期刊
JOURNAL OF ALLERGY AND CLINICAL IMMUNOLOGY
卷 143, 期 1, 页码 213-+出版社
MOSBY-ELSEVIER
DOI: 10.1016/j.jaci.2018.02.043
关键词
Cellular FLICE-inhibitory protein; apoptosis; epidermal differentiation; TNF-alpha
资金
- Japan Society for the Promotion of Science (JSPS) [17J00933, 14J12413]
- JSPS [17H04069, 17K19533, 26893265]
- MEXT (Ministry of Education, Culture, Sports, Science and Technology) [26110003]
- NOVARTIS Foundation for the Promotion of Science
- Naito Science Foundation
- Uehara Science Foundation
- Takeda Science Foundation
- Grants-in-Aid for Scientific Research [16K15681, 26110003, 17K08522, 14J12413, 17J00933, 26893265, 16K01378, 17K19533, 17H04069] Funding Source: KAKEN
Background: A delicate balance between cell death and keratinocyte proliferation is crucial for normal skin development. Previous studies have reported that cellular FLICE (FADD-like ICE)-inhibitory protein plays a crucial role in prevention of keratinocytes from TNF-alpha-dependent apoptosis and blocking of dermatitis. However, a role for cellular FLICE-inhibitory protein in TNF-alpha-independent cell death remains unclear. Objective: We investigated contribution of TNF-alpha-dependent and TNF-alpha-independent signals to the development of dermatitis in epidermis-specific Cflar-deficient (Cflar(E-KO)) mice. Methods: We examined the histology and expression of epidermal differentiation markers and inflammatory cytokines in the skin of Cflar(E-KO); Tnfrsf1a(1/2) and Cflar(E-KO); Tnfrsf1a(-/-) mice. Mice were treated with neutralizing antibodies against Fas ligand and TNF-related apoptosis-inducing ligand to block TNF-alpha-independent cell death of Cflar(E-KO); Tnfrsf1a(-/-) mice. Results: Cflar(E-KO); Tnfrsf1a(-/-) mice were born but experienced severe dermatitis and succumbed soon after birth. Cflar(E-KO); Tnfrsf1a(+/-) mice exhibited embryonic lethality caused by massive keratinocyte apoptosis. Although keratinocytes from Cflar(E-KO); Tnfrsf1a(-/-) mice still died of apoptosis, neutralizing antibodies against Fas ligand and TNF-related apoptosis-inducing ligand substantially prolonged survival of Cflar(E-KO); Tnfrsf1a(-/-) mice. Expression of inflammatory cytokines, such as Il6 and Il17a was increased; conversely, expression of epidermal differentiation markers was severely downregulated in the skin of Cflar(E-KO); Tnfrsf1a(-/-) mice. Treatment of primary keratinocytes with IL-6 and, to a lesser extent, IL-17A suppressed expression of epidermal differentiation markers. Conclusion: TNF receptor superfamily 1 (TNFR1)-dependent or TNFR1-independent apoptosis of keratinocytes promotes inflammatory cytokine production, which subsequently blocks epidermal differentiation. Thus blockade of both TNFR1-dependent and TNFR1-independent cell death might be an alternative strategy to treat skin diseases when treatment with anti-TNF-alpha antibody alone is not sufficient.
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