Ito Natsuho, Ito Taisuke, Kromminga Arno, Bettermann Albrecht, Takigawa Masahiro, Kees Frieder, Straub Rainer H, Paus Ralf
Department of Dermatology, Hamamatsu University School of Medicine, Hamamatsu, Japan.
FASEB J. 2005 Aug;19(10):1332-4. doi: 10.1096/fj.04-1968fje. Epub 2005 Jun 9.
The skin and its major appendages are prominent target organs and potent sources of key players along the classical hypothalamic-pituitary axis, such as corticotropin releasing hormone (CRH), adrenocorticotropic hormone (ACTH), and alpha melanocyte stimulating hormone (alpha-MSH), and even express key steroidogenic enzymes. Therefore, it may have established local stress response systems that resemble the hypothalamic-pituitary-adrenal (HPA) axis. However, functional evidence that this is indeed the case in normal human skin in situ has still been missing. We show that microdissected, organ-cultured human scalp hair follicles respond to CRH stimulation by up-regulating proopiomelanocortin (POMC) transcription and immunoreactivity (IR) for ACTH and alpha-MSH, which must have been processed from POMC. CRH, alpha-MSH, and ACTH also modulate expression of their cognate receptors (CRH-R1, MC1-R, MC2-R). In addition, the strongest stimulus for adrenal cortisol production, ACTH, also up-regulates cortisol-IR in the hair follicles. Isolated human hair follicles secrete substantial levels of cortisol into the culture medium, and this activity is further up-regulated by CRH. CRH also modulates important functional hair growth parameters in vitro (hair shaft elongation, catagen induction, hair keratinocyte proliferation, melanin production). Finally, human hair follicles display HPA axis-like regulatory feedback systems, since the glucocorticoid receptor agonist hydrocortisone down-regulates follicular CRH expression. Thus, even in the absence of endocrine, neural, or vascular systemic connections, normal human scalp hair follicles directly respond to CRH stimulation in a strikingly similar manner to what is seen in the classical HPA axis, including synthesis and secretion of cortisol and activation of prototypic neuroendocrine feedback loops.
皮肤及其主要附属器是经典下丘脑 - 垂体轴上关键参与者的突出靶器官和重要来源，如促肾上腺皮质激素释放激素（CRH）、促肾上腺皮质激素（ACTH）和α - 黑素细胞刺激激素（α - MSH），甚至还表达关键的类固醇生成酶。因此，皮肤可能已建立了类似于下丘脑 - 垂体 - 肾上腺（HPA）轴的局部应激反应系统。然而，在正常人体原位皮肤中确实如此的功能证据仍然缺失。我们发现，经显微切割并进行器官培养的人类头皮毛囊会通过上调阿片 - 促黑素 - 皮质素原（POMC）转录以及ACTH和α - MSH的免疫反应性（IR）来响应CRH刺激，而ACTH和α - MSH必定是由POMC加工而来的。CRH、α - MSH和ACTH还会调节其同源受体（CRH - R1、MC1 - R、MC2 - R）的表达。此外，对肾上腺皮质醇产生最强刺激的ACTH，也会上调毛囊中的皮质醇 - IR。分离出的人类毛囊会向培养基中分泌大量皮质醇，并且这种活性会被CRH进一步上调。CRH还会在体外调节重要的毛发生长参数（毛干伸长、退行期诱导、毛发角质形成细胞增殖、黑色素生成）。最后，人类毛囊表现出HPA轴样的调节反馈系统，因为糖皮质激素受体激动剂氢化可的松会下调毛囊CRH的表达。因此，即使在没有内分泌、神经或血管系统连接的情况下，正常人体头皮毛囊对CRH刺激的直接反应方式与经典HPA轴中所见的方式惊人地相似，包括皮质醇的合成与分泌以及原型神经内分泌反馈回路的激活。
