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FJ
EXPRESS SUMMARY ARTICLE The Full-length version of this article is also available, published online August 17, 2001 as doi:10.1096/fj.01-0254fje. |
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Department of Dermatology, Nippon Medical School, Tokyo, Japan; and
* Department of Pathology, Tokai University School of Medicine, Boseidai Isehara City, Kanagawa, Japan 259-1193
2Correspondence: E-mail: osamura{at}is.icc.u-tokai.ac.jp
SPECIFIC AIMS
The aim of the present study was to elucidate the local production site of corticotropin-releasing hormone (CRH) in the skin and to explore regulatory mechanisms of the expression of CRH and proopiomelanocortin (POMC), including skin paracrine and autocrine circuits that involve CRH, CRH-R, and POMC peptides. We also investigated the interaction neuropeptides with the skin immune system.
PRINCIPAL FINDINGS
1. In situ RT-PCR demonstrated that CRH and POMC mRNAs were
expressed in epidermis and pilosebaceous units of normal skin
The present study provides for the first time the exact
localization of the production site of CRH by using in situ RT-PCR. In
normal skin, CRH and POMC genes were expressed in the basal layer of
epidermis and in pilosebaceous units. A combination of laser-capture
microdissection with an RT-PCR assay was performed that demonstrated
the expression of CRH, CRH-R, and POMC mRNAs in captured sebaceous
cells (Fig. 1
). These results revealed that human epidermal cells and pilosebaceous
cells locally produce CRH and POMC peptides.
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2. Colocalization of CRH, CRH-R, and POMC peptides was demonstrated
in pilosebaceous and benign tumor cells
The strong immunoreactivity of CRH, CRH-R, and POMC peptides was
demonstrated in the outer root sheath of hair follicles in normal skin.
Intense positivity for these peptides was observed in the same cells of
compound nevus. This colocalization suggests that CRH might stimulate
POMC expression via CRH-R, as in the central nervous system (CNS).
3. In inflammatory lesions, immunoreactivity of CRH, CRH-R, and
POMC peptides and expression of these genes were stronger and more
extensive than in normal epidermis
In inflammatory psoriatic and parapsoriatic lesions,
immunoreactivity of CRH, CRH-R, and 
-MSH was observed in all layers
of the epidermis and dermal infiltrating cells. In situ RT-PCR revealed
that in the inflammatory epidermis, expression of CRH and POMC mRNAs
was more intense and extensive than in normal epidermis. Dermal
infiltrating cells also showed this expression.
4. Strong expressions of CRH, CRH-R, and POMC peptides were
demonstrated in a nonmalignant tumor and its periphery
The tumor cells of seborrheic keratosis and pigmented nevus
demonstrated immunoreactivity of CRH, CRH-R, and POMC peptides and
expression of these genes. Even in the peripheral epidermis, expression
of POMC mRNAs was more intense than in normal epidermis (Fig. 2
).
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CONCLUSION
CRH is a major regulator of the hypothalamus-pituitary-adrenal axis (HPA) and a principal coordinator of the stress response. In response to systemic stress, CRH stimulates the pituitary CRH-R, which leads to production and secretion of POMC-derived peptides, including MSH and ACTH.
The skin is exposed directly and permanently to multiple physical, chemical, and biological stress. Skin should be able to respond immediately against these stressors and reestablish tissue homeostasis.
Skin is known to be a target organ for CRH and POMC peptides, and immunohistochemical studies have demonstrated CRH, CRH-R, and POMC peptides in human skin. RT-PCR has shown that CRH, CRH-R type 1 (CRH-R1), and POMC genes are expressed in human skin as well as cultured keratinocytes and melanocytes. Therefore, the skin has been considered a source of CRH and POMC peptides. Slominski et al. proposed that an equivalent of HPA axis composed of the CRH-CRHR-POMC loop is conserved in the skin that may be activated in a skin stress response system.
In situ hybridization recently demonstrated that POMC mRNA was expressed in keratinocytes and melanocytes, but it was not clear where CRH is expressed in the skin or what regulates the production of CRH and POMC peptides. Using in situ RT-PCR, we elucidated the localization of the production sites of CRH in human skin.
We demonstrated that CRH and POMC mRNAs were expressed in the keratinocytes and melanocytes of normal epidermis and in the pilosebaceous unit. The results indicate that CRH and POMC are produced locally in the normal skin.
Using immunohistochemistry, colocalization of CRH, CRH-R,
and POMC peptides was observed in hair follicles and nevus cells. In
the CNS, CRH stimulates the pituitary CRH-R, which leads to production
and secretion of POMC-derived peptides, including -MSH and
adrenocorticotropic hormone (ACTH). Coexpression of CRH, CRH-R, and
POMC peptides indicates that cutaneous CRH exerts a comparable effect
on the expression of POMC via CRH-R, which is activated in an autocrine
and paracrine manner.
A comparison between the inflammatory lesion and normal skin suggested
the regulatory mechanism of CRH and POMC production to be modulated by
the immune system, as well as autocrine and/or paracrine regulation. In
CNS, cytokines regulates expression of CRH; tumor necrosis factor
(TNF-), interleukin-1 (IL-1), and IL-6 stimulate CRH secretion.
Strong expression of these peptides in an inflammatory lesion proposed
the possibility that proinflammatory cytokines stimulate expression of
CRH and POMC in the epidermis. Infiltrating inflammatory cells also
demonstrated expression of CRH and POMC. POMC peptides are known to
have a direct immunomodulatory role. For example, -MSH is known to
inhibit production of interferon 
(IFN-) and TNF- by
peripheral blood mononuclear cells. CRH secreted in inflammatory sites
can also modulate inflammation. CRH was found to induce mast cell
degranulation, stimulate secretion of IL-1 from monocytes and IL-2 from
lymphocytes, and promote lymphocyte proliferation. Therefore, CRH and
POMC peptides might interact with dermal infiltrating cells and affect
the immune or inflammatory process. Although the interaction needs to
be investigated further, it might underlie the stress-induced
exacerbation of such dermatosis as atopic dermatitis and psoriasis.
CRH-R and POMC were expressed strongly in the periphery of benign
tumors and tumor cells. Slominski et al. observed heterogeneous
distribution and expression of POMC peptides and their mRNAs in basal
cell carcinoma and in the peripheral areas. In addition to acting as
potent immunosuppressors, -MSH can regulate keratinocyte and enhance
the proliferation and metastatic ability of malignant melanoma.
Production of POMC peptides in the peripheral lesion as well as in
tumor cells might have a role in generating a permissive environment
for tumor development and progression, as suggested by previous
reports. Furthermore, external stressors, predominantly UV light, are
known to stimulate expression of CRH and POMC in response to stress. We
propose that the peripheral tissue synthesizes the POMC peptides as a
response to local stress such as UV light and tumor progression owing
to the effect of proliferation of tumor cells.
In summary, our study reveals the local production sites of CRH and POMC in the skin and could help in exploring the regulatory mechanisms of CRH and POMC production and the interaction between the neuroendocrine and immune system in the skin. Our results support the hypothesis proposed by Slominski et al. that a stress response system may exist in the skin mediated by the neuroendocrine system and modulated by the immune system, with the CRH-POMC loop playing an essential role.
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FOOTNOTES
1 To read the full text of this article, go to http://www.fasebj.org/cgi/doi/10.1096/fj.01-0254fje; to cite this article, use FASEB J. (August 17, 2001) 10.1096/fj.01-0254fje 
This article has been cited by other articles:
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