title: Cross-talk between interferon-gamma and interleukin-18 in melanogenesis.
abstract: Skin is the largest organ in our body and strategically placed to provide a metabolically active biological barrier against a range of noxious stressors. A lot of inflammatory cytokines, which are increased after ultraviolet (UV) irradiation produced by keratinocytes or other immunocytes, are closely related to pigmentary changes, including interleukin-18 (IL-18) and interferon-γ (IFN-γ). In this study, the effect of cross-talk between IL-18 and IFN-γ on melanogenesis was investigated. Treatment with IL-18 resulted in a dose-dependent increase of melanogenesis, while IFN-γ made an opposite effect. This influence of IL-18 and IFN-γ was mediated by regulations of microphthalmia-associated transcription factor (MITF) and its downstream enzymatic cascade expressions. Furthermore, IFN-γ inhibited basal and IL-18-induced melanogenesis. IFN-γ increased signal transducer and activator of transcription-1 (STAT-1) phosphorylation to play its position in regulating melanin pigmentation, and its inhibitory effect could be prevented by Janus Kinase 1 (JAK 1) inhibitor. IFN-γ could inhibit melanogenesis by decreasing melanocyte dendrite formation. In addition, IFN-γ inhibited the expressions of Rab Pases to suppress the mature and transport of melanosomes. IL-18 could rapidly induce Akt and PTEN phosphorylation and p65 expression in B16F10 cells. When treatment with IL-18 and IFN-γ together, the phosphorylation level of Protein Kinase B (Akt) and phosphatase and tensin homolog deleted on chromosome ten (PTEN) and expression of p65 NF-κB were inhibited, compared with treated with IL-18 only. Our studies indicated that IFN-γ could directly induce B16F10 cells apoptosis in vitro. Furthermore, we demonstrated that IFN-γ markedly up-regulated IL-18 binding protein (BP) production in normal human foreskin-derived epidermal keratinocytes in dose-dependent manner. UVB irradiation induced protease-activated receptor-2 (PAR-2) expression in NHEK, IFN-γ could inhibit this enhancement in a dose-dependent manner. These data suggest that IFN-γ plays a role in regulating inflammation- or UV-induced pigmentary changes, in direct/indirect manner.
authors: State Key Laboratory of Natural Medicines, China Pharmaceutical University, Nanjing 210009, PR China; Jiangsu Key Laboratory of TCM Evaluation and Translational Research, China Pharmaceutical University, Nanjing 211198, PR China; School of Pharmaceutical Science, Jiangnan University, Wuxi 214122, PR China.
authors: Jia
authors: J
authors: Zhou
authors: Wuxi People's Hospital affiliated to Nanjing Medical University, Wuxi 214023, PR China.
authors: Jingjing
authors: J
authors: Ling
authors: Wuxi People's Hospital affiliated to Nanjing Medical University, Wuxi 214023, PR China.
authors: Yong
authors: Y
authors: Wang
authors: State Key Laboratory of Natural Medicines, China Pharmaceutical University, Nanjing 210009, PR China; Jiangsu Key Laboratory of TCM Evaluation and Translational Research, China Pharmaceutical University, Nanjing 211198, PR China.
authors: Jing
authors: J
authors: Shang
authors: Wuxi People's Hospital affiliated to Nanjing Medical University, Wuxi 214023, PR China. Electronic address: pffzjtg2015@163.com.
authors: Fengfeng
authors: F
authors: Ping
mesh_terms: D000818:Animals; D045744:Cell Line, Tumor; D018920:Coculture Techniques; D004347:Drug Interactions; D015971:Gene Expression Regulation, Enzymologic / Q000187:drug effects; D006801:Humans; D007371:Interferon-gamma / Q000494:pharmacology*; D020382:Interleukin-18 / Q000494:pharmacology*; D015603:Keratinocytes / Q000166:cytology / Q000187:drug effects / Q000378:metabolism / Q000528:radiation effects; D008543:Melanins / Q000096:biosynthesis*; D008544:Melanocytes / Q000166:cytology / Q000187:drug effects / Q000378:metabolism; D051379:Mice; D014442:Monophenol Monooxygenase / Q000378:metabolism; D051059:PTEN Phosphohydrolase / Q000378:metabolism; D010766:Phosphorylation / Q000187:drug effects; D051057:Proto-Oncogene Proteins c-akt / Q000378:metabolism; D051996:Transcription Factor RelA / Q000378:metabolism
chemical_list: D020382:Interleukin-18; D008543:Melanins; D051996:Transcription Factor RelA; D007371:Interferon-gamma; D014442:Monophenol Monooxygenase; D051057:Proto-Oncogene Proteins c-akt; D051059:PTEN Phosphohydrolase
keywords: Apoptosis; IFN-γ; IL-18; IL-18BP; Melanogenesis; UVB-irradiation