Surgical management and outcome of adult posterior cranial fossa and spinal hemangioblastoma: a 6-case series and literature review.

OBJECTIVE: Hemangioblastomas of the posterior cranial fossa and spinal cord in adults are excessively vascularized, well-differentiated, and scarce tumors with no metastatic potential. This paper discusses its surgical management and outcome, pointing out their morphological, radiological, and histopathological aspects. This report based on a personal series of six patients and on a literature review. METHODS: A single-institution personal 6-case series of adult patients diagnosed and operated on by a senior neurosurgeon (KIA) due to posterior cranial fossa or spinal cord hemangioblastoma was analyzed. For easier understanding of hemangioblastoma, we have classified them into four different types. RESULTS: The tumors, which were all surgically treated, were located in the posterior cranial fossa in five patients (4 cerebellar, 1 brain stem) and intramedullary in the thoracic spinal cord in one patient. All patients successfully recovered neurologically after a complete tumor resection, having no post-operative neurological deficit or other complications. CONCLUSION: Surgical management of cerebellar and spinal cord hemangioblastoma in adults is highly dependent on its morphological features, as well as on microsurgical technique applied. Since huge differences exist between the cystic/nodular tumor type (Type 1) and the solid type and its two additional variants (Types 2-4), morphology is the most important consideration when deciding surgical approach. Despite significant morphological differences among different subtypes of hemangioblastomas, their histology appears to be relatively similar. Nonetheless, a meticulous and refined surgical technique has to be utilized to achieve a successful outcome.

Anterior Clinoid Metastasis Removed Extradurally: First Case Report.

Background We report a case of isolated metastasis on the anterior clinoid process (ACP) mimicking meningioma. Clinical Presentation A 58-year-old male presented with headaches, right-sided visual disturbances, and blurred and double vision. The cause of double vision was partial weakness of the right III nerve, resulting from compression of the nerve by "hypertrophied" tumor-involved right anterior clinoid. Medical history revealed two primary malignant tumors-male breast cancer and prostate cancer (diagnosed 6 and 18 months prior, respectively). The patient was treated with chemotherapy and showed no signs of active disease, recurrence, or metastasis. Postcontrast head magnetic resonance imaging (MRI) showed extra-axial well-bordered enhancing mass measuring 1.6 × 1.1 × 1 × 1 cm (anteroposterior, transverse, and craniocaudal dimensions) on the ACP, resembling a clinoidal meningioma. Extradural clinoidectomy with tumor resection was performed via right orbitozygomatic pretemporal skull base approach. Visual symptoms improved. Follow-up MRI showed no signs of tumor residual or recurrence. Conclusion This is the first case report of a metastasis of any kind on ACP. Metastasis should be included as a part of the differential diagnosis of lesions of the anterior clinoid. Extradural clinoidectomy is a safe and effective method in the treatment of these tumors.

The critical role that STAT3 plays in glioma-initiating cells: STAT3 addiction in glioma.

Glioma-Initiating Cells (GICs) are thought to be responsible for tumor initiation, progression and recurrence in glioblastoma (GBM). In previous studies, we reported the constitutive phosphorylation of the STAT3 transcription factor in GICs derived from GBM patient-derived xenografts, and that STAT3 played a critical role in GBM tumorigenesis. In this study, we show that CRISPR/Cas9-mediated deletion of STAT3 in an established GBM cell line markedly inhibited tumorigenesis by intracranial injection but had little effect on cell proliferation in vitro. Tumorigenesis was rescued by the enforced expression of wild-type STAT3 in cells lacking STAT3. In contrast, GICs were highly addicted to STAT3 and upon STAT3 deletion GICs were non-viable. Moreover, we found that STAT3 was constitutively activated in GICs by phosphorylation on both tyrosine (Y705) and serine (S727) residues. Therefore, to study STAT3 function in GICs we established an inducible system to knockdown STAT3 expression (iSTAT3-KD). Using this approach, we demonstrated that Y705-STAT3 phosphorylation was critical and indispensable for GIC-induced tumor formation. Both phosphorylation sites in STAT3 promoted GIC proliferation in vitro. We further showed that S727-STAT3 phosphorylation was Y705-dependent. Targeted microarray and RNA sequencing revealed that STAT3 activated cell-cycle regulator genes, and downregulated genes involved in the interferon response, the hypoxia response, the TGFß pathway, and remodeling of the extracellular matrix. Since STAT3 is an important oncogenic driver of GBM, the identification of these STAT3 regulated pathways in GICs will inform the development of better targeted therapies against STAT3 in GBM and other cancers.

