Abstract
The receptor transporter protein 4 (RTP4) is a receptor chaperone protein that targets class A G-protein coupled receptor (GPCR)s. Recently, it has been found to play a role in peripheral inflammatory regulation, as one of the interferon-stimulated genes (ISGs). However, the detailed role of RTP4 in response to inflammatory stress in the central nervous system has not yet been fully understood. While we have previously examined the role of RTP4 in the brain, particularly in neuronal cells, this study focuses on its role in microglial cells, immunoreactive cells in the brain that are involved in inflammation. For this, we examined the changes in the RTP4 levels in the microglial cells after exposure to inflammatory stress. We found that lipopolysaccharide (LPS) treatment (0.1~1 µg/mL, 24 h) significantly upregulated the RTP4 mRNA levels in the microglial cell line, SIM-A9. Furthermore, the interferon (IFN)-β mRNA levels and extracellular levels of IFN-β were also increased by LPS treatment. This upregulation was reversed by treatment with neutralizing antibodies targeting either the interferon receptor (IFNR) or toll-like receptor 4 (TLR4), and with a TLR4 selective inhibitor, or a Janus kinase (JAK) inhibitor. On the other hand, the mitogen-activated protein kinase kinase (MEK) inhibitor, U0126, significantly enhanced the increase in RTP4 mRNA following LPS treatment, whereas the PKC inhibitor, calphostin C, had no effect. These findings suggest that in microglial cells, LPS-induced inflammatory stress activates TLR4, leading to the production of type I IFN, the activation of IFN receptor and JAK, and finally, the induction of RTP4 gene expression. Based on these results, we speculate that RTP4 functions as an inflammation-responsive molecule in the brain. However, further research is needed to fully understand its role.