functionally, relaxin is classically described to improve blood supply to multiple organs including the uterus, mammary gland, lung, and heart (4Bani D. Gen. Pharmacol. 1997; 28: 13-22Crossref PubMed Scopus (202) Google Scholar). 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 (3Bathgate R.A. Samuel C.S. Burazin T.C. Gundlach A.L. Tregear G.W. Trends Endocrinol. Metab. 2003; 14: 207-213Abstract Full Text Full Text PDF PubMed Scopus (109) Google Scholar, 4Bani D. Gen. Pharmacol. 1997; 28: 13-22Crossref PubMed Scopus (202) Google Scholar, 5Ivell R. Einspanier A. Trends Endocrinol. Metab. 2002; 13: 343-348Abstract Full Text Full Text PDF PubMed Scopus (78) Google Scholar). 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 (6Plunkett E.R. Gammal E.B. Br. J. Cancer. 1967; 21: 592-600Crossref PubMed Scopus (7) Google Scholar). More recently, relaxin has been shown to support growth and invasiveness of breast cancer cells (7Sacchi T.B. Bani D. Brandi M.L. Falchetti A. Bigazzi M. Int. J. Cancer. 1994; 57: 129-134Crossref PubMed Scopus (58) Google Scholar, 8Binder C. Hagemann T. Husen B. Schulz M. Einspanier A. Mol. Hum. Reprod. 2002; 8: 789-796Crossref PubMed Scopus (89) Google Scholar), and elevated relaxin serum levels are positively correlated with breast cancer metastases (9Binder C. Simon A. Binder L. Hagemann T. Schulz M. Emons G. Trumper L. Einspanier A.A. Breast Cancer Res. Treat. 2004; 87: 157-166Crossref PubMed Scopus (62) Google Scholar). Relaxin immunostaining has been demonstrated in epithelial and myoepithelial cells of normal and cancerous breast tissue (10Tashima L.S. Mazoujian G. Bryant-Greenwood G.D. J. Mol. Endocrinol. 1994; 12: 351-364Crossref PubMed Scopus (62) Google Scholar), and significantly higher levels of relaxin staining occur in neoplastic breast tissues as compared with normal breast tissue (11Mazoujian G. Bryant-Greenwood G.D. Lancet. 1990; 335: 298-299Abstract PubMed Scopus (29) Google Scholar). Similarly, relaxin is produced by the normal prostate (12Ivell R. Hunt N. Khan-Dawood F. Dawood M.Y. Mol. Cell. Endocrinol. 1989; 66: 251-255Crossref PubMed Scopus (73) Google Scholar, 13Sokol R.Z. Wang X.S. Lechago J. Johnston P.D. Swerdloff R.S. J. Histochem. Cytochem. 1989; 37: 1253-1255Crossref PubMed Scopus (33) Google Scholar, 14Hansell D.J. Bryant-Greenwood G.D. Greenwood F.C. J. Clin. Endocrinol. Metab. 1991; 72: 899-904Crossref PubMed Scopus (97) Google Scholar, 15Winslow J.W. Shih A. Bourell J.H. Weiss G. Reed B. Stults J.T. Goldsmith L.T. Endocrinology. 1992; 130: 2660-2668Crossref PubMed Scopus (0) Google Scholar, 16Samuel C.S. Tian H. Zhao L. Amento E.P. Lab. Investig. 2003; 83: 1055-1067Crossref PubMed Scopus (80) Google Scholar), and expressed in prostate cancer cell lines LNCaP, DU145, and PC3 (17Gunnersen J.M. Roche P.J. Tregear G.W. Crawford R.J. J. Mol. Endocrinol. 1995; 15: 153-166Crossref PubMed Scopus (24) Google Scholar, 18Brookes D.E. Zandvliet D. Watt F. Russell P.J. Molloy P.L. Prostate. 1998; 35: 18-26Crossref PubMed Scopus (55) Google Scholar). Relaxin has been implicated in increased tumor growth and angiogenesis of PC3 prostate xenografts (19Silvertown J.D. Ng J. Sato T. Summerlee A.J. Medin J.A. Int. J. Cancer. 2006; 118: 62-73Crossref PubMed Scopus (71) Google Scholar), whereas we have found that H2 relaxin expression is up-regulated in LNCaP cells undergoing neuroendocrine differentiation (20Figueiredo K.A. Palmer J.B. Mui A.L. Nelson C.C. Cox M.E. Ann. N. Y. Acad. Sci. 2005; 1041: 320-327Crossref PubMed Scopus (10) Google Scholar). Together, these studies strongly implicate relaxin in breast and prostate cancer progression. Relaxin has been attributed with regulation of several intermediary responses or intracellular signaling events in a variety of cell types. These include cAMP, protein kinase A (21Nguyen B.T. Yang L. Sanborn B.M. Dessauer C.W. Mol. Endocrinol. 