Local Glucocorticoid Activation by 11ß-Hydroxysteroid Dehydrogenase 1 in Keratinocytes: The Role in Hapten-Induced Dermatitis.

Over the past decade, extra-adrenal cortisol production was reported in various tissues. The enzyme that catalyzes the conversion of hormonally inactive cortisone into active cortisol in cells is 11ß-hydroxysteroid dehydrogenase 1 (11ß-HSD1). We recently reported that 11ß-HSD1 is also expressed in keratinocytes and regulates inflammation and keratinocyte proliferation. To investigate the function of 11ß-HSD1 in keratinocytes during inflammation in vivo, we created keratinocyte-specific 11ß-HSD1 knockout (K5-Hsd11b1-KO) mice and analyzed the inflammatory response in models of hapten-induced contact irritant dermatitis. K5-Hsd11b1-KO mice showed enhanced ear swelling in low-dose oxazolone-, 2,4,6-trinitro-1-chlorobenzene (TNCB)-, and 2,4-dinitrofluorobenzene-induced irritant dermatitis associated with increased inflammatory cell infiltration. Topical application of corticosterone dose dependently suppressed TNCB-induced ear swelling and cytokine expression. Similarly in mouse keratinocytes in vitro, corticosterone dose dependently suppressed 2,4,6-trinitrobenzenesulfonic acid-induced IL-1α and IL-1ß expression. The effect of 11-dehydrocorticosterone was attenuated in TNCB-induced irritant dermatitis in K5-Hsd11b1-KO mice compared with wild-type mice. In human samples, 11ß-HSD1 expression was decreased in epidermis of psoriasis vulgaris compared with healthy skin. Taken together, these data suggest that corticosterone activation by 11ß-HSD1 in keratinocytes suppresses hapten-induced irritant dermatitis through suppression of expression of cytokines, such as IL-1α and IL-1ß, in keratinocytes.

Oligosaccharide modification by N-acetylglucosaminyltransferase-V in macrophages are involved in pathogenesis of bleomycin-induced scleroderma.

Oligosaccharide modification by N-acetylglucosaminyltransferase-V (GnT-V), which catalyses the formation of ß1,6 GlcNAc (N-acetylglucosamine) branches on N-glycans, is associated with various pathologies, such as cancer metastasis, multiple sclerosis and liver fibrosis. In this study, we demonstrated the involvement of GnT-V in the pathophysiology of scleroderma. High expression of GnT-V was observed in infiltrating cells in skin section samples from systemic and localized patients with scleroderma. Most of the infiltrating cells were T cells and macrophages, most of which were CD163(+) M2 macrophages. To determine the role of GnT-V in scleroderma, we next investigated skin sclerosis in GnT-V knockout (MGAT5(-/-) ) mice. Expression of GnT-V was also elevated in bleomycin (BLM)-injected sclerotic skin, and MGAT5(-/-) mice were resistant to BLM-induced skin sclerosis with reduced collagen type 1 α1 content, suggesting the biological significance of GnT-V in skin sclerosis. Furthermore, the number of CD163(+) M2 macrophages and CD3-positive T cells in BLM-induced skin sclerosis was significantly fewer in MGAT5(-/-) mice. In bone marrow-derived macrophages (BMDMs), IL-4-induced expressions of Fizz1 and Ym1 were significantly reduced in MGAT5(-/-) mice-derived BMDMs. Taken together, these results suggest the induction of GnT-V in skin sclerosis progression is possibly dependent on increased numbers of M2 macrophages in the skin, which are important for tissue fibrosis and remodelling.

Transient wheal attack corresponding to the tumor lesions of primary cutaneous diffuse large B cell lymphoma, leg type after successive rituximab treatment.

An elderly male noticed urticarial patches corresponding to cutaneous B cell lymphoma lesions after rituximab treatment. Along with the resolution of urticaria, the lymphoma lesions completely remitted without recurrence. In this communication, we present an interesting case and the pathophysiological findings of a wheal attack in a case with tumor remission following systemic treatment with rituximab, a monoclonal anti-CD20 antibody.

Immunohistochemical Analysis of Interleukin-17 Producing T Helper Cells and Regulatory T Cells Infiltration in Annular Erythema Associated with Sjögren's Syndrome.

