Tumor necrosis factor receptor signaling in keratinocytes triggers interleukin-24-dependent psoriasis-like skin inflammation in mice.

Abstract

Psoriasis is a common chronic inflammatory skin disease with a prevalence of about 2% in the Caucasian population. Tumor necrosis factor (TNF) plays an essential role in the pathogenesis of psoriasis, but its mechanism of action remains poorly understood. Here we report that the development of psoriasis-like skin inflammation in mice with epidermis-specific inhibition of the transcription factor NF-κB was triggered by TNF receptor 1 (TNFR1)-dependent upregulation of interleukin-24 (IL-24) and activation of signal transducer and activator of transcription 3 (STAT3) signaling in keratinocytes. IL-24 was strongly expressed in human psoriatic epidermis, and pharmacological inhibition of NF-κB increased IL-24 expression in TNF-stimulated human primary keratinocytes, suggesting that this mechanism is relevant for human psoriasis. Therefore, our results expand current views on psoriasis pathogenesis by revealing a new keratinocyte-intrinsic mechanism that links TNFR1, NF-κB, ERK, IL-24, IL-22R1, and STAT3 signaling to disease initiation.

• Authors: Snehlata Kumari, Marion C Bonnet, Maria H Ulvmar, Kerstin Wolk, Niki Karagianni, Ellen Witte, Claudia Uthoff-Hachenberg, Jean-Christophe Renauld, George Kollias, Rune Toftgard, Robert Sabat, Manolis Pasparakis, Ingo Haase
• Journal: Immunity (Immunity) Vol. 39 Issue 5 Pg. 899-911 (Nov 14 2013) ISSN: 1097-4180 [Electronic] United States
• PMID: 24211183 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't)
• Copyright: Copyright © 2013 Elsevier Inc. All rights reserved.

Chemical References

• Cytokines
• Il24 protein, mouse
• Interleukins
• NF-kappa B
• Reactive Oxygen Species
• Receptors, Interleukin
• Receptors, Tumor Necrosis Factor, Type I
• STAT3 Transcription Factor
• Stat3 protein, mouse
• Tnfrsf1a protein, mouse
• Tumor Necrosis Factor-alpha
• interleukin-22 receptor
• interleukin-24
• Granulocyte-Macrophage Colony-Stimulating Factor
• I-kappa B Kinase
• Ikbkb protein, mouse

Topics

• Animals
• Cells, Cultured
• Crosses, Genetic
• Cytokines (biosynthesis, genetics, physiology)
• Disease Models, Animal
• Epidermis (pathology)
• Gene Expression Regulation (physiology)
• Granulocyte-Macrophage Colony-Stimulating Factor (biosynthesis)
• Humans
• I-kappa B Kinase (deficiency, physiology)
• Interleukins (physiology)
• Keratinocytes (metabolism, pathology)
• MAP Kinase Signaling System
• Mice
• Mice, Knockout
• Mice, Transgenic
• NF-kappa B (metabolism)
• Psoriasis (etiology, pathology, physiopathology)
• Reactive Oxygen Species (metabolism)
• Receptors, Interleukin (physiology)
• Receptors, Tumor Necrosis Factor, Type I (deficiency, genetics, physiology)
• STAT3 Transcription Factor (physiology)
• Tumor Necrosis Factor-alpha (antagonists & inhibitors, physiology)