2003; 17: 1075-1084Crossref PubMed Scopus Google Scholar, B. R. Mol. Hum. Reprod. PubMed Scopus Google Scholar, M. Res. 1990; PubMed Scopus Google Scholar, Amento E.P. J. Full Text Full Text PDF PubMed Scopus Google Scholar, L. N. M. PubMed Scopus Google Scholar, T. C. Res. PubMed Scopus Google Scholar, M. C. L. Sanborn B.M. J. 1995; PubMed Google Scholar), protein protein M. M. J. Cell. 2002; PubMed Scopus Google Scholar), B. R. Mol. Hum. Reprod. PubMed Scopus Google Scholar, D.E. Weiss G. D. Goldsmith L.T. Endocrinology. PubMed Scopus Google Scholar), Bani D. Bigazzi M. T. J. Clin. Investig. 1994; PubMed Google Scholar, T. Bigazzi M. Bani D. Br. J. Pharmacol. 1995; PubMed Scopus Google Scholar, D. Bigazzi M. Bani G. T.B. Lab. Investig. 1995; Google Scholar, D. Bigazzi M. T.B. Cancer Res. 1995; Google Scholar, Bani D. Bigazzi M. T.B. Endocrinology. 1997; PubMed Scopus Google Scholar, D. C. Bani T. Bigazzi M. 1998; PubMed Scopus Google Scholar, D. F. Bigazzi M. T.B. Endocrinology. PubMed Google Scholar, A. Bani T. A. Bani D. Endocrinology. 2004; PubMed Scopus Google Scholar, D. R. A. Bigazzi M. T.B. Int. 2002; PubMed Scopus Google Scholar), and C. N. M. Sanborn B.M. L. J. PubMed Google Scholar). These intermediary signaling events are implicated in the of matrix D.E. Weiss G. D. Goldsmith L.T. Endocrinology. PubMed Scopus Google Scholar, L.S. Y. M. G. Amento E.P. J. Investig. Full Text PDF PubMed Scopus Google Scholar, J. L. Bryant-Greenwood G.D. Reprod. 1997; PubMed Scopus Google Scholar, Bryant-Greenwood G.D. Reprod. 1997; PubMed Scopus Google Scholar, L. A. Weiss G. Goldsmith L.T. Reprod. 2002; 66: PubMed Scopus Google Scholar), growth factor Y. J. Mol. Reprod. 2002; PubMed Scopus Google Scholar), growth factor Reprod. 1995; PubMed Scopus Google Scholar, J.A. P.L. PubMed Scopus Google Scholar), growth J. L. Mol. Cell. Endocrinol. 1994; PubMed Scopus Google Scholar), growth factor M. M. J. Cell. 2002; PubMed Scopus Google Scholar, L. A. Weiss G. Goldsmith L.T. Reprod. 2002; 66: PubMed Scopus Google Scholar, M. J. G. J. A. M.E. Hunt 8: PubMed Scopus Google Scholar), and cyclase D. Bigazzi M. Bani G. T.B. Lab. Investig. 1995; Google Scholar, D. Bigazzi M. T.B. Cancer Res. 1995; Google Scholar, D. C. Bani T. Bigazzi M. 1998; PubMed Scopus Google Scholar). In inflammatory sites relaxin also growth factor and growth factor in M. J. G. J. A. M.E. Hunt 8: PubMed Scopus Google Scholar). are the of to relaxin the and cells or cells and relaxin these cells to factors that tumor and Here we demonstrate that relaxin adenylate promotes substrate adhesion, and migratory capacity of mononuclear leukocytes in a relaxin receptor LGR7-dependent mechanism. Relaxin-stimulated cAMP accumulation primarily in non-adherent and is the cells have to a Relaxin of leukocytes and also their monocyte chemoattractant monocyte chemoattractant protein peripheral blood mononuclear human H2 protein kinase short hairpin monocyte chemoattractant protein peripheral blood mononuclear human H2 protein kinase short hairpin migratory These enhanced migratory responses be a of substrate adhesion in these cells. We also for the first that relaxin cAMP accumulation in peripheral blood mononuclear cells and that response is proportional to relaxin-stimulated adhesion and migratory We further demonstrate that LGR7 is critical for mediating these biological responses by use of RNA interference lentiviral short hairpin constructs. These results implicate relaxin as a novel of leukocyte blood and by in to the in in and in THP-1 cells in and THP-1 cell with cells that of THP-1 THP-1 by lentiviral and expression of short hairpin RNA LGR7 of LGR7 to P.J. A.A. 2002; PubMed Scopus Google Scholar, J. A. T. J. PubMed Scopus Google Scholar), and and the P.J. A.A. 