Lipopolysaccharide-Induced Up-Regulation of Triggering Receptor Expressed on Myeloid Cells-1 Expression on Macrophages Is Regulated by Endogenous Prostaglandin E2

Abstract

Triggering receptor expressed on myeloid cells-1 (TREM-1) is a recently identified cell surface molecule that is expressed by neutrophils and monocytes. TREM-1 expression is modulated by various ligands for TLRs in vitro and in vivo. However, the influence of PGE2, a potential mediator of inflammation, on TREM-1 expression has not been elucidated. In this study, we examined the effects of PGE2 on LPS-induced TREM-1 expression by resident murine peritoneal macrophages (RPM) and human PBMC. PGE2 significantly induced murine TREM-1 (mTREM-1) expression by RPM. Up-regulation of TREM-1 expression was specific to PGE2 among arachidonic acid metabolites, while ligands for chemoattractant receptor-homologous molecule expressed on Th2 cells and the thomboxane-like prostanoid receptor failed to induce mTREM-1 expression. PGE2 also increased expression of the soluble form of TREM-1 by PBMC. LPS-induced TREM-1 expression was regulated by endogenous PGE2 especially in late phase (>2 h after stimulation), because cyclooxygenase-1 and -2 inhibitors abolished this effect at that points. A synthetic EP4 agonist and 8-Br-cAMP also enhanced mTREM-1 expression by RPM. Furthermore, protein kinase A, PI3K, and p38 MAPK inhibitors prevented PGE2-induced mTREM-1 expression by RPM. Activation of TREM-1 expressed on PGE2-pretreated PBMC by an agonistic TREM-1 mAb significantly enhanced the production of IL-8 and TNF-α. These findings indicate that LPS-induced TREM-1 expression on macrophages is mediated, at least partly, by endogenous PGE2 followed by EP4 and cAMP, protein kinase A, p38 MAPK, and PI3K-mediated signaling. Regulation of TREM-1 and the soluble form of TREM-1 expression by PGE2 may modulate the inflammatory response to microbial pathogens.

MYD88‐dependent and ‐independent activation of TREM‐1 via specific TLR ligands

“…Recently, Murakami et al showed that PGE2 could induce TREM-1 expression by resident peritoneal macrophages and peripheral blood monocytic cells [23]. Their study suggests that activation of TREM-1 in response to LPS is related to production of PGE2 in macrophages [23]. In a recent study, we have shown that the TREM-1 gene is regulated at a transcriptional level by NF-kB, PU.1 and AP1 in macrophages in response to LPS [26].…”

“…It is known that TREM-1 is also upregulated by microbial products such as LPS, LTA, or zymosan [2,32]; however, the sequence of events that lead to their expression in response to LPS or LTA has not been defined. Recently, Murakami et al showed that PGE2 could induce TREM-1 expression by resident peritoneal macrophages and peripheral blood monocytic cells [23]. Their study suggests that activation of TREM-1 in response to LPS is related to production of PGE2 in macrophages [23].…”

“…More recently, a synergism between TREM-1 and signals induced by intracellular pattern recognition molecules such as nod-like receptors (NLR) has also been shown [22]. Downstream products of TLR activation such as PGE2 have also shown to upregulate the expression of TREM-1 [23].…”

“…More recently, a synergism between TREM-1 and signals induced by intracellular pattern recognition molecules such as nod-like receptors (NLR) has also been shown [22]. Downstream products of TLR activation such as PGE2 have also shown to upregulate the expression of TREM-1 [23].In a recent study, we investigated the functional effects of blocking TREM-1 on the TLR4-mediated signaling pathway in macrophages. We have shown that silencing of TREM-1 gene significantly altered expression of several genes, including MyD88, CD14, IkBa, IL-1b, MCP-1, and IL-10 in response to treatment with LPS in macrophage [24,25].…”

Involvement of the TREM-1/DAP12 pathway in the innate immune responses to Porphyromonas gingivalis

“…Individual microbial components, such as lipopolysaccharide (LPS) and peptidoglycan, can cause up-regulation of cell surface-localized TREM-1 by monocytes, as well as release in its soluble (s)TREM-1 form (Begum et al, 2004;Gibot et al, 2004b;Gomez-Pina et al, 2007;Murakami et al, 2007;Ramanathan et al, 2005;Zeng et al, 2007). The sTREM-1 appears to be released during the course of infection, and may well be a particularly useful marker of systemic inflammation, as demonstrated in systemic sepsis, septic arthritis, pneumonia (Collins et al, 2009;Gibot et al, 2005;Gibot et al, 2004a;Gibot et al, 2004c;Knapp et al, 2004).…”