Suppression of thymus- and activation-regulated chemokine (TARC/CCL17) production by 3-O-β-D-glucopyanosylspinasterol via blocking NF-κB and STAT1 signaling pathways in TNF-α and IFN-γ-induced HaCaT keratinocytes.

Abstract

A phytosterol derivative, 3-O-β-D-glucopyanosylspinasterol (spinasterol-Glc) isolated from leaves of Stewartia koreana was reported to inhibit LPS-induced cytokine production in macrophage cells. Thymus and activation regulated chemokine (TARC/CCL17) is produced in response to pro-inflammatory cytokines in keratinocytes, which is implicated in the development of inflammatory skin diseases. In present study, we investigated the effect of spinasterol-Glc on production of TARC/CCL17 induced by TNF-α and IFN-γ in human HaCaT keratinocytes. Spinasterol-Glc inhibited the mRNA and protein expression of TARC/CCL17 induced by TNF-α/IFN-γ in a dose-dependent manner. Inhibitors of c-Raf-1, p38 MAPK, and JAK2, suppressed the TNF-α/IFN-γ-induced production of TARC/CCL17, and phosphorylation of these signaling molecules were attenuated by spinasterol-Glc. The compound also inhibited phosphorylation of IKKα/β and IκB-α, and reduced translocation of NF-κB to the nucleus. We demonstrated that spinasterol-Glc suppressed the NF-κB-driven and the GAS-driven expression of luciferase reporter gene induced by TNF-α and IFN-γ. In addition, spinasterol-Glc inhibited the DNA binding of NF-κB and STAT1 to its cognate binding site. These results suggest that spinasterol-Glc has effective inhibitory effects on production of TARC/CCL17 in keratinocytes via inhibition of NF-κB as well as STAT activation, and could be utilized for development of a potential therapeutic agent against skin inflammatory diseases.

• Authors: Mi-ra Jung, Tae Hoon Lee, Myun-Ho Bang, Hakwon Kim, Youngsook Son, Dae Kyun Chung, Jiyoung Kim
• Journal: Biochemical and biophysical research communications (Biochem Biophys Res Commun) Vol. 427 Issue 2 Pg. 236-41 (Oct 19 2012) ISSN: 1090-2104 [Electronic] United States
• PMID: 22943853 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't)
• Copyright: Copyright © 2012 Elsevier Inc. All rights reserved.

Chemical References

• 3-O-beta-D-glucopyranosyl-spinasterol
• Anti-Inflammatory Agents, Non-Steroidal
• CCL17 protein, human
• Chemokine CCL17
• Dermatologic Agents
• NF-kappa B
• STAT1 Transcription Factor
• STAT1 protein, human
• Tumor Necrosis Factor-alpha
• Interferon-gamma
• Stigmasterol
• JAK2 protein, human
• Janus Kinase 2
• Proto-Oncogene Proteins c-raf
• p38 Mitogen-Activated Protein Kinases

Topics

• Anti-Inflammatory Agents, Non-Steroidal (pharmacology)
• Cell Line
• Chemokine CCL17 (antagonists & inhibitors, biosynthesis)
• Dermatitis, Atopic (drug therapy, metabolism)
• Dermatologic Agents (pharmacology)
• Humans
• Interferon-gamma (pharmacology)
• Janus Kinase 2 (metabolism)
• Keratinocytes (drug effects, metabolism)
• NF-kappa B (antagonists & inhibitors)
• Phosphorylation (drug effects)
• Proto-Oncogene Proteins c-raf (metabolism)
• STAT1 Transcription Factor (antagonists & inhibitors)
• Signal Transduction (drug effects)
• Stigmasterol (analogs & derivatives, pharmacology)
• Tumor Necrosis Factor-alpha (pharmacology)
• p38 Mitogen-Activated Protein Kinases (metabolism)