SPINAL DUMBBELL EPIDURAL HEMANGIOMA: TWO STAGE/SAME SITTING/SAME POSITION POSTERIOR MICROSURGICAL AND TRANSTHORACIC ENDOSCOPIC RESECTION - CASE REPORT AND REVIEW OF THE LITERATURE.

- Spinal dumbbell tumors are defined by a narrowing at the point where they penetrate the intervertebral foramina or dura mater, assuming an hourglass or dumbbell shape. Dumbbell-shaped spinal hemangiomas are extremely rare. We describe a dumbbell spinal tumor (epidural cavernous hemangioma) resected by a 2-stage single-sitting combined approach. We also conduct a substantial literature review of the subject. We present a case of a 78-year-old male who was found to have a homogeneously enhancing, dumbbell-shaped, intraspinal, extradural tumor mass extending into the left chest cavity. The tumor was resected with a single-sitting 2-stage posterior technique: a microsurgical approach, followed by endoscopic resection via a thoracoscopic approach. There are several reports in the literature on the combined approach for dumbbell tumors of the spinal cord. Our case is the first to describe 2-stage combined surgery in 1 sitting for dumbbell hemangioma with the patient in the lateral decubitus position for the thoracoscopic part of the surgery; and the use of a fat pad, which was applied in the neuroforamen via the posterior route, as a marker for resection during the transthoracic procedure.

First Report of Coexistence of Two Ectopic Pituitary Tumors: Rathke Cleft Cyst and Silent Adrenocorticotropic Hormone Adenoma.

BACKGROUND: Rathke cleft cysts (RCCs) and pituitary adenomas (PAs) are thought to have a common embryonic ancestry; however, PAs with a concomitant RCC inside the sella turcica are rarely observed. Ectopic pituitary tumors are also rare. CASE DESCRIPTION: We present the case of a 65-year-old woman with an ectopic RCC in the sphenoid sinus and outside the sella turcica concomitant with an adrenocorticotropic hormone (ACTH)-staining, clinically silent PA. The patient had headache but no endocrine or visual disturbances. Preoperative magnetic resonance imaging revealed infrasellar cystic lesion in the sphenoid sinus with erosion of the clivus and intact sellar floor. The patient underwent gross total microsurgical resection through the transnasal route with an uneventful postoperative course. CONCLUSIONS: To our knowledge, this is the first reported ectopic RCC located outside the sella turcica with a concomitant ACTH-staining PA. This also appears to be the first ACTH-staining adenoma concomitant with RCC reported in the literature, regardless of location, not presenting with Cushing disease. This case shows that we can now include pituitary adenoma with or without a concomitant RCC in the differential diagnosis of processes in the sphenoid sinus. As both PAs and RCCs are benign sellar lesions, surgical management of a concomitant occurrence of these tumors mainly depends on the size of the lesions and their clinical manifestations. For patients with PA and concomitant RCC, surgical resection should be considered, as there is an approximatrely 20% recurrence rate of the cyst after resection and the possibility of future clival erosion, if left untreated.

Cytochromes p450 and skin cancer: role of local endocrine pathways.

Skin is the largest body organ forming a metabolically active barrier between external and internal environments. The metabolic barrier is composed of cytochromes P450 (CYPs) that regulate its homeostasis through activation or inactivation of biologically relevant molecules. In this review we focus our attention on local steroidogenic and secosteroidogenic systems in relation to skin cancer, e.g., prevention, attenuation of tumor progression and therapy. The local steroidogenic system is composed of locally expressed CYPs involved in local production of androgens, estrogens, gluco- and mineralo-corticosteroids from cholesterol (initiated by CYP11A1) or from steroid precursors delivered to the skin, and of their metabolism and/or inactivation. Cutaneous 7-hydroxylases (CYP7A1, CYP7B1 and CYP39) potentially can produce 7-hydroxy/oxy-steroids/sterols with modifying effects on local tumorigenesis. CYP11A1 also transforms 7-dehydrocholesterol (7DHC)→22(OH)7DHC→20,22(OH)2-7DHC→7-dehydropregnenolone, which can be further metabolized to other 5,7- steroidal dienes. These 5,7-dienal intermediates are converted by ultraviolet radiation B (UVB) into secosteroids which show pro-differentiation and anti-cancer properties. Finally, the skin is the site of activation of vitamin D3 through two alternative pathways. The classical one involves sequential hydroxylation at positions 25 and 1 to produce active 1,25(OH)2D3, which is further inactivated through hydroxylation at C24. The novel pathway is initiated by CYP11A1 with predominant production of 20(OH)D3 which is further metabolized to biologically active but non-calcemic D3-hydroxyderivatives. Classical and non-classical (novel) vitamin D analogs show pro-differentiation, anti-proliferative and anticancer properties. In addition, melatonin is metabolized by local CYPs. In conclusion cutaneously expressed CYPs have significant effects on skin physiology and pathology trough regulation of its chemical milieu.

