Kobayashi Hiromi, Kromminga Arno, Dunlop Thomas W, Tychsen Birte, Conrad Franziska, Suzuki Naoto, Memezawa Ai, Bettermann Albrecht, Aiba Setsuya, Carlberg Carsten, Paus Ralf
Department of Dermatology, University Hospital Schleswig-Holstein, Campus Lübeck, University of Lübeck, Lübeck, Germany.
FASEB J. 2005 Oct;19(12):1710-2. doi: 10.1096/fj.04-2293fje. Epub 2005 Jul 19.
Since mammalian skin expresses the enzymatic apparatus for melatonin synthesis, it may be an extrapineal site of melatonin synthesis. However, evidence is still lacking that this is really the case in situ. Here, we demonstrate melatonin-like immunoreactivity (IR) in the outer root sheath (ORS) of mouse and human hair follicles (HFs), which corresponds to melatonin, as shown by radioimmunoassay and liquid chromatography/tandem mass spectrometry (LC/MS/MS). The melatonin concentration in organ-cultured mouse skin, mouse vibrissae follicles, and human scalp HFs far exceeds the respective melatonin serum level and is significantly increased ex vivo by stimulation with norepinephrine (NE), the key stimulus for pineal melatonin synthesis. By real-time PCR, transcripts for the melatonin membrane receptor MT2 and for the nuclear mediator of melatonin signaling, retinoid orphan receptor alpha (ROR)alpha, are detectable in murine back skin. Transcript levels for these receptors fluctuate in a hair cycle-dependent manner, and are maximal during apoptosis-driven HF regression (catagen). Melatonin may play a role in hair cycle regulation, since its receptors (MT2 and RORalpha) are expressed in murine skin in a hair cycle-dependent manner, and because it inhibits keratinocyte apoptosis and down-regulates ERalpha expression. Therefore, the HF is both, a prominent extrapineal melatonin source, and an important peripheral melatonin target tissue. Regulated intrafollicular melatonin synthesis and signaling may play a previously unrecognized role in the endogenous controls of hair growth, for example, by modulating keratinocyte apoptosis during catagen and by desensitizing the HF to estrogen signaling. As a prototypic neuroectodermal-mesodermal interaction model, the HF can be exploited for dissecting the obscure role of melatonin in such interactions in peripheral tissues.
由于哺乳动物皮肤表达褪黑素合成所需的酶系统，它可能是褪黑素合成的一个松果体外位点。然而，仍缺乏证据表明在体内确实如此。在此，我们在小鼠和人类毛囊（HF）的外根鞘（ORS）中证实了褪黑素样免疫反应性（IR），经放射免疫分析和液相色谱/串联质谱法（LC/MS/MS）检测，其与褪黑素相对应。器官培养的小鼠皮肤、小鼠触须毛囊和人类头皮HF中的褪黑素浓度远远超过各自的血清褪黑素水平，并且在体外通过用去甲肾上腺素（NE）刺激而显著增加，NE是松果体褪黑素合成的关键刺激物。通过实时PCR，在小鼠背部皮肤中可检测到褪黑素膜受体MT2以及褪黑素信号传导的核介质类视黄醇孤儿受体α（ROR）α的转录本。这些受体的转录水平以毛囊周期依赖性方式波动，并且在凋亡驱动的HF退化（退行期）期间达到最大值。褪黑素可能在毛囊周期调节中发挥作用，因为其受体（MT2和RORα）以毛囊周期依赖性方式在小鼠皮肤中表达，并且因为它抑制角质形成细胞凋亡并下调ERα表达。因此，HF既是一个突出的松果体外褪黑素来源，也是一个重要的外周褪黑素靶组织。调节性的毛囊内褪黑素合成和信号传导可能在毛发生长的内源性控制中发挥以前未被认识到的作用，例如，通过在退行期调节角质形成细胞凋亡以及使HF对雌激素信号脱敏。作为一个典型的神经外胚层 - 中胚层相互作用模型，HF可用于剖析褪黑素在周围组织这种相互作用中的模糊作用。
