ナカノ　ヒロヤス   Nakano Hiroyasu   中野　裕康    所属   東邦大学  医学部 医学科    東邦大学  医学部 医学科    職種   教授
言語種別	英語
発表タイトル	Blockade of TNFR1-dependent and -independent cell death is crucial for normal epidermal differentiation
会議名	Gordon Research Conference
主催者	GRC
学会区分	国際学会
発表形式	ポスター掲示
講演区分	一般
発表者・共同発表者	◎Ryosuke Miura, Xuehua Piao, Sanae Miyake, Sachiko Komazawa-Sakon, Chiharu Nishiyama, Hiroyasu Nakano.
発表年月日	2018/08/06
開催地 （都市, 国名）	Newry, USA
概要	Delicate balance between cell death and proliferation of keratinocytes is crucial for normal development of the skin. Previous studies have reported that cellular FLICE-inhibitory protein (cFLIP) plays a crucial role in prevention of keratinocytes from TNF-dependent apoptosis and blocking the development of dermatitis. However, it is unclear whether TNF-independent signal might contribute to the development of dermatitis in epidermis-specific Cflar-deficient (Cflar) mice. Here, we generated Cflar mice under Tnfrsf1a-proficient and -deficient genetic background. Cflar;Tnfrsf1a-/- mice were born at the expected Mendelian ratio, but developed severe dermatitis and succumbed soon after birth. In sharp contrast, CflarE-KO;Tnfrsf1a+/- mice exhibited embryonic lethality due to massive apoptosis of keratinocytes. While keratinocytes from Cflar;Tnfrsf1a-/- mice still died by apoptosis, neutralizing antibodies against FasL and TRAIL substantially prolonged survival of Cflar;Tnfrsf1a-/- mice. Expression of inflammatory cytokines, such as interleukin (Il)6 and Il17a was elevated, conversely, expression of epidermal differentiation markers was severely downregulated in the skin of Cflar;Tnfrsf1a-/- mice. Treatment of primary keratinocytes with IL-6, and to a lesser extent IL-17A suppressed expression of epidermal differentiation markers. Thus, blockade of both TNFR1-dependent and -independent cell death might be an alternative strategy to treat skin diseases when treatment with anti-TNF antibody alone is not sufficient.