Putative role of HIF transcriptional activity in melanocytes and melanoma biology.

Hypoxia-inducible factor-1α (HIF-1α) is a highly oxygen sensitive bHLH protein that is part of the heterodimeric HIF-1 transcription factor. Under hypoxic stress, HIF-1 activity is induced to control expression of multiple downstream target genes, including vascular endothelial growth factor (VEGF). The normal epidermis exists in a constant mild hypoxic microenvironment and constitutively expresses HIF-1α and HIF-2α. Expression of HIF-1α and/or HIF-2α has been suggested to correlate with the increased malignant potential of melanocytes, therefore, failures of melanoma therapies may be partially linked to high HIF activity. Notably, melanomas that have the V600E BRAF mutation exhibit increased HIF-1α expression. We have utilized a bioinformatics approach to identify putative hypoxia response elements (HREs) in a set of genes known to participate in the process of melanogenesis (includingTRPM1, SLC45A2, HRAS, C-KIT, PMEL and CRH). While some of the mechanistic links between these genes and the HIF pathway have been previously explored, others await further investigation. Although agents targeting HIF activity have been proposed as novel treatment modalities for melanoma, there are currently no clinical trials in progress to test their efficacy in melanoma.

Key role of CRF in the skin stress response system.

The discovery of corticotropin-releasing factor (CRF) or CRH defining the upper regulatory arm of the hypothalamic-pituitary-adrenal (HPA) axis, along with the identification of the corresponding receptors (CRFRs 1 and 2), represents a milestone in our understanding of central mechanisms regulating body and local homeostasis. We focused on the CRF-led signaling systems in the skin and offer a model for regulation of peripheral homeostasis based on the interaction of CRF and the structurally related urocortins with corresponding receptors and the resulting direct or indirect phenotypic effects that include regulation of epidermal barrier function, skin immune, pigmentary, adnexal, and dermal functions necessary to maintain local and systemic homeostasis. The regulatory modes of action include the classical CRF-led cutaneous equivalent of the central HPA axis, the expression and function of CRF and related peptides, and the stimulation of pro-opiomelanocortin peptides or cytokines. The key regulatory role is assigned to the CRFR-1α receptor, with other isoforms having modulatory effects. CRF can be released from sensory nerves and immune cells in response to emotional and environmental stressors. The expression sequence of peptides includes urocortin/CRF→pro-opiomelanocortin→ACTH, MSH, and ß-endorphin. Expression of these peptides and of CRFR-1α is environmentally regulated, and their dysfunction can lead to skin and systemic diseases. Environmentally stressed skin can activate both the central and local HPA axis through either sensory nerves or humoral factors to turn on homeostatic responses counteracting cutaneous and systemic environmental damage. CRF and CRFR-1 may constitute novel targets through the use of specific agonists or antagonists, especially for therapy of skin diseases that worsen with stress, such as atopic dermatitis and psoriasis.

Steroidogenesis in the skin: implications for local immune functions.