2002; PubMed Scopus Google Scholar). to the the lentiviral H. H. R. J.T. Mol. Full Text Full Text PDF PubMed Scopus Google Scholar). of was with of the and of the cells H. H. R. J.T. Mol. Full Text Full Text PDF PubMed Scopus Google Scholar, L. D. Acad. Sci. A. PubMed Scopus Google Scholar, T. M. Acad. Sci. A. PubMed Scopus Google to the was for through and to THP-1 by to the enhanced protein expression the and LGR7 expression in THP-1 are described in these cAMP cells with human H2 relaxin (20Figueiredo K.A. Palmer J.B. Mui A.L. Nelson C.C. Cox M.E. Ann. N. Y. Acad. Sci. 2005; 1041: 320-327Crossref PubMed Scopus (10) Google and or or and for H2 for the with the of the and as described (20Figueiredo K.A. Palmer J.B. Mui A.L. Nelson C.C. Cox M.E. Ann. N. Y. Acad. Sci. 2005; 1041: 320-327Crossref PubMed Scopus (10) Google Scholar). cells the by and in of the cAMP the cells by with the of the cells. of THP-1 and cells as and cyclase was by cAMP and to cell by protein to the and expressed as of of and adhesion cells of tissue and or with or and for cells by and the three with cells in the of cell with or with of the was for and was for The of or cells was by M. J. PubMed Scopus Google Scholar). was and by and for cell and or cells for and results are expressed as adhesion or to cell of expression of and THP-1 cells was cells normal RNA was and to system to the RNA was for a The was to LGR7 levels a system and the The LGR7 and and the The was with a A of protein was was to the was by or expression and a for the results to The such that the LGR7 and and The in the LGR7 and cells in of for cell LGR7 expression by with for for to cell a cell was with a the intracellular with cells with a of for with and with and was for or and was with by of and between multiple of by a of in the adenylate cyclase and substrate adhesion of THP-1 cells. THP-1 cells a tissue by with and or and for and cells in the cyclase was expressed as of intracellular cAMP to cell the of with in adenylate cyclase in and THP-1 cells was in cells as in A that cells and cells. cells for of the cell as by cell the of in relaxin-stimulated substrate adhesion of THP-1 cells was in cells with or and for as described adhesion was as a of to that of the of the of in peripheral blood mononuclear cell biology. relaxin-stimulated of cAMP in was in cells with and or for cyclase is as of cAMP to of cell of in for relaxin-stimulated adhesion of to tissue cells and with or and for as described adhesion was as of to that of the of the of three to relaxin-stimulated of cells in the of by with or for that to the by and the was of to the in Relaxin in THP-1 the capacity of relaxin to affect leukocyte we have (20Figueiredo K.A. Palmer J.B. Mui A.L. Nelson C.C. Cox M.E. Ann. N. Y. Acad. Sci. 2005; 1041: 320-327Crossref PubMed Scopus (10) Google Scholar). of by was by its to adenylate cyclase activity in cells. We demonstrated that adenylate cyclase in cells (20Figueiredo K.A. Palmer J.B. Mui A.L. Nelson C.C. Cox M.E. Ann. N. Y. Acad. Sci. 2005; 1041: 320-327Crossref PubMed Scopus (10) Google Scholar). Here we observed that a dose-dependent increase in intracellular cAMP levels in the cell line THP-1 with first cAMP levels significantly elevated levels by as as and levels of of with a of stimulation These results are with for adenylate cyclase of THP-1 cells (21Nguyen B.T. Yang L. Sanborn B.M. Dessauer C.W. Mol. Endocrinol. 2003; 17: 1075-1084Crossref PubMed Scopus Google Scholar, B. R. Mol. Hum. Reprod. PubMed Scopus Google Scholar, Amento E.P. J. Full Text Full Text PDF PubMed Scopus Google and that is a relaxin THP-1 cells in are in between and with to differentiation or and relaxin in adenylate cyclase by in and non-adherent the non-adherent THP-1 monocyte for of the cell responsible for of the cAMP response to This that non-adherent THP-1 cells to relaxin and that adenylate cyclase response be substrate Relaxin of THP-1 the of THP-1 cells to to relaxin through of adenylate cyclase and signaling has been (21Nguyen B.T. Yang L. Sanborn B.M. Dessauer C.W. Mol. Endocrinol. 