PGE2 induced in and released by dying cells functions as an inhibitory DAMP

Abstract

Cellular components released into the external milieu as a result of cell death and sensed by the body are generally termed damage-associated molecular patterns (DAMPs). Although DAMPs are conventionally thought to be protective to the host by evoking inflammatory responses important for immunity and wound repair, there is the prevailing notion that dysregulated release of DAMPs can also underlie or exacerbate disease development. However, the critical issue for how resultant DAMP-mediated responses are regulated has heretofore not been fully addressed. In the present study, we identify prostaglandin E2 (PGE2) as a DAMP that negatively regulates immune responses. We show that the production of PGE2 is augmented under cell death-inducing conditions via the transcriptional induction of the cyclooxygenase 2 (COX2) gene and that cell-released PGE2 suppresses the expression of genes associated with inflammation, thereby limiting the cell’s immunostimulatory activities. Consistent with this, inhibition of the PGE2 synthesis pathway potentiates the inflammation induced by dying cells. We also provide in vivo evidence for a protective role of PGE2 released upon acetaminophen-induced liver injury as well as a pathogenic role for PGE2 during tumor cell growth. Our study places this classically known lipid mediator in an unprecedented context—that is, an inhibitory DAMP vis-à-vis activating DAMPs, which may have translational implications for designing more effective therapeutic regimens for inflammation-associated diseases.

Novel chemical compound SINCRO with dual function in STING‐type I interferon and tumor cell death pathways

“…Mouse T‐lymphoma EL4 cells were obtained from RIKEN BioResource Research Center (Ibaraki, Japan) and maintained in DMEM (Nacalai Tesque, Kyoto, Japan) supplemented with 10% FBS (Hyclone, Logan, UT, USA). GM‐CSF‐induced BMDC, peritoneal macrophages, and MEF were prepared as described previously …”

“…cDNA encoding mouse STING tagged with human influenza hemagglutinin molecule corresponding to amino acids 98‐106 (HA‐STING) was cloned into pCXNII vector and expressed in HEK293T cells. Whole cell lysate was extracted using RIPA lysis buffer and was subjected to immunoprecipitation with anti‐HA antibody (12CA5; Roche, Basel, Switzerland) and Dynabeads Protein G (Life Technologies, Carlsbad, CA, USA). Then, HA‐STING‐bound beads were incubated with SINCRO (100 μg/mL) in PBS for 2 hours at 4°C and boiled in 15 μL PBS.…”

“…B16F1 cells (2 × 10 6 cells) were treated with SINCRO (10 μg/mL) or cisplatin (50 μmol/L) for 0, 6, or 12 hours. Whole cell lysates were prepared and immunoblot analysis was carried out as described previously . Antibodies for γH2AX (20E3), H2AX (D17A3), and cleaved caspase‐3 were purchased from Cell Signaling Technology (Danvers, MA, USA).…”

“…GM-CSF-induced BMDC, peritoneal macrophages, and MEF were prepared as described previously. 18,20 2.2 | Mice C57BL/6 mice were purchased from CLEA Japan (Tokyo, Japan).…”

The renaissance of anti‐neoplastic immunity from tumor cell demise

“…A variety of cancer cells can drive malignant growth through prostaglandin E2 (PGE2) synthesis by cyclooxygenase (COX), which provokes inflammation in the TME while subverting type I immune response against cancer . PGE2 can be induced and released upon various forms of cell death, effectively serving as an additional immunosuppressive DAMP . Therefore, Mincle blockade or COX inhibition may provide synergistic benefits to cytotoxic cancer therapies.…”