The skin has developed a hierarchy of systems that encompasses the skin immune and local steroidogenic activities in order to protect the body against the external environment and biological factors and to maintain local homeostasis. Most recently it has been established that skin cells contain the entire biochemical apparatus necessary for production of glucocorticoids, androgens and estrogens either from precursors of systemic origin or, alternatively, through the conversion of cholesterol to pregnenolone and its subsequent transformation to biologically active steroids. Examples of these products are corticosterone, cortisol, testosterone, dihydrotesterone and estradiol. Their local production can be regulated by locally produced corticotropin releasing hormone (CRH), adrenocorticotropic hormone (ACTH) or cytokines. Furthermore the production of glucocorticoids is affected by ultraviolet B radiation. The level of production and nature of the final steroid products are dependent on the cell type or cutaneous compartment, e.g., epidermis, dermis, adnexal structures or adipose tissue. Locally produced glucocorticoids, androgens and estrogens affect functions of the epidermis and adnexal structures as well as local immune activity. Malfunction of these steroidogenic activities can lead to inflammatory disorders or autoimmune diseases. The cutaneous steroidogenic system can also have systemic effects, which are emphasized by significant skin contribution to circulating androgens and/or estrogens. Furthermore, local activity of CYP11A1 can produce novel 7Δ-steroids and secosteroids that are biologically active. Therefore, modulation of local steroidogenic activity may serve as a new therapeutic approach for treatment of inflammatory disorders, autoimmune processes or other skin disorders. In conclusion, the skin can be defined as an independent steroidogenic organ, whose activity can affect its functions and the development of local or systemic inflammatory or autoimmune diseases. This article is part of a Special Issue entitled 'CSR 2013'.

Nottingham-defined mitotic score: comparison with visual and image cytometric phosphohistone H3 labeling indices and correlation with Oncotype DX recurrence score.

Prognosis of breast cancer patients has been determined traditionally by lymph node status, tumor size, and histologic grade. In recent years the Oncotype DX recurrence score (RS) assay has emerged as an expensive adjunct prognostic tool. Markers of proliferation play a large role in determination of RS, and we have shown previously that immunohistochemical expression of proliferation markers Ki-67 and phosphohistone H3 (PPH3) correlates with RS. Our current goal is comparison of the hematoxylin and eosin (H&E) mitotic score, defined by the Nottingham grading system, with anti-PPH3 mitotic figure labeling assessed by both visual and automated image analysis and correlation of mitotic score results with RS. Estrogen receptor-positive breast carcinomas from 137 patients with Oncotype DX testing were selected. A representative H&E-stained tumor section was evaluated. Mitoses were counted per 10 high-power fields and tumors graded using the Nottingham criteria by 1 pathologist in accordance with College of American Pathologists-recommended mitotic count cutoffs for a field diameter of 0.55 mm. An additional section was immunostained with PPH3 antibody. PPH3 mitotic scores were determined visually and by automated imaging system. Statistical analysis was performed using univariate tests and Spearman coefficient. There was a statistically significant positive correlation among the 3 methods of mitotic score assessment. Specifically, correlation of tumor grades obtained using visual and automated methods of assessment of mitotic activity with PPH3 stain was the strongest and most statistically significant (weighted κ value 0.84, P<0.001; Spearman coefficient 0.89, P<0.001). There was a statistically significant positive correlation between H&E mitosis score and RS (P<0.001, Spearman coefficient 0.30) and between visual PPH3 mitotic score and RS (P<0.001, Spearman coefficient 0.28). In conclusion, mitotic score by any of the 3 methods studied may be useful in assessing tumor grade, proliferation, and prognosis.

Sensing the environment: regulation of local and global homeostasis by the skin's neuroendocrine system.

Skin, the body's largest organ, is strategically located at the interface with the external environment where it detects, integrates, and responds to a diverse range of stressors including solar radiation. It has already been established that the skin is an important peripheral neuro-endocrine-immune organ that is tightly networked to central regulatory systems. These capabilities contribute to the maintenance of peripheral homeostasis. Specifically, epidermal and dermal cells produce and respond to classical stress neurotransmitters, neuropeptides, and hormones. Such production is stimulated by ultraviolet radiation (UVR), biological factors (infectious and noninfectious), and other physical and chemical agents. Examples of local biologically active products are cytokines, biogenic amines (catecholamines, histamine, serotonin, and N-acetyl-serotonin), melatonin, acetylocholine, neuropeptides including pituitary (proopiomelanocortin-derived ACTH, beta-endorphin or MSH peptides, thyroid-stimulating hormone) and hypothalamic (corticotropin-releasing factor and related urocortins, thyroid-releasing hormone) hormones as well as enkephalins and dynorphins, thyroid hormones, steroids (glucocorticoids, mineralocorticoids, sex hormones, 7-delta steroids), secosteroids, opioids, and endocannabinoids. The production of these molecules is hierarchical, organized along the algorithms of classical neuroendocrine axes such as hypothalamic-pituitary-adrenal axis (HPA), hypothalamic-thyroid axis (HPT), serotoninergic, melatoninergic, catecholaminergic, cholinergic, steroid/secosteroidogenic, opioid, and endocannbinoid systems. Dysregulation of these axes or of communication between them may lead to skin and/ or systemic diseases. These local neuroendocrine networks are also addressed at restricting maximally the effect of noxious environmental agents to preserve local and consequently global homeostasis. Moreover, the skin-derived factors/systems can also activate cutaneous nerve endings to alert the brain on changes in the epidermal or dermal environments, or alternatively to activate other coordinating centers by direct (spinal cord) neurotransmission without brain involvement. Furthermore, rapid and reciprocal communications between epidermal and dermal and adnexal compartments are also mediated by neurotransmission including antidromic modes of conduction. In conclusion, skin cells and skin as an organ coordinate and/or regulate not only peripheral but also global homeostasis.