2003; 17: 1075-1084Crossref PubMed Scopus Google Scholar, B. R. Mol. Hum. Reprod. PubMed Scopus Google Scholar, Amento E.P. J. Full Text Full Text PDF PubMed Scopus Google Scholar, M. M. J. Cell. 2002; PubMed Scopus Google Scholar, M. J. G. J. A. M.E. Hunt 8: PubMed Scopus Google Scholar), of relaxin stimulation has the we that relaxin substrate adhesion of non-adherent monocytic cells. relaxin adhesion of to tissue THP-1 cells compared with cells with or agent known to THP-1 adhesion and differentiation J. 1991; PubMed Scopus Google Scholar). In a the of cells in and THP-1 in cell adhesion was observed a increase in THP-1 adhesion levels to whereas the adhesion of of the monocytic These results indicate that relaxin has the of stimulating monocyte substrate Relaxin of THP-1 that increased of to to or migratory capacity through in J. PubMed Scopus Google Scholar, J. PubMed Scopus Google Scholar). of THP-1 a in migratory of stimulation increased of cells be observed was stimulation a was in THP-1 cells in the to in the or or in THP-1 cell the was significantly increased in three THP-1 cells to the of in demonstrated increased to to the of the the Similarly, of cells to when to the or was enhanced to to the a migratory capacity compared with cells to in of the of when is the These demonstrate that relaxin is capable of dose-dependent proportional to its capacity to cAMP accumulation and Relaxin of THP-1 of the that relaxin of the adenylate cyclase signaling in multiple cell (21Nguyen B.T. Yang L. Sanborn B.M. Dessauer C.W. Mol. Endocrinol. 2003; 17: 1075-1084Crossref PubMed Scopus Google Scholar, B. R. Mol. Hum. Reprod. PubMed Scopus Google Scholar, M. Res. 1990; PubMed Scopus Google Scholar, Amento E.P. J. Full Text Full Text PDF PubMed Scopus Google Scholar, L. N. M. PubMed Scopus Google Scholar, T. C. Res. PubMed Scopus Google Scholar, M. C. L. Sanborn B.M. J. 1995; PubMed Google Scholar), we was important in mediating the migratory response in THP-1 cells. We that be by the of the adenylate cyclase and that is by the protein kinase This that relaxin through a and protein kinase The J. 1989; PubMed Scopus Google Scholar, A. M. 1991; PubMed Google Scholar, M. B. C. A. J. 1991; Google was to the to the of THP-1 cells increased of THP-1 cells the such that of the cells the we also observed that chemotaxis was significantly enhanced when was to In the of was increased to such that of THP-1 cells the This of chemotaxis was when cells with These results indicate that adenylate cyclase important to monocyte to the protein kinase response H. Y. J. 1997; PubMed Scopus (89) Google Scholar, K.A. J. 2003; Full Text Full Text PDF PubMed Scopus Google Scholar). further the capacity of relaxin to we compared the of THP-1 cells to of in the or of THP-1 cell was to stimulation with We observed that increased THP-1 cell by that of cells with The of relaxin is that the response be of in the of in These results support the that relaxin the cells to and that the of relaxin leukocytic of such as The adhesion response of the cells to relaxin is to the protein kinase response of the cells to the of observed in and cells. Relaxin and of the of these in the of leukocyte we relaxin regulate responses in adenylate cyclase activity in was that observed in THP-1 cells of of the first dose-dependent of THP-1 cells cAMP levels in significantly elevated levels by as as and The for of stimulation was the for THP-1 cells described for with the response of THP-1 a increase in adhesion of to a tissue substrate to that was proportional to their response to relaxin