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The Journal of Clinical Endocrinology & Metabolism Vol. 83, No. 3 1020-1024
Copyright © 1998 by The Endocrine Society

Original Studies

Characterization of Corticotropin-Releasing Hormone (CRH) in Human Skin1

Andrzej Slominski, Gennady Ermak, Joseph E. Mazurkiewicz, James Baker and Jacobo Wortsman

Department of Pathology, Loyola University Medical Center (A.S.), Maywood, Illinois 60153; the Department of Microbiology, Immunology, and Molecular Genetics, Albany Medical College (J.E.M.), Albany, New York 12208; Andrus Gerontology Center, University of Southern California (G.E.), Los Angeles, California 90089; and the Department of Medicine, Southern Illinois University (J.W.), Springfield, Illinois 62901

Address all correspondence and requests for reprints to: Andrzej Slominski, M.D., Ph.D., Department of Pathology, Loyola University Medical Center, 2160 South First Avenue, Maywood, Illinois 60153.


   Abstract
Top
 Abstract
Introduction
 Materials and Methods
 Results and Discussion
 References
 
We have confirmed the expression of CRH and CRH receptor type 1 genes in human skin, cultured HaCaT keratinocytes, squamous cell carcinoma, and melanoma cells. The size of CRH messenger ribonucleic acid (mRNA), estimated by Northern blot hybridization, was 1.5 kilobases. CRH peptide was identified by reverse phase high pressure liquid chromatography separation in both whole skin and cultured cells. Forskolin and dexamethasone at concentrations of 10 µmol/L stimulated and inhibited, respectively, CRH peptide production in squamous cell carcinoma and melanoma cells, but had no significant effect on the CRH mRNA level. In melanoma cells, stimulation of melanogenesis down-regulated CRH receptor type 1 mRNA expression, but was without effect on CRH mRNA production. We suggest that in human skin the CRH signaling system is both operative and under regulatory control.


   Introduction
Top
 Abstract
 Introduction
Materials and Methods
 Results and Discussion
 References
 
CRH IS AN important component of the adaptive hypothalamic-pituitary response to stress (1, 2, 3). CRH acts as the stimulator for expression of the proopiomelanocortin (POMC) gene and for the production and secretion of POMC peptides (1, 2, 3, 4, 5, 6). These include ACTH, MSH, and ß-endorphin. ACTH stimulates the production and release of cortisol, which by a feedback mechanism attenuates hypothalamic CRH and pituitary POMC production (1, 2, 3, 4, 5, 6).

The peptide CRH is a 41-amino acid long peptide that results from cleavage of a larger prohormone precursor containing 191 amino acids (1, 2, 3). The CRH gene is composed of two exons; the first one encodes most of the 5'-untranslated region of the messenger ribonucleic acid (mRNA), whereas the second contains the prohormone sequence and the 3'-untranslated region (1, 2, 3, 6, 7, 8). CRH transcripts in rodent and human brain are very similar in size, approximately 1.4 and 1.5 kilobases (kb), respectively (7, 8). The CRH gene is also expressed in extracranial tissues (1, 2, 3, 6, 7, 8, 9).

The skin is a target for POMC-derived peptides (10). Thus, MSH and ACTH act as regulators of mammalian pigmentation (11) and inhibitors of the skin immune system (12); they may also influence keratinocyte proliferation and differentiation (13, 14, 15). In addition to being a target for those peptides, the skin has the capability of expressing POMC and locally producing ACTH, MSH, and ß-endorphin peptides (10, 12, 16, 17). Moreover, expression of the CRH receptor type 1 gene (CRH-R1) has been detected in rodent and human skin (18, 19) and in cultured human melanocytes stimulated by UV radiation (20). Based on these observations it has been hypothesized that the components of the hypothalamus-pituitary-adrenal axis expressed locally in the skin would function as a response mechanism to external stress (16). In the present work, we have characterized the expression of CRH in human skin in a further attempt at defining its functional significance (16).


