Upregulation of miR-18a-5p contributes to epidermal necrolysis in severe drug eruptions Asako Ichihara, MD, PhD, Zhongzhi Wang, PhD, Masatoshi Jinnin,

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Upregulation of miR-18a-5p contributes to epidermal necrolysis in severe drug eruptions Asako Ichihara, MD, PhD, Zhongzhi Wang, PhD, Masatoshi Jinnin, MD, PhD, Yuki Izuno, Naoki Shimozono, PhD, Keitaro Yamane, Akihiko Fujisawa, MD, Chikako Moriya, MD, PhD, Satoshi Fukushima, MD, PhD, Yuji Inoue, MD, PhD, Hironobu Ihn, MD, PhD Journal of Allergy and Clinical Immunology Volume 133, Issue 4, Pages 1065-1074 (April 2014) DOI: 10.1016/j.jaci.2013.09.019 Copyright © 2013 American Academy of Allergy, Asthma & Immunology Terms and Conditions

Fig 1 Expression of miR-18a-5p in cutaneous drug eruptions in vivo. A, Relative miRNA levels in tissues of 6 subjects with healthy skin, 8 patients with EM, 3 patients with SJS, 4 patients with TEN, 4 patients with psoriasis, and 4 patients with atopic dermatitis. Error bars represent SDs. *P < .05 compared with values in the other disease samples. B, Upper panels, Hematoxylin and eosin (HE) staining. Bars = 200 μm. Lower panels, In situ detection of miR-18a-5p. miR-18a-5p stained brown. Journal of Allergy and Clinical Immunology 2014 133, 1065-1074DOI: (10.1016/j.jaci.2013.09.019) Copyright © 2013 American Academy of Allergy, Asthma & Immunology Terms and Conditions

Fig 2 Role of miR-18a-5p in cell apoptosis. NHEKs were transfected with miR-18a-5p mimic, miR-18a-5p inhibitor, or controls for 72 hours. A and B, Flow cytometric histograms showing the percentage of apoptotic cells in the TUNEL or Annexin V assays. C, miR-18a-5p levels, relative apoptotic cell ratios by TUNEL or Annexin V assays, and activities of caspase-9 or caspase-3 (n = 3). *P < .05 compared with control cells (1.0). Journal of Allergy and Clinical Immunology 2014 133, 1065-1074DOI: (10.1016/j.jaci.2013.09.019) Copyright © 2013 American Academy of Allergy, Asthma & Immunology Terms and Conditions

Fig 3 BCL2L10 expression in vitro and in vivo. A, BCL2L10 protein or mRNA levels in NHEKs transfected with miRNA mimics, protectors, or both (n = 3). B, NHEKs were transfected with wild-type or mutated BCL2L10 3′ UTR luciferase constructs together with control or miR-18a-5p mimic. The bar graph shows luciferase activities (n = 3). C and D, mRNA (Fig 3, C) or protein (Fig 3, D) levels of BCL2L10 in skin samples. E, Immunostaining of BCL2L10. Bars = 100 μm. *P < .05. Journal of Allergy and Clinical Immunology 2014 133, 1065-1074DOI: (10.1016/j.jaci.2013.09.019) Copyright © 2013 American Academy of Allergy, Asthma & Immunology Terms and Conditions

Fig 4 Function of BCL2L10 in patients with TEN. A, NHEKs were transfected with BCL2L10 siRNA for 72 hours. BCL2L10 mRNA levels, apoptotic cell ratios, and caspase activities are shown (n = 3). *P < .05. B, Immunoblotting with NHEKs transfected with BCL2L10 siRNA. C, Immunostaining of active caspase-9. Bars = 100 μm. Asterisks indicate apoptotic cells. D, NHEKs were transfected with miRNA mimics or inhibitors. Active caspases were determined by using immunoblotting. Journal of Allergy and Clinical Immunology 2014 133, 1065-1074DOI: (10.1016/j.jaci.2013.09.019) Copyright © 2013 American Academy of Allergy, Asthma & Immunology Terms and Conditions

Fig 5 Serum concentrations of miR-18a-5p in patients with drug eruptions. A, Serial dilutions of cDNA (as is, 10-fold dilution, 100-fold dilution, and 0) synthesized from serum miRNA were used as templates for real-time PCR. B, Serum miR-18a-5p levels. Bars show means. *P < .05. C, Correlation between serum and skin miR-18-5p level of each patient. D-F, Correlation between serum miR-18a-5p levels and clinical features of patients. Journal of Allergy and Clinical Immunology 2014 133, 1065-1074DOI: (10.1016/j.jaci.2013.09.019) Copyright © 2013 American Academy of Allergy, Asthma & Immunology Terms and Conditions

Fig E1 Journal of Allergy and Clinical Immunology 2014 133, 1065-1074DOI: (10.1016/j.jaci.2013.09.019) Copyright © 2013 American Academy of Allergy, Asthma & Immunology Terms and Conditions