Ayumi Honda

Protective effects of platinum nanoparticles against UV‐light‐induced epidermal inflammation

Please cite this paper as: Protective effects of platinum nanoparticles against UV‐light‐induced epidermal inflammation. Experimental Dermatology 2010; 19: 1000–1006.

Tissue Regeneration Using Macrophage Migration Inhibitory Factor-Impregnated Gelatin Microbeads in Cutaneous Wounds

Migration inhibitory factor (MIF) responds to tissue damage and regulates inflammatory and immunological processes. To elucidate the function of MIF in cutaneous wound healing, we analyzed MIF knockout (KO) mice. After the excision of wounds from the dorsal skin of MIF KO and wild-type (WT) mice, healing was significantly delayed in MIF KO mice compared to WT mice. Lipopolysaccharide treatment significantly increased [(3)H]thymidine uptake in WT mouse fibroblasts compared to MIF KO mouse fibroblasts. Furthermore, there was a significant reduction in fibroblast and keratinocyte migration observed in MIF KO mice after 1-oleoyl-2-lysophosphatidic acid treatment. We subsequently examined whether MIF-impregnated gelatin slow-release microbeads could accelerate skin wound healing. Injection of more than 1.5 microg/500 microl of MIF-impregnated gelatin microbeads around a wound edge accelerated wound healing compared to a single MIF injection without the use of microbeads. MIF-impregnated gelatin microbeads also accelerated skin wound healing in C57BL/6 mice and diabetic db/db mice. Furthermore, incorporating MIF-impregnated gelatin microbeads into an artificial dermis implanted into MIF KO mice accelerated procollagen production and capillary formation. These findings suggest that MIF is crucial in accelerating cutaneous wound healing and that MIF-impregnated gelatin microbeads represent a promising treatment to facilitate skin wound healing.

Promoter region polymorphism of macrophage migration inhibitory factor is strong risk factor for young onset of extensive alopecia areata

We have demonstrated that serum macrophage migration inhibitory factor (MIF) was significantly elevated in patients with extensive alopecia areata (AA). Recently, functional polymorphisms have been identified in the MIF promoter region. To address the functional and prognostic relevance of the −173G/C and −794[CATT]5–8 repeat polymorphisms in MIF genes in patients with extensive AA, 113 patients with extensive AA and 194 healthy controls were genotyped. We found that MIF−173*C was a risk factor for early onset (<20 years) of extensive AA (odds ratio for GC heterozygotes with −173G/C was 4.88 (95% CI, 2.04–11.8), P=0.00038; odds ratio for CC homozygotes with −173G/C was 10.42 (95% CI, 2.56–43.5), P=0.0011). We found no statistically significant differences in the genotype frequencies of the −794[CATT]5–8 repeat polymorphism and extensive AA. These results suggest that polymorphisms within the MIF−173*C allele confer an increased risk of susceptibility to the extensive forms of AA, especially with an early onset of disease. MIF is therefore suggested to be closely implicated in the pathogenesis of the more extensive forms of AA.

Macrophage Migration Inhibitory Factor Is Essential for Eosinophil Recruitment in Allergen-Induced Skin Inflammation

Macrophage migration inhibitory factor (MIF) is a pluripotent cytokine that has an essential role in the pathophysiology of experimental allergic inflammation. Recent findings suggest that MIF is involved in several allergic disorders, including atopic dermatitis (AD). In this study, the role of MIF in allergic skin inflammation was examined using a murine model of AD elicited by epicutaneous sensitization with ovalbumin (OVA). We observed the number of skin-infiltrating eosinophils to significantly increase in OVA-sensitized MIF transgenic (Tg) mice compared with their wild-type (WT) littermates. On the other hand, eosinophils were virtually absent from the skin of MIF knockout (KO) mice and failed to infiltrate their skin after repeated epicutaneous sensitization with OVA. The mRNA expression levels of eotaxin and IL-5 were significantly increased in OVA-sensitized skin sites of MIF Tg mice, but were significantly decreased in MIF KO mice in comparison with the levels in WT littermates. Eotaxin expression was induced by IL-4 stimulation in fibroblasts in MIF Tg mice, but not in MIF KO mice. These findings indicate that MIF can induce eosinophil accumulation in the skin. Therefore, the targeted inhibition of MIF might be a promising new therapeutic strategy for allergic skin diseases.

