An endogenous tryptophan photo-product, FICZ, is potentially involved in photo-aging by reducing TGF-β-regulated collagen homeostasis. Issue 1 (January 2018)

• Record Type: Journal Article
• Authors: Murai, Mika; Tsuji, Gaku; Hashimoto-Hachiya, Akiko; Kawakami, Yoshihito; Furue, Masutaka; Mitoma, Chikage
• Is Part Of: Journal of dermatological science. Volume 89:Issue 1(2018)
• Page Start: 19
• Page End: 26
• Publication Date: 2018-01
• Subjects: FICZ formylindolo[3, 2-b]carbazole -- AHR aryl hydrocarbon receptor -- NHDF normal human dermal fibroblast -- ROS reactive oxygen species -- ACTA2 α2-smooth muscle actin -- ITE 2-(1′H-indole-3′-carbonyl)-thiazole-4-carboxylic acid methyl ester -- pSmad2/3 phosphorylated Smad2/3; 6-Formylindolo[3, 2-b]carbazole -- FICZ -- Photo-aging -- Ultraviolet -- Dermal fibroblast -- Aryl hydrocarbon receptor; Dermatology -- Periodicals; Skin Diseases -- Periodicals; Dermatologie -- Périodiques; 616.5005
• DOI: 10.1016/j.jdermsci.2017.10.002
• Languages: English
• ISSNs: 0923-1811

Abstract

Highlights: We evaluate the effects of an endogenous photo-product FICZ on dermal fibroblasts. FICZ inhibits the TGF-β-induced collagen production in human dermal fibroblasts. FICZ disturbs the cytoplasmic-to-nuclear translocation of phosphorylated Smad2/3. The inhibitory actions of FICZ are independent of AHR signaling. FICZ may be involved in photo-aging of the skin. Abstract: Background: Persistent ultraviolet (UV) radiation in the form of sunlight causes photo-aging of the skin by reducing the production of type I collagen, the major constituent of the extracellular matrix of the dermis. Transforming growth factor (TGF)-β transforms dermal fibroblasts into α2-smooth muscle actin (ACTA2)-expressing myofibroblasts. Myofibroblasts produce a precursor form of type I collagen, type I procollagen (collagen I), consisting of pro-alpha1 (produced by the COL1A1 gene) and pro-alpha2 chains (produced by the COL1A2 gene). Smad2/3 is a key downstream molecule of TGF-β signaling. The mechanisms through which UV inhibits collagen I synthesis are not fully understood. 6-Formylindolo[3, 2- b ]carbazole (FICZ) is an endogenous tryptophan photo-metabolite generated by UV irradiation. FICZ is well known as a high-affinity ligand for aryl hydrocarbon receptor (AHR). However, the physiological roles of FICZ in photo-aging have yet to be addressed. Objective: To evaluate the effects of FICZ on the TGF-β-mediated ACTA2 and collagen I expression in normal human dermal fibroblasts (NHDFs). Methods: Quantitative real-time polymerase chain reaction and western blot analysis were performed to determine the expression of ACTA2, COL1A1, and COL1A2 in NHDFs with or without FICZ and TGF-β. The phosphorylated Smad2/3 (pSmad2/3) protein levels in cytoplasmic or nuclear portions were investigated by western blot analysis. Immunofluorescence staining was conducted to evaluate pSmad2/3 localization, and F-actin staining with phalloidin was performed to visualize actin polymerization in myofibroblasts. The actions of FICZ on the TGF-β-mediated collagen I expression and nuclear translocation of pSmad2/3 were analyzed in the presence of selective AHR antagonists or in AHR-knockdown NHDFs. Results: We found that FICZ significantly inhibited the TGF-β-induced upregulation of mRNA and protein levels of ACTA2 and collagen I and actin polymerization in myofibroblasts. FICZ did not disturb the phosphorylation of Smad2/3. Notably, FICZ reduced the expression of pSmad2/3 in the nucleus, while it increased that in the cytoplasm, suggesting that it inhibits the nuclear translocation of pSmad2/3 induced by TGF-β. The inhibitory actions of FICZ on the TGF-β-mediated collagen I expression and nuclear translocation of pSmad2/3 were independent of AHR signaling. Another endogenous AHR agonist, kynurenine, also inhibited the TGF-β-mediated ACTA2 and collagen I upregulation in NHDFs in an AHR-independent manner; however, its effects were insignificant in comparison with those of FICZ. Conclusions: These findings suggest that the endogenous photo-product FICZ may be a key chromophore that involves in photo-aging. Downregulation of FICZ signaling is thus a potential strategy to protect against photo-aging.