Interferon-gamma is a potent inducer of catagen-like changes in cultured human anagen hair follicles

Ito, Taisuke; Ito, Natsuho; Saathoff, Matthias; Bettermann, Albrecht; Takigawa, Masaharu; Paus, Ralf

doi:10.1111/j.1365-2133.2005.06453.x

Cited by 118 publications

(100 citation statements)

References 34 publications

(123 reference statements)

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“…Here, we show clearly that, in addition, RXR AF-2 must be functional in this heterodimer, because the keratinocyte-selective inactivation of AF-2 in RXR␣ and RXR␤ (RXR␣␤ epaf2o mutant) results in a similar alopecia. Furthermore, our finding of a Th1-like inflammatory reaction in RXR␣␤ epaf2o skin with increased expression of IFN-␥ and IFN-␥-induced chemokines (CCL10 and CCL20) (38,39), suggests that the occurrence of this alopecia could be related to an increase in IFN-␥ signaling (40). In this respect, we note that there is a similar Th1-like inflammatory reaction in VDR epϪ/Ϫ skin (our unpublished data).…”

Section: ) Increasesmentioning

confidence: 51%

Retinoid X receptor ablation in adult mouse keratinocytes generates an atopic dermatitis triggered by thymic stromal lymphopoietin

Messaddeq

Teletin

et al. 2005

Proc. Natl. Acad. Sci. U.S.A.

203

206

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To investigate the role of retinoid X receptors (RXRs) in epidermal homeostasis, we generated RXR␣␤ ep؊/؊ somatic mutants in which both RXR␣ and RXR␤ are selectively ablated in epidermal keratinocytes of adult mice. These mice develop a chronic dermatitis mimicking that observed in atopic dermatitis (AD) patients. In addition, they exhibit immunological abnormalities including elevated serum levels of IgE and IgG, associated with blood and tissue eosinophilia, indicating that keratinocyte-selective ablation of RXRs also generates a systemic syndrome similar to that found in AD patients. Furthermore, the profile of increased expression of cytokines and chemokines in skin of keratinocyte-selective RXR␣␤-ablated mutants was typical of a T helper 2-type inflammation, known to be crucially involved in human AD pathogenesis. Finally, we demonstrate that thymic stromal lymphopoietin, whose expression is rapidly and strongly induced in RXR␣␤-ablated keratinocytes, plays a key role in initiating the skin and systemic AD-like pathologies.keratinocyte-selective gene ablation ͉ nuclear receptors ͉ conditional mutagenesis ͉ Cre-ER T2 A topic dermatitis (AD), a chronic skin inflammatory disease with a strong genetic component that affects children (10-20%) and adults (1-3%), is characterized by pruritic and eczematoid skin lesions, associated with systemic immunological abnormalities, including peripheral eosinophilia and hyper IgE immunoglobulinemia (1). Immunological mechanisms have been involved in AD pathogenesis (2), but the possible role of epidermal keratinocytes in AD initiation and maintenance is still largely unexplored (3).Nuclear receptors (NRs) belong to a superfamily of transcriptional regulators that include ligand-dependent and orphan receptors (4, 5). NRs play critical roles as signal transducers in vertebrate development and homeostasis, including immune functions (4, 6-8). Within the NR superfamily, the retinoid X receptor isotypes (RXR ␣, ␤, and ␥) play a key role as heterodimeric partners for some 15 NRs, e.g., retinoic acid receptors, 1,25-dihydroxyvitamin D 3 receptor (VDR), peroxisome proliferator-activated receptors, and liver X activated receptors (4, 5, 9). Ligand-dependent transcriptional activation by NRs requires the integrity of the core of activation function 2 (AF-2) (the ␣-helix 12 of the ligand-binding domain; see refs. 9 and 10).In epidermis, RXR␣ is predominant, RXR␤ level is lower, and RXR␥ is undetectable (11-13). Keratinocyte-selective ablation of RXR␣ in adult mouse skin results in a number of abnormalities, including a progressive alopecia, keratinocyte hyperproliferation, and abnormal differentiation, and an inflammatory reaction (11,14). In contrast, the skin of RXR␤-null mice is apparently normal (11,14,15).To investigate the origin of this inflammatory reaction and to avoid any functional redundancies between keratinocytic RXR␣ and RXR␤, we have now generated RXR␣␤ epϪ/Ϫ somatic mutants in which both RXR␣ and RXR␤ are selectively ablated in epidermal keratinocytes of adult mice. T...

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Section: ) Increasesmentioning

confidence: 51%

Retinoid X receptor ablation in adult mouse keratinocytes generates an atopic dermatitis triggered by thymic stromal lymphopoietin

Messaddeq

Teletin

et al. 2005

Proc. Natl. Acad. Sci. U.S.A.