   Materials and Methods
Top
 Abstract
 Introduction
 Materials and Methods
Results and Discussion
 References
 
Materials

Skin samples were obtained from patients seen at the Albany Medical Center or affiliated offices. The use of human tissues was approved by the Albany Medical College committee on research involving human subjects (protocol: skin as neuroendocrine organ, exemption, category 4). Human pituitaries were obtained from the National Hormone and Pituitary Program, NIDDK. HaCaT keratinocytes were a gift from Dr. P. Higgins (Albany Medical Center), and squamous cell carcinoma (C4–1) and melanoma (SK-MEL188) cells were obtained from Dr. A. Chakraborty (Yale University). Human CRH and human CRH-R1 cDNAs were obtained from Dr. J. Majzub (Children’s Hospital, Boston, MA) and Dr. M. Perrin (Salk Institute, La Jolla, CA), respectively.

Semiconfluent cultures of HaCaT keratinocytes, C4–1 squamous cell carcinoma, and SK-MEL188 melanoma cells were grown in a 75-cm2 flask in 10 mL Ham’s F-10 medium or DMEM when specified, supplemented with 5% FCS, 5% horse serum, and antibiotics as described previously (21, 22). When specified, 10 µmol/L dexamethasone or forskolin (Sigma Chemical Co., St. Louis, MO) or vehicle (dimethylsulfoxide) were added. Media were changed every second day. Cells were harvested and used for RNA and peptide isolations.

Reverse phase high pressure liquid chromatography (RP-HPLC) separation and RIAs

Peptides were extracted from human skin, cultured normal and malignant keratinocytes, and melanoma cells and purified using SEPCOL-1 containing 200 mg C18 as described previously (21). The eluted fractions were lyophilized and resuspended in buffer for RIA or in 0.1% trifluoroacetic acid for RP-HPLC separation. RP-HPLC was performed using Beckman Ultrasphere C18 IP column (150 x 4.6; 5-µm particle size; Beckman, Fullerton, CA) as described previously (20). The RIAs were performed according to the manufacturer’s protocol (CRH RIA kit, Advanced ChemTech, KY) (20). The cross-reactivity of the CRH antibody with CRH from human/rat was 100%, and that with bovine or ovine CRH was 0.1%. The antibody did not cross-react with prepro-CRH-(125–151) (human), urocortin (rat), urotensin (catostomus commersoni), ACTH, [Arg8]vasopressin, or brain natriuretic peptide-45 (rat). The intra- and interassay variation coefficients were below 4.9% and 12.7%, respectively.

RT-PCR assays, and Southern and Northern blot hybridizations

Total RNA was extracted, and RT was performed as described previously (18, 19, 20, 21, 22). The sequence of primers and conditions for PCR amplification of 413- and 334-bp fragments from the coding regions of the CRH and CRH-R1 genes, respectively, were detailed previously (18). In addition, to amplify a second 380-bp CRH-R1 cDNA fragment, a new lower primer with the sequence 5'-CTGTCACCAACCTGCACCAG-3' (nucleotides 783 to 803) was used. The upper primer was the same as that reported previously (18). To amplify the 380-bp CRH-R1 fragment, samples were heated at 94 C for 3 min and then amplified for 35 cycles of 30 s at 96 C, 2 min at 54 C, and 3 min at 72 C. The reaction mixture consisted of 25 mmol/L (NH4)2SO4 buffer (pH 9.5), 1.5 mmol/L MgCl2, 0.4 mmol/L deoxy-NTP, and 4 µmol/L of primers. All samples were analyzed by gel electrophoresis and standardized by amplification of the housekeeping gene glyceraldehyde-3-phosphate dehydrogenase (GAPDH). RNA samples without prior RT were run in parallel, and only the samples that showed no DNA contamination were used in the experiments. Separation of PCR products and Southern blotting methodologies were detailed previously (18, 19, 20, 21, 22).

For Northern blotting, polyadenylated [poly(A)+] mRNA was extracted from cultured cells using the FAST Track isolation kit following the manufacturer’s protocol (Invitrogen, San Diego, CA). The RNA concentration was quantified spectrophotometrically, and its relative content was further confirmed on ethidium bromide-stained agarose gels. Two micrograms of poly(A)+ mRNA were subjected to electrophoresis through 1% agarose formaldehyde gels, transfered to nylon membranes with HETS (Cinna/Biotecx), and cross-linked by UV radiation.

