Identification of PGRMC1 as a regulator of the TLR3–TICAM1–IFNβ1 signaling axis in RAW264.7 macrophages

PGRMC1 is a member of the membrane-associated progesterone receptor (MAPR) family, which plays various roles under both pathological and physiological conditions. Although PGRMC1 is expressed in macrophages, its functions in macrophages remain to be fully elucidated. In this study, we aimed to investigate the roles of PGRMC1 in regulating Toll-like receptor (TLR) signaling in macrophages by inhibiting PGRMC1. The expression levels of <i>Pgrmc1</i> in RAW264.7 cells, a monocyte/macrophage-like cell line, were significantly increased by TLR3 stimulation but not by TLR4 stimulation. Inhibition of PGRMC1 in RAW264.7 cells significantly suppressed the increased expression of interferon beta1 (<i>Ifnb1</i>) induced by TLR3 stimulation. Additionally, inhibition of PGRMC1 significantly suppressed the upregulation of <i>Ticam1</i>, an essential regulator of TLR3 signaling. However, inhibition of PGRMC1 had little effect on the expression levels of interferon regulatory factor 3 (<i>Irf3</i>), a key transcriptional regulator of IFNβ1. Inhibition of PGRMC1 in RAW264.7 cells also exhibited a minimal effect on the increased expression of interleukin-6 (<i>Il-6</i>) induced by TLR4 stimulation. PGRMC2, another member of the MAPR family, was expressed in RAW264.7 cells, but it did not compensate for the absence of PGRMC1, despite the high homology between the amino acid sequences of PGRMC1 and PGRMC2. In conclusion, our results suggest that PGRMC1 in RAW264.7 cells modulates <i>Ifnb1</i> expression by regulating <i>Ticam1</i> expression. To the best of our knowledge, this is the first study to demonstrate that PGRMC1 contributes to regulating IFNβ1 production in response to TLR3 stimulation in RAW264.7 cells.