Abstract
Primary cutaneous amyloidosis (PCA) is a chronic skin disease that most frequently occurs in Southeast Asia and South America. Based on the etiology, PCA can be classified into sporadic and familial types. Recently, mutations on IL-31RA or oncostatin M receptor β (OSMRβ) gene have been found to correlate with familial primary cutaneous amyloidosis (FPCA). MCP-1, upon induction by IL-31 can recruit monocytes/macrophages to clean the cell debris on the skin. However, when certain mutations occur in IL-31 receptor, the levels of MCP-1 would decrease, leading to the accumulation of cell debris on the surface of skin. In this study, a cell-based drug screening system was established in which human keratinocyte cells (HaCaT) were transfected with mutant IL-31RA plasmid. In lieu of this system, several potential activators of MCP-1 in IL-31RA mutant cells were discovered. Subsequently, the underlying mechanism was explored. Results from this study showed that the levels of MCP-1 were increased by MEK1/2 kinase inhibitors, PD 198306 or Trametinib. The expression levels of MCP-1 mRNA increased when the cells were treated with PD 198306. The expression levels phospho-STAT1 (Tyr701), one transcription factor of MCP-1 promoter, were also significantly increased when the HaCaT cells harboring mutant IL-31RA were treated with either MEK1/2 kinase inhibitors. Overall, these results might suggest that inhibition of MEK1/2 activity might increase the expression levels of phospho-STAT1 (Tyr701). The phospho-STAT1 (Tyr701) can act as a transcription activator and bind on MCP-1 promoter to enhance the transcription. Although the exact interplays between MEK1/2 and FPCA remains to be further investigated, this study indicate that MEK1/2 pathway may be a novel target for development of effective FPCA treatment.