Björn E. Wenzel

Thyroid-stimulating hormone, a novel, locally produced modulator of human epidermal functions, is regulated by thyrotropin-releasing hormone and thyroid hormones

Several elements of the hypothalamic-pituitary-thyroid axis (HPT) reportedly are transcribed by human skin cell populations, and human hair follicles express functional receptors for TSH. Therefore, we asked whether the epidermis of normal human skin is yet another extrathyroidal target of TSH and whether epidermis even produces TSH. If so, we wanted to clarify whether intraepidermal TSH expression is regulated by TRH and/or thyroid hormones and whether TSH alters selected functions of normal human epidermis in situ. TSH and TSH receptor (TSH-R) expression were analyzed in the epidermis of normal human scalp skin by immunohistochemistry and PCR. In addition, full-thickness scalp skin was organ cultured and treated with TSH, TRH, or thyroid hormones, and the effect of TSH treatment on the expression of selected genes was measured by quantitative PCR and/or quantitative immunohistochemistry. Here we show that normal human epidermis expresses TSH at the mRNA and protein levels in situ and transcribes TSH-R. It also contains thyrostimulin transcripts. Intraepidermal TSH immunoreactivity is up-regulated by TRH and down-regulated by thyroid hormones. Although TSH-R immunoreactivity in situ could not be documented within the epidermis, but in the immediately adjacent dermis, TSH treatment of organ-cultured human skin strongly up-regulated epidermal expression of involucrin, loricrin, and keratins 5 and 14. Thus, normal human epidermis in situ is both an extrapituitary source and (possibly an indirect) target of TSH signaling, which regulates defined epidermal parameters. Intraepidermal TSH expression appears to be regulated by the classical endocrine controls that determine the systemic HPT axis.

Thyrotropin releasing hormone (TRH): a new player in human hair-growth control

Thyrotropin‐releasing hormone (TRH) is the most proximal component of the hypothalamic‐pituitary‐thyroid axis that regulates thyroid hormone synthesis. Since transcripts for members of this axis were detected in cultured normal human skin cells and since human hair follicles (HFs) respond to stimulation with thyrotropin we now have studied whether human HF functions are also modulated by TRH. Here we report that the epithelium of normal human scalp HFs expresses not only TRH receptors (TRH‐R) but also TRH itself at the gene and protein level. Stimulation of microdissected organ‐cultured HFs with TRH promotes hair‐shaft elongation prolongs the hair cycle growth phase (anagen) and antagonizes its termination by TGF‐β2. It also increases proliferation and inhibits apoptosis of hair matrix keratinocytes. These TRH effects may be mediated in part by reducing the ATM/Atr‐dependent phosphorylation of p53. By microarray analysis several differentially up‐ or down‐regulated TRH‐target genes were detected (e.g., selected keratins). Thus human scalp HFs are both a source and a target of TRH which operates as a potent hair‐growth stimulator. Human HFs provide an excellent discovery tool for identifying and dissecting nonclassical functions of TRH and TRH‐mediated signaling in situ, which emerge as novel players in human epithelial biology.—Gáspár, E., Hardenbicker, C., Bodó, E., Wenzel B. Ramot Y. Funk W. Kromminga A. Paus R. Thyrotropin releasing hormone (TRH): a new player in human hair‐growth control. FASEB J. 24, 393–403 (2010). www.fasebj.org

Thyrotropin powers human mitochondria

Here we demonstrate that the neuropeptide hormone thyrotropin (TSH), which controls thyroid hormone production, exerts a major nonclassical function in mitochondrial biology. Based on transcriptional, ultrastructural, immunohistochemical, and biochemical evidence, TSH up‐regulates mitochondrial biogenesis and consequently activity in organ‐cultured normal human epidermis in situ. Mitochondrial activity was assessed by measuring 2 key components of the respiratory chain. The abundance of mitochondria was assessed employing 2 independent morphological techniques: counting their numbers in human epidermis by high‐magnification light microscopy of skin sections immunostained for mitochondria‐selective cytochrome‐c‐oxidase subunit 1 (MTCO1) and transmission electron microscopy (TEM). Treatment with 10 mU/ml of TSH for 6 d strongly up‐regulates the number of light‐microscopically visualized, MTCO1‐demarcated mitochondria. On the ultrastructural level, TEM confirms that TSH indeed stimulates mitochondrial proliferation and biogenesis in the perinuclear region of human skin epidermal keratinocytes. On the transcriptional level, TSH up‐regulates MTCO1 mRNA (quantitative RT‐PCR) and significantly enhances complex I and IV (cytochrome‐c‐oxidase) activity. This study pioneers the concept that mitochondrial energy metabolism and biogenesis in a normal, prototypic human epithelial tissue underlies potent neuroendocrine controls and introduces human skin organ culture as a clinically relevant tool for further exploring this novel research frontier in the control of mitochondrial biology.—Poeggeler, B., Knuever, J., Gáspár, E., Bíró, T., Klinger, M., Bodó, E., Wiesner, R J., Wenzel, B. E., Paus, R. Thyrotropin powers human mitochondria. FASEB J. 24, 1525–1531 (2010). www.fasebj.org

Too early to dismiss Yersinia enterocolitica infection in the aetiology of Graves’ disease: evidence from a twin case–control study

Background  Yersinia enterocolitica (YE) infection has long been implicated in the pathogenesis of Graves’ disease (GD). The association between YE and GD could, however, also be due to common genetic or environmental factors affecting the development of both YE infection and GD. This potential confounding can be minimized by investigation of twin pairs discordant for GD.

