Adrenocorticotropin Hormone Stimulates Interleukin-18 Expression in Human HaCaT Keratinocytes

• Published in: Journal of investigative dermatology Vol. 127; no. 5; pp. 1210 - 1216
• Main Authors: Park, Hyun Jeong, Kim, Hee Jung, Lee, Jun Young, Cho, Baik Kee, Gallo, Richard L., Cho, Dae Ho
• Format: Journal Article
• Language: English
• Published: United States Elsevier Inc 01.05.2007; Elsevier Limited
• Subjects: Adrenocorticotropic hormone; Adrenocorticotropic Hormone - physiology; Caspase 1 - physiology; Caspase-1; Cell Line; Corticotropin-releasing hormone; Dermatology; Enzyme Inhibitors - pharmacology; Extracellular signal-regulated kinase; Extracellular Signal-Regulated MAP Kinases - antagonists & inhibitors; Extracellular Signal-Regulated MAP Kinases - physiology; Flavonoids - pharmacology; Gene Expression Regulation - drug effects; Hormones; Humans; Hypothalamic-pituitary-adrenal axis; Imidazoles - pharmacology; Immunomodulation; Inflammation; Interleukin 18; Interleukin-18 - genetics; Interleukin-18 - metabolism; Internet; Keratinocytes; Keratinocytes - cytology; Keratinocytes - physiology; Melanocortin receptors; p38 Mitogen-Activated Protein Kinases - antagonists & inhibitors; p38 Mitogen-Activated Protein Kinases - physiology; Phosphorylation; Proopiomelanocortin; Pyridines - pharmacology; Receptors, Pituitary Hormone - physiology; RNA, Messenger - genetics; RNA, Messenger - physiology; Signal transduction; Skin; Stress; Transcription
• ISSN: 0022-202X; 1523-1747
• DOI: 10.1038/sj.jid.5700703

The hypothalamic–pituitary–adrenal (HPA) axis is activated by stress. This involves the production of corticotropin releasing hormone (CRH) with the subsequent release of proopiomelanocortin (POMC) peptides, of which adrenocorticotropin hormone (ACTH) is most important. Although the skin has the capacity to produce CRH and POMC peptides, the immunomodulatory roles of ACTH in skin are yet unknown. IL-18 has been known to affect cells involved in the inflammatory response. In this study, we aimed to identify the regulatory effect of ACTH on IL-18 expression of skin keratinocytes. Exposure of HaCaT cells to ACTH stimulated formation of IL-18 mRNA transcript and its protein products in a dose-dependent manner. Furthermore, we suggest that ACTH-induced IL-18 production is via the caspase-1 activation pathway, as IL-18 production induced by ACTH could be suppressed by caspase-1 inhibitor, and ACTH could increase caspase-1 activity. The effect of ACTH on IL-18 production was blocked by specific inhibitors of p38 kinase (SB203580) or extracellular signal-regulated kinase (ERK) (PD98059). In addition, ACTH-induced rapid phosphorylation of p38 kinase and ERK, and ACTH signaling occurred via melanocortin receptor 1 (MC1R) and receptor 2 (MC2R). These results suggest that ACTH stimulates IL-18 expression in human keratinocytes, which provides an insight into the interaction between ACTH and inflammatory mediators.