BACKGROUND: Peculiar erythema known as annular erythema associated with Sjögren's syndrome (AESS) can be differentiated from autoimmune annular erythema and subacute cutaneous lupus erythematosus, both clinically and histologically. However, there are no detailed investigations on immune competent cells infiltration. OBJECTIVE: Preferential infiltration of interleukin-17-producing T helper (Th17) cells and regulatory T (Treg) cells into the labial salivary gland is reported to play a role in maintaining mucoepithelitis in patients with Sjögren's syndrome. In this study, we evaluated Th17 and Treg cell infiltration into the lesional skin of AESS. METHODS: We analyzed the numbers and infiltration patterns of Th17 and FoxP3 (+) Treg cells in seven cases of AESS using immunohistochemistry. Seven patients with systemic lupus erythematosus (SLE), atopic dermatitis (AD) and psoriasis vulgaris (PV), which are representatives of Th17 cell-involved skin disorders, were enrolled as disease controls. RESULTS: Periappendageal and epidermal changes, such as follicular plugging and liquefaction, were evident in the annular erythema of SLE, not AESS, tissue samples. In AESS tissue samples, dense perivascular and periappendageal infiltration of lymph cells was observed in the middle-to-deep dermis, as previously described, in contrast to the superficial infiltration pattern observed in both AD and PV samples. While the total number of infiltrated lymphocytes was similar between AESS and SLE tissue samples, Th17 cells were found to be preferentially infiltrated in the middle-to-deep dermis in AESS samples. CONCLUSION: These results suggest that an increased number and distribution of infiltration of Th17 cells is a preferential feature of AESS, rather than a characteristic feature of annular erythema of SLE.

A rare case of male bullous lupus erythematosus complicated with subsequent annular hypopigmentation.

A 57-year-old male had been suffering from an itchy map-shaped symmetrical erosive erythema with a crust that was attached to his upper arm and buttock, and occasionally he suffered from spiking fever. Laboratory examinations showed neither anti-desmoglein 1/3 antibodies nor anti-BP 180 antibodies, and he fulfilled the criteria for a diagnosis of systemic lupus erythematosus (SLE). Histologically, there was eosinophilic necrosis of keratinocytes, liquefaction and degradation with severe lymphocyte infiltration into the epidermis and subepidermal blister formation, suggestive of a variant of SLE, bullous lupus erythematosus (BLE). One month after remission of BLE, peculiar annular hypopigmentation appeared on the peripheral borders. An immunohistochemical analysis showed a decrease in Melan A-positive melanocytes and concomitant pigment incontinentia, with dense infiltration of CD8(+) T cells and IL-17A(+) Th17 cells. An ultrastructural analysis revealed a decrease, but not a complete disappearance, of both melanocytes and melanosomes, and no impairment in melanosomal transfer. In this case report, we would like to introduce the development of annular depigmentation complicated with BLE, and discuss the effects of lupus condition on melanocyte damage based on immunohistological and electromicroscopic findings of those vitiliginous lesions.

11ß-hydroxysteroid dehydrogenase 1 specific inhibitor increased dermal collagen content and promotes fibroblast proliferation.

Glucocorticoids (GCs) are one of the most effective anti-inflammatory drugs for treating acute and chronic inflammatory diseases. However, several studies have shown that GCs alter collagen metabolism in the skin and induce skin atrophy. Cortisol is the endogenous GC that is released in response to various stressors. Over the last decade, extraadrenal cortisol production in various tissues has been reported. Skin also synthesizes cortisol through a de novo pathway and through an activating enzyme. 11ß-hydroxysteroid dehydrogenase 1 (11ß-HSD1) is the enzyme that catalyzes the conversion of hormonally inactive cortisone to active cortisol in cells. We previously found that 11ß-HSD1 negatively regulates proliferation of keratinocytes. To determine the function of 11ß-HSD1 in dermal fibroblasts and collagen metabolism, the effect of a selective 11ß-HSD1 inhibitor was studied in mouse tissues and dermal fibroblasts. The expression of 11ß-HSD1 increased with age in mouse skin. Subcutaneous injection of a selective 11ß-HSD1 inhibitor increased dermal thickness and collagen content in the mouse skin. In vitro, proliferation of dermal fibroblasts derived from 11ß-HSD1 null mice (Hsd11b1(-/-) mice) was significantly increased compared with fibroblasts from wild-type mice. However, in vivo, dermal thickness of Hsd11b1(-/-) mice was not altered in 3-month-old and 1-year-old mouse skin compared with wild-type mouse skin. These in vivo findings suggest the presence of compensatory mechanisms in Hsd11b1(-/-) mice. Our findings suggest that 11ß-HSD1 inhibition may reverse the decreased collagen content observed in intrinsically and extrinsically aged skin and in skin atrophy that is induced by GC treatment.

