Action of prolactin, IFN-g, TNF-a and LPS on heme oxygenase-1 expression and VEGF release in human monocytes/macrophages L. Malaguarnera * , R. Imbesi, M. Di Rosa, A. Scuto, P. Castrogiovanni, A. Messina, S. Sanfilippo Department of Biomedical Sciences, University of Catania, Via E. De Amicis, 24, 95039 Trecastagni-Catania, Italy Received 3 December 2004; received in revised form 4 April 2005; accepted 6 April 2005 Abstract The pituitary hormone prolactin (PRL) has recently been regarded as a local regulator of macrophage responses. Our goal in this study was to investigate the regulatory interaction between PRL, interferon-gamma (IFN-g), tumor necrosis factor-alpha (TNF-a) and lipopolysaccharide (LPS) in the heme oxygenase-1 (HO-1) expression and the vascular endothelial growth factor (VEGF) production in human monocytes/macrophages (HMMs). In vitro treatment of HMMs with PRL, IFN-g, TNF-a and LPS was found to increase both HO-1 expression and protein synthesis in a time-dependent manner. HMMs treated with PRL, IFN-g, TNF-a and LPS also showed an enhanced release of VEGF. Moreover, co-stimulation of PRL with LPS caused activation of HMMs functions, enhancement of HO-1 expression and induction of VEGF release, whereas addition of PRL inhibited up-regulation of HO-1 or VEGF induced by IFN-g or TNF-a. Our results demonstrate that PRL, IFN-g, TNF-a and LPS modulate the expression of angiogenic factors providing additional information about the regulatory mechanism, which controls the angiogenic function of macrophages. D 2005 Elsevier B.V. All rights reserved. Keywords: Prolactin; IFN-g; TNF-a; LPS; Heme-oxygenase-1; Human monocytes/macrophages; Angiogenesis 1. Introduction Prolactin (PRL), which was originally associated with milk secretion, is now known to possess a wide array of physiological functions [1] and diverse sites of production in extra-pituitary tissues including endothelial [2], neuronal and immune cells [1]. PRL also acts as a critical component of the regulatory loop of neuroendocrine–immune interactions. Structurally, it is related to several cytokines and its receptor (PRL- R) belongs to the superfamily of hematopoietic cyto- kine receptors [3]. The cytokine nature of PRL and its importance in immune response is strongly indicated by the expression of PRL-R in the lympho-hemopoie- tic system. In fact, PRL is involved in lympho-pro- liferation and in the induction of interleukin-2 (IL-2) 1567-5769/$ - see front matter D 2005 Elsevier B.V. All rights reserved. doi:10.1016/j.intimp.2005.04.002 * Corresponding author. Tel./fax: +39 95 7807843. E-mail address: lucmal@mbox.unict.it (L. Malaguarnera). International Immunopharmacology 5 (2005) 1458 – 1469 www.elsevier.com/locate/intimp