a increase in the migratory response of to of This response was the migratory response by of and is in with in THP-1 cells. these that relaxin is a key mediator of adenylate cyclase activation, substrate adhesion, and migratory responses of LGR7 and in THP-1 that the relaxin LGR7 J. M. A.J. 2002; PubMed Scopus Google Scholar), was responsible for mediating adenylate cyclase and responses of THP-1 we RNA interference to LGR7 expression lentiviral and expression of short hairpin RNA of LGR7 these to be in LGR7 expression the and protein levels A and we found that LGR7 expression was substantially in cells LGR7 and lines designated and THP-1 cell lines and of the and LGR7 levels that that of THP-1 cells the protein we of cells LGR7 the for cell cell LGR7 expression in cells was that observed in THP-1 whereas LGR7 expression in cells was that of THP-1 cells. In the cell LGR7 expression was that of THP-1 cell the of the that is of expression levels between the THP-1 cell these results are with of expression and that the LGR7 and protein expression is substantially in and cells and is in the cell LGR7 for in THP-1 we LGR7 expression relaxin-stimulated adenylate cyclase the adenylate cyclase in cells was and to intracellular cAMP and adenylate cyclase in cells was that by THP-1 cells. However, a of cAMP accumulation to THP-1 cells stimulation with cells also a response to to relaxin, cells cAMP and cells a response significantly THP-1 cells. This that lentiviral of THP-1 cells in their to to relaxin and that the of LGR7 is proportional to the of the Together, these results indicate that of LGR7 levels in cells their to to and that response is to relaxin the and adenylate cyclase response These provide evidence that relaxin cAMP accumulation in THP-1 cells through LGR7-dependent signaling and that the LGR7 receptor is for LGR7 for in THP-1 the migratory response of THP-1 cells is by we compared the migratory responses of THP-1 cells with and cells. demonstrate the properties of the relaxin peptide a THP-1 and cells for migratory responses to relaxin that for such C. T. D. Z. J. M. J. PubMed Scopus Google Scholar). THP-1 migratory response was cells responses to and to observed and compared with We observed a of the response in cells that was observed in the cells These demonstrate that the migratory responses occur when with the substrate and that the LGR7 signaling is for mediating such between tissue a of inflammation and blood cells of cells in inflammatory that N. J. PubMed Scopus Google Scholar). cells be to their to support their and recruitment and of immune cells surveillance (1Coussens L.M. Werb Z. Nature. 2002; 420: 860-867Crossref PubMed Scopus (11050) Google Scholar). In for to first the immune cells in the In we stimulation of THP-1 cell by adenylate cyclase responses to in non-adherent and and found that non-adherent cells for of the cAMP response to relaxin This that non-adherent cells are the and that cells have response be This to relaxin adhesion of leukocytes and be correlated with enhanced migratory we that relaxin a in THP-1 cell adhesion that is to the enhanced and the of and A and These responses proportional to cAMP accumulation and in be by adenylate cyclase and We also that relaxin cAMP adhesion, and migratory responses of migratory responses of leukocytes be relaxin-stimulated substrate adhesion through a mechanism. These of migratory response are substantially when are as adhesion and substrate that are substrate is that these be further in the of is required for leukocytic and to in cell have been shown to have biological was shown to a of monocyte C. 2004; PubMed Scopus Google and a of H. A. R. L. B. J. 2003; 17: PubMed Scopus Google Scholar). This of monocyte is correlated with biological M.E. E.R. D. L. Nature. 