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¹ Department of Biological Chemistry and ² Department of Veterinary Resources, The Weizmann Institute of Science, Rehovot 76100, Israel
³ Institute of Biochemistry, Medical School Hannover, Hannover D-30625, Germany
⁴ Rudolf-Buchheim-Institute of Pharmacology, Justus Liebig University Giessen, Giessen D-35392, Germany

CORRESPONDENCE David Wallach: d.wallach{at}weizmann.ac.il

Expression of enzymatically inactive caspase-8, or deletion of caspase-8 from basal epidermal keratinocytes, triggers chronic skin inflammation in mice. Unlike similar inflammation resulting from arrest of nuclear factor B activation in the epidermal cells, the effect induced by caspase-8 deficiency did not depend on TNF, IL-1, dermal macrophage function, or expression of the toll-like receptor adapter proteins MyD88 or TRIF. Both interferon regulatory factor (IRF) 3 and TANK-binding kinase were constitutively phosphorylated in the caspase-8–deficient epidermis, and knockdown of IRF3 in the epidermis-derived cells from these mice abolished the expression of up-regulated genes. Temporal and spatial analyses of the alterations in gene expression that result from caspase-8 deficiency reveal that the changes are initiated before birth, around the time that cornification develops, and occur mainly in the suprabasal layer. Finally, we found that caspase-8–deficient keratinocytes display an enhanced response to gene activation by transfected DNA. Our findings suggest that an enhanced response to endogenous activators of IRF3 in the epidermis, presumably generated in association with keratinocyte differentiation, contributes to the skin inflammatory process triggered by caspase-8 deficiency.

Abbreviations used: BAC, bacterial artificial chromosome; cDNA, complementary DNA; Ct, cycle-threshold; DAMP, damage-associated molecular pattern; IRES, internal ribosome entry site; IRF, IFN regulatory factor; K5, keratin 5; mRNA, messenger RNA; PAMP, pathogen-associated molecular pattern; siRNA, small interfering RNA; TBK, TANK-binding kinase; TLR, toll-like receptor; TUNEL, terminal transferase-mediated dUTP nick-end labeling.

© 2009 Kovalenko et al.
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This article has been cited by other articles:

• Kovalenko, A., Kim, J.-C., Kang, T.-B., Rajput, A., Bogdanov, K., Dittrich-Breiholz, O., Kracht, M., Brenner, O., Wallach, D. (2009). Caspase-8 deficiency in epidermal keratinocytes triggers an inflammatory skin disease. JCB 186: i10-i10 [Full Text]  

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