Regulated proenkephalin expression in human skin and cultured skin cells.

Skin responds to environmental stressors via coordinated actions of the local neuroimmunoendocrine system. Although some of these responses involve opioid receptors, little is known about cutaneous proenkephalin expression, its environmental regulation, and alterations in pathology. The objective of this study was to assess regulated expression of proenkephalin in normal and pathological skin and in isolated melanocytes, keratinocytes, fibroblasts, and melanoma cells. The proenkephalin gene and protein were expressed in skin and cultured cells, with significant expression in fibroblasts and keratinocytes. Mass spectroscopy confirmed Leu- and Met-enkephalin in skin. UVR, Toll-like receptor (TLR)4, and TLR2 agonists stimulated proenkephalin gene expression in melanocytes and keratinocytes in a time- and dose-dependent manner. In situ Met/Leu-enkephalin peptides were expressed in differentiating keratinocytes of the epidermis in the outer root sheath of the hair follicle, in myoepithelial cells of the eccrine gland, and in the basement membrane/basal lamina separating epithelial and mesenchymal components. Met/Leu-enkephalin expression was altered in pathological skin, increasing in psoriasis and decreasing in melanocytic tumors. Not only does human skin express proenkephalin, but this expression is upregulated by stressful stimuli and can be altered by pathological conditions.

Inhibitors of melanogenesis increase toxicity of cyclophosphamide and lymphocytes against melanoma cells.

High mortality rate for metastatic melanoma is related to its resistant to the current methods of therapy. Melanogenesis is a metabolic pathway characteristic for normal and malignant melanocytes that can affect the behavior of melanoma cells or its surrounding environment. Human melanoma cells in which production of melanin pigment is dependent on tyrosine levels in medium were used for experiments. Peripheral blood mononuclear cells were derived from the buffy coats purchased from Lifeblood Biological Services. Cell pigmentation was evaluated macroscopically, and tyrosinase activity was measured spectrophotometrically. Cell proliferation and viability were measured using lactate dehydrogenase release MTT, [(3)H]-thymidine incorporation and DNA content analyses, and gene expression was measured by real time RT-PCR. Pigmented melanoma cells were significantly less sensitive to cyclophosphamide and to killing action of IL-2-activated peripheral blood lymphocytes. The inhibition of melanogenesis by either blocking tyrosinase catalytic site or chelating copper ions sensitized melanoma cells towards cytotoxic action of cyclophosphamide, and amplified immunotoxic activities of IL-2 activated lymphocytes. Exogenous L-DOPA inhibited lymphocyte proliferation producing the cell cycle arrest in G1/0 and dramatically inhibited the production of IL-1beta, TNF-alpha, IL-6 and IL-10. Thus, the active melanogenesis could not only impair the cytotoxic action of cyclophosphamid but also has potent immunosuppressive properties. This resistance to a chemotherapeutic agent or immunotoxic activity of lymphocytes could be reverted by the action of tyrosinase inhibitors. Thus, the inhibition of melanogenesis might represent a valid therapeutic target for the management of advanced melanotic melanomas.

20-Hydroxyvitamin D3, a product of vitamin D3 hydroxylation by cytochrome P450scc, stimulates keratinocyte differentiation.