The hybridization with [{alpha}-32P]deoxy-CTP-labeled cDNAs coding exon 2 of human CRH, human CRH-R1, or chicken GAPDH was performed as described previously (18, 19, 20, 21, 22). Membranes were washed and exposed on x-ray films (18, 19, 20, 21, 22). To rehybridize RNA, old probes were removed by washing the filters in a solution of 0.1 x SSC (standard saline citrate)-0.1% SDS and 10 mmol/L Tris-HCl (pH 7.0) in water at 90 C for 10 min.


   Results and Discussion
Top
 Abstract
 Introduction
 Materials and Methods
 Results and Discussion
References
 
We demonstrate the expression of CRH mRNA in human squamous cell carcinoma and melanoma cells (Figs. 1Go and 2Go). Figure 1AGo demonstrates the predicted 413-bp product representative of the CRH exon 2 transcript that hybridized to human CRH cDNA, whereas it was absent in RNA amplified without RT. These results are in agreement with our previous RT-PCR detection of CRH mRNA in biopsies of human scalp, basal cell carcinoma, and compound pigmented nevus (18). Northern blot hybridization showed 1.5-kb mRNA transcripts hybridizing to the human CRH cDNA (Fig. 1BGo). The size of the cutaneous CRH mRNA message is similar to that of the mRNA from human hypothalamus, i.e. 1.5 kb (7). RP-HPLC separation, monitoring the eluted fraction with specific anti-CRH RIA, demonstrated the presence of CRH peptide in facial human skin, cultured nonmalignant HaCaT keratinocytes, squamous cell carcinoma cells, and melanoma cells (Fig. 2Go). The evidence provided thus confirms that both CRH mRNA and CRH peptide are produced in human skin and in cultured nonmalignant and malignant human cutaneous cells.



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  		Figure 1. Production of CRH mRNA in human skin cells. A, Detection of a 413-bp product representative of CRH mRNA by RT-PCR (ethidium bromide-stained gels). 1, Human pituitary; 2, pollution control (reaction mixture without DNA template); 3, DNA size markers of 1000, 700, 525, 500, 400, and 300 bp; 4–6, melanoma cells; 7–10, squamous cell carcinoma cells. B, Northern hybridization of 2 µg poly(A)+ RNA with CRH cDNA. 1, Squamous cell carcinoma (SSC); 2, melanoma (melanoma); 3, RNA size markers (kilobases, right).

 


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  		Figure 2. Production of CRH by human skin. A, Human skin; B, HaCaT keratinocytes; C, squamous cell carcinoma cells; D, melanoma cells. CRH, CRH standard eluting at 30–31 min.

 
Hypothalamic CRH production is known to be stimulated through a cAMP-dependent pathway, whereas it is inhibited by glucocorticoids (1, 2, 3). In the present work we demonstrate that production of CRH in cultured malignant keratinocytes and melanocytes is modified by forskolin, a stimulator of cAMP production, and by dexamethasone, a synthetic glucocorticoid. These agents significantly stimulated and inhibited CRH production, respectively (Table 1Go). In contrast, Northern blot analysis showed that dexamethasone did not inhibit and forskolin did not stimulate CRH mRNA production (Fig. 3Go). This finding is interesting, as it suggest that their action may be similar to that of UVB, another factor that stimulates CRH production in human melanocytes without significantly effecting CRH mRNA levels (20). Taken together, these observations are compatible with a posttranscriptional mechanism of regulation. Although additional studies may be required to define the exact regulation of CRH gene transcription in skin, it appears safe to conclude that external factors can stimulate or inhibit CRH peptide production by skin cells.


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  		Table 1. Effects of dexamethasone and forskolin on CRH peptide production by squamous cells carcinoma and melanoma cells

 


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  		Figure 3. Dexamethasone and forskolin have no effect on CRH mRNA production by squamous cell carcinoma and melanoma cells. Upper panel, Northern hybridization of 2 µg poly(A)+ RNA with CRH cDNA. Lower panel, After stripping of the CRH cDNA, mRNA was rehybridized with the housekeeping gene GAPDH. 1–3, Squamous cell carcinoma; 4–6, melanoma. 1 and 4, No addition; 2 and 5, addition of 10 µmol/L dexamethasone; 3 and 6, addition of forskolin.

