Roles of TLR7 in activation of NF-κB signaling of keratinocytes by imiquimod

• Published in: PloS one Vol. 8; no. 10; p. e77159
• Main Authors: Li, Zheng Jun, Sohn, Kyung-Cheol, Choi, Dae-Kyoung, Shi, Ge, Hong, Dongkyun, Lee, Han-Eul, Whang, Kyu Uang, Lee, Young Ho, Im, Myung, Lee, Young, Seo, Young-Joon, Kim, Chang Deok, Lee, Jeung-Hoon
• Format: Journal Article
• Language: English
• Published: United States Public Library of Science 11.10.2013; Public Library of Science (PLoS)
• Subjects: Activation; Adenine; Aminoquinolines - pharmacology; Calcium; Calcium - metabolism; Calcium - pharmacology; Cell Differentiation - drug effects; Cell Differentiation - genetics; Cells, Cultured; Chemokines; Cytokines; Cytokines - genetics; Cytokines - metabolism; Dendritic cells; Dermatology; Enzyme Activation - drug effects; Gene Expression; Humans; Imiquimod; Immunology; Interleukin 8; Keratinocytes; Keratinocytes - cytology; Keratinocytes - drug effects; Keratinocytes - metabolism; Ligands; Medicine; miRNA; NF-kappa B - genetics; NF-kappa B - metabolism; NF-κB protein; Psoriasis; Signal Transduction - drug effects; Signaling; Skin diseases; TLR7 protein; Toll-Like Receptor 7 - genetics; Toll-Like Receptor 7 - metabolism; Toll-like receptors; Transcription, Genetic; Tumor Necrosis Factor-alpha - genetics; Tumor Necrosis Factor-alpha - metabolism; Tumor necrosis factor-TNF; Tumor necrosis factor-α; Zheng Jun
• ISSN: 1932-6203; 1932-6203
• DOI: 10.1371/journal.pone.0077159

Imiquimod is known to exert its effects through Toll-like receptor 7 (TLR7) and/or TLR8, resulting in expression of proinflammatory cytokines and chemokines. Keratinocytes have not been reported to constitutively express TLR7 and TLR8, and the action of imiquimod is thought to be mediated by the adenine receptor, not TLR7 or TLR8. In this study, we revealed the expression of TLR7 in keratinocytes after calcium-induced differentiation. After addition of calcium to cultured keratinocytes, the immunological responses induced by imiquimod, such as activation of NF-κB and induction of TNF-α and IL-8, were more rapid and stronger. In addition, imiquimod induced the expression TLR7, and acted synergistically with calcium to induce proinflammatory cytokines. We confirmed that the responses induced by imiquimod were significantly inhibited by microRNAs suppressing TLR7 expression. These results suggest that TLR7 expressed in keratinocytes play key roles in the activation of NF-κB signaling by imiquimod, and that their modulation in keratinocytes could provide therapeutic potential for many inflammatory skin diseases.