Prolactin promotes normal liver growth, survival, and regeneration in rodents: effects on hepatic IL-6, suppressor of cytokine signaling-3, and angiogenesis

Abstract

Prolactin (PRL) is a potent liver mitogen and proangiogenic hormone. Here, we used hyperprolactinemic rats and PRL receptor-null mice (PRLR(-/-)) to study the effect of PRL on liver growth and angiogenesis before and after partial hepatectomy (PH). Liver-to-body weight ratio (LBW), hepatocyte and sinusoidal endothelial cell (SEC) proliferation, and hepatic expression of VEGF were measured before and after PH in hyperprolactinemic rats, generated by placing two anterior pituitary glands (AP) under the kidney capsule. Also, LBW and hepatic expression of IL-6, as well as suppressor of cytokine signaling-3 (SOCS-3), were evaluated in wild-type and PRLR(-/-) mice before and after PH. Hyperprolactinemia increased the LBW, the proliferation of hepatocytes and SECs, and VEGF hepatic expression. Also, liver regeneration was increased in AP-grafted rats and was accompanied by elevated hepatocyte and SEC proliferation, and VEGF expression compared with nongrafted controls. Lowering circulating PRL levels with CB-154, an inhibitor of AP PRL secretion, prevented AP-induced stimulation of liver growth. Relative to wild-type animals, PRLR(-/-) mice had smaller livers, and soon after PH, they displayed an approximately twofold increased mortality and elevated and reduced hepatic IL-6 and SOCS-3 expression, respectively. However, liver regeneration was improved in surviving PRLR(-/-) mice. PRL stimulates normal liver growth, promotes survival, and regulates liver regeneration by mechanisms that may include hepatic downregulation of IL-6 and upregulation of SOCS-3, increased hepatocyte proliferation, and angiogenesis. PRL contributes to physiological liver growth and has potential clinical utility for ensuring survival and regulating liver mass in diseases, injuries, or surgery of the liver.

Prolactin blocks the expression of receptor activator of nuclear factor κB ligand and reduces osteoclastogenesis and bone loss in murine inflammatory arthritis

“…These findings are consistent with PRL treatment inhibiting the expression of the same cytokines in the joints of rats with AIA [18] and with previous reports showing that targeted disruption of PRL [13] and of PRL receptors [49] enhances immune responses and mortality under stress-related conditions. Besides their crucial effects on joint inflammation, TNFα, IL-1β, IL-6, and IL-17A also drive bone loss.…”

Regulation of Blood Vessels by Prolactin and Vasoinhibins

“…PRL stimulates angiogenesis during development (chick chorioallantoic membrane, CAM) and in adult tissues (corpus luteum, testis, and heart). These observations were recently extended to include the angiogenesis of transplanted pancreatic islets [37] and the neovascularization associated with normal and regenerative liver growth, where inducing hyperprolactinemia increased hepatic endothelial cell proliferation and vascular endothelial growth factor (VEGF) expression [38,39]. Moreover, in addition to the known effects of PRL on endothelial cell proliferation and VEGF expression, PRL was recently shown to stimulate the migration and tube formation of endothelial cells [40,41], to reduce vasopermeability by upregulating the expression of tight-junction proteins between endothelial cells [42], and to promote intussusceptive angiogenesis in the CAM [40].…”

“…Liver growth is angiogenesis-dependent and coincides with the hyperprolactinemia ocurring during pregnancy and lactation, cirrhosis [68], and after partial hepatectomy [69]. Absence of the PRL receptor confers reduced liver mass, and elevating systemic PRL promotes growth and neovascularization of the normal and regenerating adult liver [38]. During pregnancy, the need for insulin action results in pancreatic islet growth, which is angiogenesis dependent.…”

Identification of an epigenetic signature of early mouse liver regeneration that is disrupted by Zn-HDAC inhibition

“…Many of these hyperacetylated genes are known to be induced during, to positively regulate, or to interact with factors that promote liver regeneration. For example, Ccnd1 (i.e., cyclin d1), Cdkn1a (i.e., p21), Gadd45g, Lcn2, and Myc are induced in early regenerating liver [4][5][6][7] ; Ccnd1, Egfr, and Prlr promote liver regeneration [8][9][10][11] ; and Tcf7l2 (also known as Tcf4) binds to b-catenin, whose signaling is activated during and promotes regeneration. 12 Deacetylated genes Similar examination of genes deacetylated in response to PH showed 37 of 392 associated with cell cycle-and 31 linked to cell death-related gene category terms ( Tables 1 and 2).…”