Activator protein 1-mediated expression of monocyte chemoattractant protein 1 in cultured rat luteal cells.

We have proposed that luteal cells undergo apoptosis-dependent phagocytosis by invading monocyte-derived macrophages in regressive corpora lutea of the rat. Accumulation of monocytes/macrophages seems to be mediated by monocyte chemoattractant protein 1 (MCP-1) or CCL2, because apoptosis and the production of MCP-1 mRNA occur simultaneously, but in different luteal cells, in a manner dependent on nuclear factor kappaB (NF-kappaB). In this study, we determined the mechanisms underlying the induction of these two events using primary cultures of rat luteal cells. We found that the activity of the transcription factor activator protein 1 (AP-1) increased during culturing concomitantly with an increase of MCP-1 mRNA. The increase of MCP-1 mRNA was abolished when cultures were maintained in the presence of an inhibitor of either AP-1 or c-Jun amino-terminal kinase (JNK) that phosphorylates and activates c-Jun, a subunit of AP-1. Furthermore, the presence of an inhibitor of NF-kappaB abrogated an increase in the activity of both AP-1 and JNK. In contrast, the induction of apoptosis in cultured luteal cells required the action of JNK but appeared to be independent of AP-1. This may explain why apoptosis and MCP-1 mRNA production are concomitantly but differentially induced in distinct luteal cells. We therefore suggest the following signaling pathways for the induction of apoptosis and mcp-1 gene expression during involution of the corpus luteum; NF-kappaB's actions lead to the activation of JNK, and the active JNK, at one side, stimulates mcp-1 gene transcription by activating AP-1 and, at the other side, induces apoptosis.