Prolactin and the Skin: A Dermatological Perspective on an Ancient Pleiotropic Peptide Hormone  Kerstin Foitzik, Ewan A. Langan, Ralf Paus  Journal of Investigative Dermatology  Volume 129, Issue 5, Pages 1071-1087 (May 2009) DOI: 10.1038/jid.2008.348 Copyright © 2009 The Society for Investigative Dermatology, Inc Terms and Conditions

Figure 1 Pituitary PRL regulation (modified afterFreemanet al., 2000). Pulsatile PRL secretion is regulated by a light-entrained circadian rhythm. Environmental input interacts with the internal milieu, and reproductive stimuli modify the inhibitory and stimulatory elements of the hypothalamic circuit. Hypothalamic neuroendocrine neurons release PRL-inhibiting factors (PIFs) and PRL-releasing factors (PRFs), which regulate PRL secretion by lactotrophs of the anterior lobe of the pituitary gland. Lactotrophs are also regulated by PRF and PIF, in an autocrine and paracrine fashion, from neighboring cells (paracrine) and lactotrophs (autocrine). Blue, growth factors so far found to regulate PRL secretion in the rat pituitary. Abbreviations: Ach, acetylcholine; ANG, angiotensin; ANP, atrial natriuretic peptide; BOM, bombesin-like peptide; CCK, cholecystokinin; CT, calcitonin; DA, dopamine; EGF, epidermal growth factor; Est, estrogen; FGF, fibroblast growth factor; GABA, γ-aminobutyric acid; GAL, galanin; H, histamine; 5-HT, serotonin; IGF, insulin-like growth factor; IL-1, interleukin-1; L, lactotrophs; MSH, melanocyte-stimulating hormone; NO, nitric oxide; NorA, norepinephrine; NPY, neuropeptide Y; NT, neurotensin; PACAP, pituitary adenylate cyclase-activating peptide; PC, pituitary cell; SST, somatostatin; TGF-β, transforming growth factor-β; TRH, thyrotropin-releasing factor; TIDA, tuberoinfundibular dopaminergic system; TSH, thyroid-stimulating hormone; VIP, vasoactive intestinal peptide. Journal of Investigative Dermatology 2009 129, 1071-1087DOI: (10.1038/jid.2008.348) Copyright © 2009 The Society for Investigative Dermatology, Inc Terms and Conditions

Figure 2 Simplified overview of the main PRLR signaling pathways (modified afterGoffinet al., 2006). Several signaling cascades are triggered by the ligand-induced activation of PRL receptor. The main pathway involves the tyrosine kinase Jak2, which activates three members of the STAT family: STAT1, STAT3, and mainly STAT5. The MAPK pathway is another important cascade, which involves Shc/Grb2/Sos/Ras/Raf intermediaries upstream to MAPK kinase and ERK-1/2 kinases. Also, Src kinase activation has been reported. Journal of Investigative Dermatology 2009 129, 1071-1087DOI: (10.1038/jid.2008.348) Copyright © 2009 The Society for Investigative Dermatology, Inc Terms and Conditions

Figure 3 Proposed functions of PRL in skin biology and in skin pathology (modified afterPaus, 1991). The PRL circuit provides a cross-talk mechanism, between the skin and the central nervous system (CNS). PRL participates in physiological and pathological processes in the skin. This overview shows the complex network among CNS, liver, thymus, peripheral blood cells, and the skin, mediated by selected growth factors and neuropeptides. The arrows in the micrograph indicate the distinct cell populations influenced by PRL. The arrows for fibroblasts indicate dermal fibroblasts and fibroblasts of the dermal sheath of the hair follicle. *See also Table 2. Abbreviations: CNS, central nervous system; IFN, interferon; IL, interleukin; IGF, insulin-like growth factor; L, lymphocyte; MAC, macrophage; NK, natural killer cell; TSH, thyroid-stimulating hormone; VEGF, vascular endothelial growth factor. Journal of Investigative Dermatology 2009 129, 1071-1087DOI: (10.1038/jid.2008.348) Copyright © 2009 The Society for Investigative Dermatology, Inc Terms and Conditions

Figure 4 Hair follicle morphogenesis and cycling, with arrows showing catagen induction by PRL. PRL interferes with the hair cycle by induction of apoptosis and inhibition of keratinocytes during late anagen-inducing premature catagen development (arrow). The hair cycle modulatory effects of PRL were observed in murine back skin pelage follicles and on male occipital scalp-hair follicles. It cannot be excluded that the effects of PRL differ depending on hair follicle subpopulations. Journal of Investigative Dermatology 2009 129, 1071-1087DOI: (10.1038/jid.2008.348) Copyright © 2009 The Society for Investigative Dermatology, Inc Terms and Conditions