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

Abstract

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.

Prostaglandin F2α regulation of mRNA for activating protein 1 transcriptional factors in porcine corpora lutea (CL): lack of induction of JUN and JUND in CL without luteolytic capacity

“…Likewise, we observed a similar response in the porcine CL with a dramatic and rapid increase in CCL2 mRNA only in CL with luteolytic capacity. Expression of CCL2 is regulated by AP-1 proteins in many cell types [42] including luteal cells [16]. A simplified scenario could be that lack of AP-1 activation due to lack of JUN induction leads to lack of CCL2 induction in CL without luteolytic capacity.…”

“…For example, PGF2α increases CYP19A1 [10] and CCL2 mRNA [9], and decreases STAR mRNA [7] only in CL with luteolytic capacity. All three of these genes ( CYP19A1 , STAR , and CCL2 ) are regulated by AP-1 transcriptional complexes [16–20]. Therefore, this study was undertaken to determine whether AP-1 transcription factors are differentially regulated by PGF2α in porcine CL before and after acquisition of luteolytic capacity.…”

Prostaglandin F2α induces expression of activating transcription factor 3 (ATF3) and activates MAPK signaling in the rat corpus luteum

“…Based on recent studies it also seems that the activation of JNK may contribute to the rapid induction of chemokines that occurs during luteal regression (Talbott et al, 2014;Walusimbi and Pate, 2013). Nagaosa et al (2008) demonstrated that treatment of rat luteal cell cultures with inhibitors of either JNK or AP-1 abolished increases in mRNA of the chemokine MCP-1. Likewise, the stimulatory effect of PGF 2␣ on expression of IL8 mRNA in vitro was prevented by an inhibitor of JNK signaling (Talbott et al, 2014).…”

Phagocytosis: Invitation to a Feast

“…In normal resolution of the corpus luteum, macrophages accumulate and are responsible for clearance of the dying luteal cells. Here, induction of the monocyte/ macrophage chemoattractant chemokine (CCL12, MCP-1) from remaining viable cells apparently responding to the neighboring apoptotic cells seemed to mediate the attraction [8,9]. This may be a mechanism that applies in other situations in vivo.…”