It has been shown that mammalian cytochrome P450scc can metabolize vitamin D3 to 20-hydroxyvitamin D3 (20(OH)D3) and 20,22(OH)2D3. To define the biological significance of this pathway, we tested the effects of 20(OH)D3 on the differentiation program of keratinocytes and on the expression of enzymes engaged in vitamin D3 metabolism. Immortalized HaCaT and adult human epidermal keratinocytes were used as a model and the effects of 20(OH)D3 were compared with those of 25(OH)D3 and 1,25(OH)2D3. 20(OH)D3 inhibited proliferation and caused G2/M arrest. 20(OH)D3 stimulated involucrin and inhibited cytokeratin 14 expression. The potency of 20(OH)D3 was comparable to that of 1,25(OH)2D3. 20(OH)D3 decreased the expression of cytochrome P450 enzyme (CYP)27A1 and CYP27B1, however, having only slight effect on CYP24. The effect of 20(OH)D3 was dependent on the vitamin D receptor (VDR). As shown by electrophoretic mobility shift assay, 20(OH)D3 stimulated the binding of nuclear proteins to the VDRE. Transfection of cells with VDR-specific siRNA decreased 20(OH)D3-stimulated transcriptional activity of the VDRE promoter and the expression of involucrin and CYP24 mRNA. Therefore, the above studies identify 20(OH)D3 as a biologically active secosteroid that induces keratinocyte differentiation. These data imply that the previously unreported pathway of vitamin D3 metabolism by P450scc may have wider biological implications depending, for example, on the extent of adrenal gland or cutaneous metabolism.

Current concepts of metastasis in melanoma.

The main cause of death in melanoma patients is widespread metastases. Staging of melanoma is based on the primary tumor thickness, ulceration, lymph node and distant metastases. Metastases develop in regional lymph nodes, as satellite or in-transit lesions, or in distant organs. Lymph flow and chemotaxis is responsible for the homing of melanoma cells to different sites. Standard pathologic evaluation of sentinel lymph nodes fails to find occult melanoma in a significant proportion of cases. Detection of small numbers of malignant melanoma cells in these and other sites, such as adjacent to the primary site, bone marrow or the systemic circulation, may be enhanced by immunohistochemistry, reverse transcription PCR, evaluation of lymphatic vessel invasion and proteomics. In the organs to which melanoma cells metastasize, extravasation of melanoma cells is regulated by adhesion molecules, matrix metalloproteases, chemokines and growth factors. Melanoma cells may travel along external vessel lattices. After settling in the metastatic sites, melanoma cells develop mechanisms that protect them against the attack of the immune system. It is thought that one of the reasons why melanoma cells are especially resistant to killing is the fact that melanocytes (cells from which melanoma cells derive) are resistant to such noxious factors as ultraviolet light and reactive oxygen species. Targeted melanoma therapies are, so far, largely unsuccessful, and new ones, such as adjuvant inhibition of melanogenesis, are under development.

Structure-activity relationship studies of arylthiazolidine amides as selective cytotoxic agents for melanoma.

UNLABELLED: New drugs are urgently needed for improved therapy for melanoma. MATERIALS AND METHODS: Ninety-one novel compounds were evaluated in two melanoma and one normal skin cell lines to identify potential lead compounds with high potency and selectivity. Mechanisms of action for the best compound were also investigated. RESULTS: Three potent lead structures (serine amino alcohols, serine amides and thiazolidines) were identified, with thiazolidines having both excellent potency and high selectivity when compared with sorafenib, a drug used extensively in clinical trials for melanoma. Analyzing the effect of the lead compound showed that it induced DNA degradation consistent with necrotic cell death. CONCLUSION: The lead structure represents a novel class of compounds that can be further optimized for potential drug to treat advanced melanoma.

CRH inhibits NF-kappa B signaling in human melanocytes.

Corticotropin releasing hormone (CRH), a messenger of stress at the central level, is expressed in the epidermis where it operates within local equivalent of hypothalamo-pituitary axis. CRH inhibits NF-kappaB activity in human immortalized epidermal (PIG1) melanocytes. In melanocytes CRH stimulates pro-opiomelanocortin (POMC) mRNA and adrenocorticotropin (ACTH) peptide production. Knockdown of POMC levels by transfecting cells with antisense oligonucleotides blocks the effect of CRH on NF-kappaB signaling indicating that the above inhibition is indirect, e.g. through activation of POMC. We suggest that induction of POMC by CRH serves as a feedback mechanism to self-restrict inflammatory response in the skin.