Topical cholesterol treatment ameliorates hapten-evoked cutaneous hypersensitivity by sustaining expression of 11ß-HSD1 in epidermis.

Changes in the stratum corneum extracellular matrix impair epidermal barrier function and may cause dermatoses. The aim of this study was to examine the effect of exogenous cholesterol application on skin barrier function and cutaneous inflammation. Skin barrier-disrupted or hapten-stimulated mice were treated with topical cholesterol. The effect of topical cholesterol application on an oxazolone (OXA)-induced hypersensitivity reaction was evaluated. Topical application of cholesterol efficiently decreased transepidermal water loss in areas of barrier-disrupted skin and ameliorated OXA-induced cutaneous hypersensitivity. These favourable effects may have resulted from sustained expression of 11ß-hydroxysteroid dehydrogenase type 1 (11ß-HSD1) in the cholesterol-treated skin. As 11ß-HSD1 is known to produce active cortisol, topical cholesterol may attenuate contact hypersensitivity by normalizing secretion of hormonally active cortisol from the skin.

11ß-Hydroxysteroid dehydrogenase 1 contributes to the pro-inflammatory response of keratinocytes.

The endogenous glucocorticoid, cortisol, is released from the adrenal gland in response to various stress stimuli. Extra-adrenal cortisol production has recently been reported to occur in various tissues. Skin is known to synthesize cortisol through a de novo pathway and through an activating enzyme. The enzyme that catalyzes the intracellular conversion of hormonally-inactive cortisone into active cortisol is 11ß-hydroxysteroid dehydrogenase 1 (11ß-HSD1). We recently reported that 11ß-HSD1 is expressed in normal human epidermal keratinocytes (NHEKs) and negatively regulates proliferation of NHEKs. In this study, we investigated the role of 11ß-HSD1 in skin inflammation. Expression of 11ß-HSD1 was induced by UV-B irradiation and in response to the pro-inflammatory cytokines, IL-1ß and TNFα. Increased cortisol concentrations in culture media also increased in response to these stimuli. To investigate the function of increased 11ß-HSD1 in response to pro-inflammatory cytokines, we knocked down 11ß-HSD1 by transfecting siRNA. Production of IL-6 and IL-8 in response to IL-1ß or TNFα stimulation was attenuated in NHEKs transfected with si11ß-HSD1 compared with control cells. In addition, IL-1ß-induced IL-6 production was enhanced in cultures containing 1 × 10(-13) M cortisol, whereas 1 × 10(-5) M cortisol attenuated production of IL-6. Thus, cortisol showed immunostimulatory and immunosuppressive activities depending on its concentration. Our results indicate that 11ß-HSD1 expression is increased by various stimuli. Thus, regulation of cytosolic cortisol concentrations by 11ß-HSD1 appears to modulate expression of inflammatory cytokines in NHEKs.

Alopecia areata: infiltration of Th17 cells in the dermis, particularly around hair follicles.

BACKGROUND: The precise pathogenesis of alopecia areata remains unknown, although this disease seems to be triggered by helper T cell infiltration in hair follicles. Recent studies of psoriasis and vitiligo have demonstrated the involvement of Th17 cells. Psoriasis and vitiligo occasionally develop concomitantly or inversely in patients with alopecia areata. OBJECTIVE: The aim of this study was to determine whether Th17 cells are present in the affected lesions of alopecia areata. METHODS: We performed immunofluorescent staining of representative immunocompetent cells that had infiltrated into the skin of the scalp in 4 individuals with alopecia areata (single patchy alopecia areata, multiple patchy alopecia areata, alopecia totalis and alopecia universalis). RESULTS: We found the infiltration of CD4(+)IL-17A(+) Th17 cells in the dermis, particularly around hair follicles, in all 4 cases. CONCLUSIONS: These findings suggest the possibility that alopecia areata is induced by a Th17 cell-associated autoimmune mechanism.

Expression profiles of cortisol-inactivating enzyme, 11ß-hydroxysteroid dehydrogenase-2, in human epidermal tumors and its role in keratinocyte proliferation.

