Tumor Necrosis Factor-Alpha–Nuclear Factor-Kappa B-Signaling Enhances St2b2 Expression during 12-O-Tetradecanoylphorbol-13-acetate-Induced Epidermal Hyperplasia

• Published in: Biological & Pharmaceutical Bulletin Vol. 34; no. 2; pp. 183 - 190
• Main Authors: Matsuda, Toshihiro, Shimada, Miki, Sato, Akira, Akase, Takanori, Yoshinari, Kouichi, Nagata, Kiyoshi, Yamazoe, Yasushi
• Format: Journal Article
• Language: English
• Published: Japan The Pharmaceutical Society of Japan 2011; Pharmaceutical Society of Japan; Japan Science and Technology Agency
• Subjects: Animals; Antibodies - pharmacology; Cholesterol Esters - metabolism; cholesterol sulfate; epidermal differentiation; Epidermis - metabolism; Epidermis - pathology; Female; Hyperplasia; Inflammation - metabolism; Mice; Mice, Inbred Strains; NF-kappa B - metabolism; Nitriles - pharmacology; nuclear factor-kappa B; phorbol ester; Protein Precursors - metabolism; Receptors, Tumor Necrosis Factor - antagonists & inhibitors; RNA, Small Interfering - metabolism; Signal Transduction; Skin Neoplasms - chemically induced; Skin Neoplasms - metabolism; Sulfones - pharmacology; sulfotransferase; Sulfotransferases - genetics; Sulfotransferases - metabolism; Tetradecanoylphorbol Acetate; tumor necrosis factor-alpha; Tumor Necrosis Factor-alpha - antagonists & inhibitors; Tumor Necrosis Factor-alpha - metabolism
• ISSN: 0918-6158; 1347-5215
• DOI: 10.1248/bpb.34.183

The mouse cholesterol sulfotransferase St2b2 contributes to epidermal differentiation by biosynthesizing cholesterol sulfate (CS) from cholesterol in the epidermis. 12-O-Tetradecanoylphorbol-13-acetate (TPA) causes epidermal hyperplasia, an abnormal increase in epidermal cell numbers resulting from aberrant cell differentiation and an increase in St2b2 protein levels. The mechanisms underlying enhanced St2b2 expression and the pathophysiologic significance of the increased expression are unclear, however. To verify whether increased St2b2 levels are necessary for TPA-induced epidermal hyperplasia, the effects of St2b2-specific small hairpin RNA (St2b2-shRNA) on hyperplasia were examined in mice. St2b2-shRNA clearly suppressed TPA-induced epidermal hyperplasia and the expression of a marker of epidermal differentiation, involucrin (INV). Interestingly, treating mouse epidermal cells with tumor necrosis factor-alpha (TNFα) increased St2b2 expression. Furthermore, treatment with TNFα-siRNA or anti-TNF receptor antibodies reduced the TPA-induced enhancement of St2b2 expression. Treatment with BAY 11-7082, a specific inhibitor of nuclear factor-kappa B (NF-κB), diminished TPA-induced St2b2 expression. These results suggested that enhancement of St2b2 expression by TPA treatment occurs mainly through the TNFα–NF-κB inflammatory signaling pathway, which in turn leads to increased CS concentrations in epidermal cells and hyperplasia.