1997; PubMed Scopus Google Scholar, J. C. R. G. Y. J. L. J. H. F. Acad. Sci. A. PubMed Scopus Google Scholar). of leukocytes to several that in regulate the migratory response M. 2004; PubMed Scopus Google Scholar). and adhesion of to M. A. Nature. PubMed Scopus Google Scholar). In addition, the adhesion between leukocytes and of to further activate the immune response T. and Cancer. Google Scholar). This that adhesion also immune the study is the first to demonstrate stimulatory of relaxin in mononuclear a of studies have for relaxin through a in cells Bani D. Bigazzi M. T. J. Clin. Investig. 1994; PubMed Google Scholar), D. Bigazzi M. Bani G. T.B. Lab. Investig. 1995; Google Scholar), and the leukocytes A. Bani T. A. Bani D. Endocrinology. 2004; PubMed Scopus Google and D. R. A. Bigazzi M. T.B. Int. 2002; PubMed Scopus Google Scholar). relaxin has of the during Reprod. 1998; PubMed Scopus Google Scholar), studies have that relaxin positively the migratory capacity of epithelial cells. Relaxin and of human breast cancer cells and C. Hagemann T. Husen B. Schulz M. Einspanier A. Mol. Hum. Reprod. 2002; 8: 789-796Crossref PubMed Scopus (89) Google Scholar). Similarly, relaxin of breast cancer cells be J.D. Summerlee A.J. Endocrinology. 2003; PubMed Scopus Google Scholar). Relaxin also of epithelial cells in a J.H. 2002; Google Scholar). studies indicate that migratory responses are to cells of a and are mediator that are by the cells as of that of blood cells for is that of these responses in cell including epithelial (1Coussens L.M. Werb Z. Nature. 2002; 420: 860-867Crossref PubMed Scopus (11050) Google Scholar, D. A. PubMed Scopus Google Scholar). the between a and a or of these cell types. The study for the first that the role for relaxin as a regulator of epithelial and (4Bani D. Gen. Pharmacol. 1997; 28: 13-22Crossref PubMed Scopus (202) Google be to include a role in blood cells as a and a Our a role for relaxin in regulation of cells of the immune A of migratory response is observed in the of relaxin in THP-1 cells and and in THP-1 cells This that relaxin activate the migratory response substrate This is the first of through cell in the enhanced migratory response in the of relaxin is of these we that by substrate adhesion, relaxin response to such as and that relaxin in with and to recruitment and infiltration of mononuclear cells to tumor expression has been in prostate L. A. M. M. J.A. C. J. Google Scholar), its expression is substantially elevated in breast T. M. R. N. Res. 1998; PubMed Scopus Google Scholar, H. M. T. M. M. Cancer. PubMed Scopus Google Scholar). relaxin is expressed in of these is that relaxin role in these In the of prostate and breast inflammatory tumor relaxin is in with and to regulate recruitment and infiltration of the mononuclear cells. that the relaxin receptor LGR7 is required to these biological responses in THP-1 cells in LGR7 expression was by expression of RNA of LGR7 A and We have that cAMP and migratory activity are LGR7 biological responses are in and in cell lines A and results that the migratory response to relaxin is by of protein kinase we that protein kinase is required to relaxin-stimulated migratory response The response and the response of the relaxin receptor and these responses be by adenylate cyclase This that a is to regulate the migratory further studies are required to the role of relaxin in leukocyte and infiltration of the the study that relaxin has a role in recruitment of leukocytes. leukocytes cancer in response to factors the tumor the of a relaxin a tumor be of a for cancer provide for and studies of and differentiation by We D. and H. for and and J. for with

Fetched live from OpenAlex and de-inverted. Abstracts are not stored in this database: the inverted indexes are 8.6 GB of the frame’s 9.3 GB of text, and the host has 13 GB free.