Deficient deletion of apoptotic cells by macrophage migration inhibitory factor (MIF) overexpression accelerates photocarcinogenesis

Chronic ultraviolet (UV) exposure can increase the occurrence of p53 mutations, thus leading to a dysregulation of apoptosis and the initiation of skin cancer. Therefore, it is extremely important that apoptosis is induced quickly after UV irradiation, without any dysregulation. Recent studies have suggested a potentially broader role for macrophage migration inhibitory factor (MIF) in growth regulation via its ability to antagonize p53-mediated gene activation and apoptosis. To further elucidate the possible role of MIF in photocarcinogenesis, the acute and chronic UVB effect in the skin was examined using macrophage migration inhibitory factor transgenic (MIF Tg) and wild-type (WT) mice. The MIF Tg mice exposed to chronic UVB irradiation began to develop skin tumors after approximately 14 weeks, whereas the WT mice began to develop tumors after 18 weeks. A higher incidence of tumors was observed in the MIF Tg in comparison with the WT mice after chronic UVB irradiation. Next, we clarified whether the acceleration of photo-induced carcinogenesis in the MIF Tg mice was mediated by the inhibition of apoptosis There were fewer sunburned cells in the epidermis of the MIF Tg mice than the WT mice after acute UVB exposure. The epidermis derived from the MIF Tg mice exhibited substantially decreased levels of p53, bax and p21 after UVB exposure in comparison with the WT mice. Collectively, these findings suggest that chronic UVB exposure enhances MIF production, which may inhibit the p53-dependent apoptotic processes and thereby induce photocarcinogenesis in the skin.

Macrophage migration inhibitory factor ameliorates UV-induced photokeratitis in mice.

Acute ultraviolet (UV) exposure causes photokeratitis, and induces apoptosis in corneal cells of the eye. Macrophage migration inhibitory factor (MIF) was originally identified as a lymphokine. Today, MIF is considered as an integral component of the host antimicrobial alarm system and stress response that promotes the proinflammatory functions of immune cells. Also, MIF is considered to contribute the wound healing process. The aim of the present study is to determine the effects of MIF expression on UV irradiated corneal damage. MIF transgenic (MIF-Tg), wild type (WT), and MIF deficient (MIF KO) mice were UVB-irradiated of 400mJ/cm2 to induce acute UV-photokeratitis. MIF Tg mice constitutively produce high levels of MIF. Morphological changes were most severe in MIF KO mice, and WT and MIF Tg mice were following. Corneal basement membrane of MIF-Tg was well preserved. Prominent higher level of MIF was observed in MIF-Tg than WT after UVB irradiation in cornea. TUNEL staining showed a significantly smaller number of TUNEL positive nuclei in MIF-Tgm (6.2+/-4.3 cells/section, p<0.01 compared with WT) than WT (30.7+/-9.1) and MIF KO mice (32.1+/-12.7) 24h after UV exposure. The number of c-Jun positive nuclei was significantly higher in MIF Tg (p<0.01) than in WT and MIF KO mice. Serial observation revealed that BrdU incorporation was significantly upregulated in MIF Tg (p<0.01), but downregulated in MIF KO (p<0.01) than WT mice. MIF expression may thus be related to the amelioration of UVB-caused corneal injury, and this association was attributable to the upregulation of cell proliferation after acute UV-induced corneal damage, which involves the c-Jun dependent pathway. In conclusion, UV-damaged cornea is recoverable without MIF, however it takes longer time than normal condition. Cornea is less damaged and can make a quick recovery when ocular tissue is enough supplied with MIF.