203

206

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“…63 We also show that the catagen-promoting activity of PRL is independent of the hypothalamus-pituitary-adrenal axis and systemic hormone levels. It applies to HFs of a mammalian species with mosaic and seasonally independent HF cycling (ϭhuman scalp HF).…”

Section: Discussionmentioning

confidence: 84%

Human Scalp Hair Follicles Are Both a Target and a Source of Prolactin, which Serves as an Autocrine and/or Paracrine Promoter of Apoptosis-Driven Hair Follicle Regression

Foitzik

Krause

Conrad

et al. 2006

The American Journal of Pathology

135

171

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The prototypic pituitary hormone prolactin (PRL) exerts a wide variety of bioregulatory effects in mammals and is also found in extrapituitary sites, including murine skin. Here, we show by reverse transcriptase-polymerase chain reaction and immunohistology that, contrary to a previous report, human skin and normal human scalp hair follicles (HFs), in particular, express both PRL and PRL receptors (PRL-R) at the mRNA and protein level. PRL and PRL-R immunoreactivity can be detected in the epithelium of human anagen VI HFs, while the HF mesenchyme is negative. During the HF transformation from growth (anagen) to apoptosisdriven regression (catagen), PRL and PRL-R immunoreactivity appear up-regulated. Treatment of organ-cultured human scalp HFs with high-dose PRL (400 ng/ml) results in a significant inhibition of hair shaft elongation and premature catagen development, along with reduced proliferation and increased apoptosis of hair bulb keratinocytes (Ki-67/terminal dUTP nick-end labeling immunohistomorphometry). This shows that PRL receptors, expressed in HFs, are functional and that human skin and human scalp HFs are both direct targets and sources of PRL. Our data suggest that PRL acts as an autocrine hair growth modulator with catagenpromoting functions and that the hair growth-inhibitory effects of PRL demonstrated here may underlie the as yet ill-understood hair loss in patients with hyperprolactinemia.

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“…The measurement area was 5 mm in diameter, and the instrument was calibrated using black and white calibration plates. Skin biopsies were harvested and processed for FontanaMasson staining, as described (49).…”

Section: Methodsmentioning

confidence: 99%

Suppression of Melanin Production by Expression of HSP70

Hoshino

Matsuda

Yamashita

et al. 2010

Journal of Biological Chemistry

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Skin hyperpigmentation disorders due to abnormal melanin production induced by ultraviolet (UV) irradiation are both a clinical and cosmetic problem. UV irradiation stimulates melanin production in melanocytes by increasing intracellular cAMP. Expression of heat shock proteins (HSPs), especially HSP70, is induced by various stressors, including UV irradiation, to provide cellular resistance to such stressors. In this study we examined the effect of expression of HSP70 on melanin production both in vitro and in vivo. 3-Isobutyl-1-methylxanthine (IBMX), a cAMP-elevating agent, stimulated melanin production in cultured mouse melanoma cells, and this stimulation was suppressed in cells overexpressing HSP70. IBMX-dependent transcriptional activation of the tyrosinase gene was also suppressed in HSP70-overexpressing cells. Expression of microphthalmia-associated transcription factor (MITF), which positively regulates transcription of the tyrosinase gene, was up-regulated by IBMX; however, this up-regulation was not suppressed in HSP70-overexpressing cells. On the other hand, immunoprecipitation and immunostaining analyses revealed a physical interaction between and co-localization of MITF and HSP70, respectively. Furthermore, the transcription of tyrosinase gene in nuclear extract was inhibited by HSP70. In vivo, UV irradiation of wild-type mice increased the amount of melanin in the basal layer of the epidermis, and this increase was suppressed in transgenic mice expressing HSP70. This study provides the first evidence of an inhibitory effect of HSP70 on melanin production both in vitro and in vivo. This effect seems to be mediated by modulation of MITF activity through a direct interaction between HSP70 and MITF.

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Interferon-gamma is a potent inducer of catagen-like changes in cultured human anagen hair follicles

Cited by 118 publications

References 34 publications

Retinoid X receptor ablation in adult mouse keratinocytes generates an atopic dermatitis triggered by thymic stromal lymphopoietin

Retinoid X receptor ablation in adult mouse keratinocytes generates an atopic dermatitis triggered by thymic stromal lymphopoietin

Human Scalp Hair Follicles Are Both a Target and a Source of Prolactin, which Serves as an Autocrine and/or Paracrine Promoter of Apoptosis-Driven Hair Follicle Regression

Suppression of Melanin Production by Expression of HSP70

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