Increased Radioiodine Uptake of Thyroid Cell Cultures after External Irradiation

Background:Radioiodine uptake (RIU) is one of the main prognostic factors for curative results of radioiodine therapy in patients with differentiated thyroid cancer. Some days after application of 131I, the uptake of a subsequent administration of radioiodine was found to be reduced. In contrast, early after irradiation with high-energy photons glucose and amino acid uptake were observed to be increased. Effects of external irradiation on RIU of thyrocytes using high-energy photons have not been investigated so far.Material and Methods:Two different cell lines (FRTL-5 and ML-1 cells) derived from thyroid tissue were studied in vitro. Cell lines were either incubated with 131I only (controls) or additionally irradiated with single doses of 6 or 10 Gy of high-energy photons using a linear accelerator. Cell number and RIU were determined 24–96 h after 131I application. RIU measurements were repeated after application of sodium perchlorate in excess to investigate specificity of the uptake. Statistical analyses were performed using non-parametric tests.Results:Incubation with radioiodine as well as irradiation with high-energy photons slowed down proliferation in investigated cell lines significantly. Irradiation with solely 131I resulted in stable or slightly decreased iodide uptake. Compared to those cells, the RIU increased significantly in externally irradiated cells, i. e., additional irradiation with 10 Gy resulted in an almost threefold increase of RIU in FRTL-5 after 72 h. The increase of RIU after irradiation was dose-dependent in both cell lines and could be blocked by perchlorate excess.Conclusion:It could be demonstrated that external irradiation increases RIU in thyroid cell cultures early after irradiation. The increase was dose-dependent and specific, as it could be blocked by perchlorate. This effect appears to be similar to the increase of other actively transported substances after irradiation with high-energy photons. Therefore, the results of this study may contribute to the knowledge of a generalized irradiation-induced mechanism which causes the activation of different cellular transporters. The clinical impact of these findings on combined therapy concepts has to be investigated in further experiments.Hintergrund:Der Radioiod-Uptake (RIU) ist ein wesentlicher prognostischer Faktor für den kurativen Erfolg der Radioiodtherapie bei Patienten mit differenziertem Schilddrüsenkarzinom. Es konnte gezeigt werden, dass einige Tage nach 131I-Gabe der Uptake bei einer erneuten Radioiodapplikation deutlich vermindert war. Im Gegensatz dazu wurde eine Zunahme des Glukose- und Aminosäure-Uptakes kurz nach der Bestrahlung mit hochenergetischen Photonen beschrieben. Effekte einer externen Bestrahlung mit hochenergetischen Photonen auf den RIU von Thyreozyten sind bisher noch nicht untersucht worden.Material und Methodik:Die Untersuchungen wurden in vitro an zwei unterschiedlichen Zelllinien (FRTL-5- und ML-1-Zellen) thyreoidalen Ursprungs durchgeführt. Die Zellkulturen wurden entweder nur mit Radioiod inkubiert (Kontrollen) oder zusätzlich einzeitig mit Hilfe eines Linearbeschleunigers mit 6 oder 10 Gy bestrahlt. Die Bestimmung der Zellzahl und des RIU erfolgte 24–96 h nach der 131I-Applikation. Die Messungen wurden nach Zugabe von Natriumperchlorat im Überschuss wiederholt. Statistische Analysen erfolgten mittels nichtparametrischer Tests.Ergebnisse:Die Proliferation der untersuchten Zelllinien wurde sowohl durch die Inkubation mit Radioiod als auch durch die Bestrahlung signifikant vermindert. Die Bestrahlung mit 131I allein führte zu gleichbleibendem oder leicht vermindertem Iodid-Uptake. Verglichen mit diesen Zellen erhöhte die externe Bestrahlung den RIU signifikant. So konnte bei FRTL-5-Zellen durch die zusätzliche Bestrahlung mit 10 Gy der RIU nach 72 h beinahe verdreifacht werden. Der Anstieg des RIU nach Bestrahlung war bei beiden Zelllinien dosisabhängig und konnte durch einen Überschuss an Perchlorat blockiert werden.Schlussfolgerung:In dieser Studie konnte gezeigt werden, dass eine externe Bestrahlung mit hochenergetischen Photonen zu einem Anstieg des RIU von Schilddrüsen-Zellkulturen führt. Dieser Anstieg war dosisabhängig und spezifisch, da er durch Perchlorat geblockt werden konnte. Dieser Effekt weist Ähnlichkeiten zum Anstieg anderer aktiv transportierter Substanzen nach Bestrahlung auf. Die Ergebnisse dieser Studie liefern einen Beitrag zur Kenntnis eines generalisierten Mechanismus, welcher auf eine Aktivierung unterschiedlicher zellulärer Transporter nach Bestrahlung mit hochenergetischen Photonen hinweist. Die klinische Relevanz dieser Ergebnisse für kombinierte Therapieverfahren sollte in weiteren Untersuchungen geklärt werden.

Chronic infection with Yersinia enterocolitica in patients with clinical or latent hyperthyroidism

In hyperthyroidism a high prevalence of YOP-Ab, of IgG and IgA class was detected. There are always a minimum number (>20%) of patients without any YOP-Ab. This may be due to inconsistencies in the diagnosis, in the definition of cohorts or to other factors/agents involved; i.e.: hormone status, committing immune factors or other infectious agents.

In old age the majority of thyroid peroxidase autoantibodies are directed to a single TPO domain irrespective of thyroid function and iodine intake.

We have examined (1) which epitopes on thyroid peroxidase (TPO) are recognized by TPO autoantibodies (TPO‐Aab) in old age and to what extent? (2) Does the TPO‐Aab pattern differ in euthyroid and hypothyroid elderly subjects or does it depend on their iodine intake?