 
CRH signal is translated by interaction with CRH receptor(s) (1, 2, 3, 4, 5, 23, 24). Using primers from the coding region of the CRH-R1 and Southern hybridization, we detected the corresponding RT-PCR-amplified cDNA products with a predicted size of 334 bp in squamous cell carcinoma and melanoma cells (Fig. 4AGo). This finding was further confirmed by detection of a 380-bp CRH-R1 cDNA fragment using the new sets of primers described in Materials and Methods. Stimulation of melanogenesis, accomplished by changing medium from Ham’s F-10 (low in tyrosine) to DMEM (high in tyrosine) (25), down-regulated CRH-R1 mRNA expression in melanoma cells (Fig. 4BGo), but had no effect on CRH mRNA production (not shown). Conversely, there was no difference in CRH-R1 mRNA production between squamous cell carcinoma cultured in Ham’s F-10 or DMEM. This suggests that in pigment cells, stimulation of the differentiation program (melanin production) may change the expression of CRH-R1 mRNA. The above data are in accordance with our previous demonstration of CRH-R1 mRNA in human skin biopsies and in cultured keratinocytes and melanocytes exposed to UVB (18). Therefore, we suggest that paracrine and/or autocrine mechanisms actively modify CRH signal transduction in human skin in vivo. Such mechanisms would involve the local production of CRH and activation of the corresponding receptors. This hypothesis is further supported by our recent finding in mouse skin of the expression both CRH-R1 mRNA and high affinity CRH-binding sites (receptors) (26).



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  		Figure 4. Expression of CRH-R1 mRNA in squamous cell carcinoma and melanoma cells. A, Southern blot hybridization of human CRH-R1 cDNA with a 334-bp RT-PCR-amplified fragment from pituitary (1), melanoma (2) and squamous cell carcinoma (3–5). B, Southern blot hybridization of human CRH-R1 cDNA with a 380-bp RT-PCR-amplified fragment from melanoma cells cultured in Ham’s F-10 (1) or DMEM (2 and 3) and from human pituitary (4) (positive control). The upper panel represents PCR amplification without prior RT, and the lower panel represents RT-PCR amplification.

 
We previously proposed that molecular elements of the hypothalamus-pituitary axis, including CRH and POMC peptides, operate locally in the skin as a part of an organized response to stress (16). In this report we provide experimental evidence supporting that hypothesis, i.e. that regulated local CRH signals may play a role in skin physiology and pathology. In fact, CRH, in addition to its central neuroendocrine and neurotransmitter role, can act as an immunomodifier, as a regulator in the cardiovascular and reproductive systems, and perhaps as a growth factor (1, 2, 9, 27, 28, 29, 30, 31, 32, 33). Moreover, both CRH and CRH receptors are expressed in several peripheral tissues, including adrenals, gonads, placenta, gastrointestinal system, pancreas, and immune cells (1, 2, 3, 6, 7, 8), again implying a paracrine mode of action. Similarly, cutaneous CRH could locally regulate several components in the skin, such as the immune, vascular, adnexal, and perhaps epithelial and melanocytic systems. This could be accomplished directly, via an interaction with specific receptors, or indirectly, via stimulation of local production of ACTH, MSH, and ß-endorphin. Locally produced POMC peptides are known to regulate skin functions (10, 12, 16, 17).

In summary, we provide further evidence of CRH and CRH-R1 mRNAs and CRH production in human skin cells. The production of peptide CRH, but not of CRH mRNA, was stimulated by forskolin and inhibited by dexamethasone. We suggest that a local CRH signaling system is involved in the regulation of skin responses to local stressors.


   Acknowledgments
 
We thank Dr. J. Majzub for CRH cDNA, Dr. M. Perrin for CRH-R1 cDNA, Dr. Higgins for HaCaT cells, and Dr. Chakraborty for SK-MEL188 and C4-1 cells.


   Footnotes
 
1 This work was supported by NSF Grant IBN-9604364. Back

Received October 7, 1997.

Revised November 24, 1997.

Accepted December 2, 1997.


   References
Top
 Abstract
 Introduction
 Materials and Methods
 Results and Discussion
 References
 

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