Trends in Endocrinology & Metabolism
ReviewProlactin: an emerging force along the cutaneous–endocrine axis
Section snippets
Human skin is a source of prolactin
The skin is not only a vital physical barrier to the environment and a key interface between the immune and nervous systems, but also a major endocrine organ 1, 2. Its complex neuroendocrine activities include production of the pleiotropic 23 kDa hormone prolactin (PRL) 3, 4, 5. That the skin produces PRL is not surprising, considering one of the defining features of mammals, the mammary gland, is an epidermal derivative developmentally related to sweat glands [6], whose epithelium is an
Basics of prolactin and prolactin receptor biology
PRL belongs to the PRL/growth hormone (GH)/placental lactogen (PL) family and acts systemically as a hormone and locally as a cytokine or growth factor [21]. In humans, variants of PRL of 14–17 and 22 kDa have been identified, some with differing biological activities. For example, the 16 kDa variant exerts important antiangiogenic functions, in contrast to the classic 23 kDa PRL, which has proangiogenic properties 11, 22. Secreted in a circadian rhythm, serum levels vary between non-pregnant
Regulation of extrapituitary prolactin expression: lessons from the skin
The complex regulation of pituitary PRL secretion [11] (Figure 3) includes dopamine as a key inhibitor and hypothalamic thyrotropin-releasing hormone (TRH) and estrogen as potent stimulators 10, 11. Although many of these factors might also regulate intracutaneous PRL transcription, peptide synthesis and/or secretion, the control of pituitary PRL transcription and secretion was thought to differ from that at extrapituitary sites. This concept was based on the existence of an alternative
Prolactin and key skin cell populations
Human skin is a source and target of a wide variety of hormones, is richly innervated, and produces neurotrophins, neuropeptides and neurotransmitters, thus creating multiple levels of neural–endocrine–immune interplay within the same organ 2, 34, 35, 36. Moreover, the skin displays complex neuroendocrine regulatory loops. For example, organ cultured microdissected human scalp HFs express TRH and its receptor [37], and display a fully functional peripheral equivalent to the
Keratinocytes
Keratinocytes are the predominant epidermal cells and play a key role in skin biology by maintaining the epidermal barrier, regulating cutaneous antimicrobial defenses and the skin immune system, and contributing to the skin's structural integrity. PRL and PRLR expression have been demonstrated in human and murine HF keratinocytes, both in situ and in vitro3, 4, 5. Intracutaneous PRLRs are functionally active, promoting apoptosis of mouse and human HF keratinocytes, with subsequent induction of
Fibroblasts
Dermal fibroblasts are central for maintaining and remodeling the extracellular matrix of the skin, providing structural support and for normal wound healing. Therefore it is interesting to note that mouse skin fibroblasts produce and process PRL [48], and human dermal fibroblasts produce both PRL and PRLR 45, 46. Indeed, dermal fibroblasts cultured in vitro produce PRL protein. The detected 23 kDa PRL protein is identical to pituitary and decidual PRL. Moreover, the PRL mRNA detected by
Endothelial cells
Angiogenesis is a prominent feature of psoriasis and of the anagen stage of HF cycling 49, 50, 51, 52. Indeed, serum levels of a key angiogenic factor, vascular endothelial growth factor (VEGF) correlate with the presence and severity level of psoriasis [53], a common, chronic, hyperproliferative T-cell mediated inflammatory skin disease, whose pathogenesis remains incompletely understood. Low levels of PRL mRNA and expression of PRL protein in endothelial cells have been reported [54]. These
Sebaceous glands
The pilosebaceous unit (PSU) consists of the HF, arrector pili muscle and sebaceous and apocrine glands. It can differentiate into a terminal HF or sebaceous follicle depending on the effects of hormones, particularly androgens [59]. PRL and PRLR immunoreactivity are present in sebaceous glands of human skin [3], and PRL stimulates sebum production in humans [60]. These effects are evident in women with hyperprolactinemia, who develop hirsutism and seborrhea, not uncommonly associated with
Sweat glands
Sweat glands are a skin appendage, and can be classified into eccrine and apocrine sweat glands, depending on their secretory product and mechanism of secretion. They play an important role in thermo- and osmoregulation. Lessons on the role of PRL in human sweat gland regulation can be drawn from non-mammals. In fish skin, for example, PRL plays an important role in osmoregulation by preventing both the loss of ions and the excessive uptake of water [63]. In teleost fish, environmental
Prolactin and the hair follicle
In human male occipital scalp skin, PRL exerts inhibitory effects on hair growth [4], at least in vitro, which might explain the telogen effluvium seen in patients with hyperprolactinemia 38, 68. However, the modulatory effects of PRL on hair growth could well be site- and/or gender- specific because PRL instead stimulates hair growth in organ-cultured female frontotemporal HFs in vitro[13]. Hyperprolactinemia in women is also associated with an androgenetic alopecia-type hair loss pattern and
Prolactin in cutaneous pathology: an aetiological factor in psoriasis?
The pathological hallmarks of psoriasis are keratinocyte hyperproliferation, dysregulated angiogenesis, and expression of proinflammatory T helper (Th) 1 cytokines [72]. Psoriasis is also triggered and/or exacerbated by psychological stress [73]. Given that PRL is a stress hormone, it has been hypothesized that PRL might play an important role in triggering or exacerbating this disease [9]. PRL stimulates the proliferation of cultured human primary foreskin keratinocytes [39], and PRLR is
Conclusion
As a prototypical interface organ, where the nervous, immune and endocrine systems interconnect with environmental stimuli, the skin presents an instructive, easily accessible and clinically relevant model to determine the functions and regulation of extrapituitary PRL production. Larger studies are clearly needed to validate the available preliminary evidence that cutaneous PRL effects and/or PRL production might be gender- and/or site-dependent, not unlike those of androgens. Future studies
Acknowledgements
We are grateful to Dr B. Poeggeler, Professor C.E.M. Griffiths and Professor J.R.E. Davis for their helpful suggestions. Writing of this review was supported in part by a Walport Academic Clinical Fellowship in Dermatology to EAL.
Glossary
- Acne vulgaris
- an inflammatory skin disease affecting the pilosebaceous unit, characterised by the formation of papules, pustules and open and closed commedones.
- Alopecia
- status of thinned or absent hair in a defined skin region, usually as the result of prior effluvium (see below).
- Anagen
- growth stage of the hair cycle, characterised by production of a pigmented hair shaft.
- Androgenetic alopecia
- a characteristic, androgen-dependent pattern of scalp hair loss, occurring in both males and females.
- Catagen
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2022, AnimalCitation Excerpt :Interpretation of the consequences of the SLICK1 mutation must include consideration of the fact that prolactin interacts with its receptor in multiple ways and the impact of the SLICK1-induced truncation of PRLR will depend on the pathways through which prolactin mediates specific biological effects. Signaling through the full-length PRLR (termed the long form) involves prolactin-induced dimerization of long PRLR isoforms (reviewed by Langan et al., 2010; Trott et al., 2012; Bernard et al., 2015). The resultant change in receptor conformation leads to recruitment of the tyrosine kinase JAK2 that causes phosphorylation of the receptor, JAK2 itself, and STAT proteins that function as transcription factors to regulate gene expression.
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