The enzyme 11ß-hydroxysteroid dehydrogenase (11ß-HSD) catalyzes the interconversion between hormonally active cortisol and inactive cortisone within cells. There are two isozymes: 11ß-HSD1 activates cortisol from cortisone and 11ß-HSD2 inactivates cortisol to cortisone. 11ß-HSD1 was recently discovered in skin, and we subsequently found that the enzyme negatively regulates keratinocyte proliferation. We verified 11ß-HSD1 and 11ß-HSD2 expression in benign and malignant skin tumors and investigated the role of 11ß-HSD in skin tumor pathogenesis. Randomly selected formalin-fixed sections of skin lesions of seborrheic keratosis (SK), squamous cell carcinoma (SCC), and basal cell carcinoma (BCC) were stained with 11ß-HSD1 and 11ß-HSD2 antibodies, and 11ß-HSD expression was also evaluated in murine epidermis in which hyperproliferation was induced by 12-O-tetradecanoylphorbol-13 acetate (TPA). We observed that 11ß-HSD1 expression was decreased in all SK, SCC, and BCC lesions compared with unaffected skin. Conversely, 11ß-HSD2 expression was increased in SK and BCC but not in SCC. Overexpression of 11ß-HSD2 in keratinocytes increased cell proliferation. In the murine model, 11ß-HSD1 expression was decreased in TPA-treated hyperproliferative skin. Our findings suggest that 11ß-HSD1 expression is decreased in keratinocyte proliferative conditions, and 11ß-HSD2 expression is increased in basal cell proliferating conditions, such as BCC and SK. Assessing 11ß-HSD1 and 11ß-HSD2 expression could be a useful tool for diagnosing and characterizing skin tumors.

Etanercept is safely used for treating psoriatic arthritis in a patient complicated with type 1 hereditary angioedema.

Hereditary angioedema (HAE) is a life-threatening disorder caused by deficiency or dysfunction of the C1 inhibitor protein. Patients with HAE are restricted in various medical treatments, which can induce an HAE attack. We herein report the first case of psoriatic arthritis (PSA) with type 1 HAE successfully treated with 25 mg of etanercept without HAE attack. Etanercept may represent a useful choice for treating patients with HAE accompanied by intractable PSA and rheumatoid arthritis (RA).

Dysregulation of melanocyte function by Th17-related cytokines: significance of Th17 cell infiltration in autoimmune vitiligo vulgaris.

The aim of this study was to determine whether CD4(+) IL-17A(+) Th17 cells infiltrate vitiligo skin and to investigate whether the proinflammatory cytokines related to Th17 cell influence melanocyte enzymatic activity and cell fate. An immunohistochemical analysis showed Th17 cell infiltration in 21 of 23 vitiligo skin samples in addition to CD8(+) cells on the reticular dermis. An in vitro analysis showed that the expression of MITF and downstream genes was downregulated in melanocytes by treatment with interleukin (IL)-17A, IL-1ß, IL-6, and tumor necrosis factor (TNF)-α. Treatment with these cytokines also induced morphological shrinking in melanocytes, resulting in decreased melanin production. In terms of local cytokine network in the skin, IL-17A dramatically induced IL-1ß, IL-6, and TNF-α production in skin-resident cells such as keratinocytes and fibroblasts. Our results provide evidence of the influence of a complex Th17 cell-related cytokine environment in local depigmentation in addition to CD8(+) cell-mediated melanocyte destruction in autoimmune vitiligo.

A case of disseminated DLE complicated by atopic dermatitis and Sjögren's syndrome: link between hypohidrosis and skin manifestations.

We report an unusual case of disseminated discoid lupus erythematosus (DLE) complicated by pre-existing atopic dermatitis (AD) and late-onset Sjögren's syndrome (SS). Disseminated DLE lesions were sparse on the expected sites for AD, such as the medial region of the extremities or v-neck area. The patient fulfilled the diagnostic criteria for AD and SS but not for systemic lupus erythematosus. Histopathological analysis of the crusted erythematous lesions revealed typical DLE with few FoxP3(+) cells and a moderate number of IL-17(+) cells. A quantitative sweating test showed impaired sweating of both lesional and non-lesional skin due to underlying hypohidrosis that was related to AD and SS. This finding suggests that dissemination of DLE was triggered by scratching and a Köbner phenomenon-like effect related to hypohidrotic and xerotic skin. To the best of our knowledge, this is the first reported case of disseminated DLE complicated by AD and SS.