Carebastine, an H1‐receptor antagonist, suppresses the expression of macrophage migration inhibitory factor

regular prescribed or over-the-counter medication. Further direct and specific questioning revealed that each episode began with vulval pruritus, which the patient selfdiagnosed as thrush and self-treated with oral fluconazole. Several hours after taking fluconazole, her symptoms changed, and she developed intense pain in both the vulva and left chest wall, associated with tender vesicles and blisters followed by oral ulceration. The patient was diagnosed as having an FDE caused by fluconazole. Fixed drug eruptions are an uncommon side-effect of drug ingestion, accounting for approximately 0.5% of all drug-related rashes. Classically, one (or several) annular, well-demarcated, erythematous, oedematous plaques occur, which may develop central vesicles, blisters or erosions. The lesions spontaneously resolve over several days, usually leaving postinflammatory hyperpigmentation, but nonpigmenting variants have also been described. Re-administration of the causative drug results in recurrence of lesions at the same sites and may lead to extension of the reaction to additional sites. The most commonly involved site is the genital mucosa (51%) followed by the trunk (38%), lips (37%) and hands (32%). Most reports of FDEs in the genital region describe lesions occurring in men, predominantly on the glans penis. Recently, a series of 13 cases of vulval FDE has been reported; two of these patients had acute and recurrent symptoms, both related directly to the ingestion of ibuprofen. FDEs affecting the vulva are likely to be underdiagnosed by both patient and physician, and may be frequently misdiagnosed clinically as a candidal or herpes simplex virus infection. The most commonly described causative agent in FDE is trimethoprim–sulfamethoxazole (cotrimoxazole) followed by nonsteroidal anti-inflammatory agents, paracetamol, barbiturates, tetracyclines and carbamazepine. Several case reports describing FDEs secondary to fluconazole have been published but none has described lesions in the genital region. Patch testing in the context of FDE lacks both sensitivity and specificity. A recent study reported that only 8 ⁄ 28 patients with FDE had a positive patch test result to the suspect drug. None was subsequently challenged with oral administration of the drug; however, of seven patients with a history of FDE and negative patch tests, three developed a further FDE on oral-challenge testing. Patch testing at a previously affected site is reported to give higher sensitivity; these false negatives largely represent patients with genital FDEs in whom patch testing was performed on the back. In most cases, the diagnosis of FDE is made on clinical criteria alone. The diagnosis is supported by a positive patch test (although not refuted by a negative test). The gold-standard diagnostic test is, however, the oral-provocation test, in which the FDE is induced by repeat ingestion of the drug. Ethically, this may be difficult to justify. E. M. Wain and S. Neill St John s Institute of Dermatology, St Thomas Hospital, Lambeth Palace Road, London SE1 7EH, UK E-mail: marywain@doctors.net.uk Conflict of interest: none declared. Accepted for publication 24 January 2008

Expression of macrophage migration inhibitory factor in rat skin during embryonic development

Abstract:  We have previously shown that human epidermal keratinocytes express macrophage migration inhibitory factor (MIF) mRNA, and immunohistochemical studies showed that MIF is expressed in human epidermis. To explore the possible pathophysiological roles of MIF in skin during rat fetal development, we examined the expression patterns of MIF during rat epidermal development using Northern blot analysis and in situ hybridization. Expression of MIF mRNA was first detected by in situ hybridization in the developing epidermis and hair germ cells from embryonic day (ED) 16. From ED 19, moderate levels of MIF expression were detected in the epidermis and epithelial sheath cells of growing hair follicles. In postnatal rat skin, higher MIF expression was detected in the epidermis and hair follicles on postnatal day 3. These observations were also confirmed by Northern blot analysis. Immunohistochemical analysis with an anti‐MIF antibody showed a similar distribution to that of the mRNA. Our results suggest that MIF is associated with epidermal and hair follicle development.