Abstract
Dying or damaged cells that are not completely eradicated by the immune system release their intracellular components in the extracellular space. Aberrant exposure of the damage-associated molecules to the immune system is often associated with inflammation and cancer pathogenesis. Thus, elucidating the role of damage-associated molecules in inducing sterile immune responses is crucial. In this study, we show that prostaglandin E2 (PGE2) is produced in the supernatants from several types of canine necrotic tumor cell lines. Inhibition of PGE2 production by indomethacin, a potent inhibitor of cyclooxygenase (COX) enzymes, induces the expression of tumor necrosis factor (Tnf) mRNA in the necrotic tumor cell supernatants. These results comply with the previous observations reported in mouse cell lines. Furthermore, comprehensive ribonucleic acid-sequencing (RNA-seq) analysis revealed that three categories of genes were induced by the damage-associated molecules: (i) a group of PGE2-inducible genes, (ii) genes that promote inflammation and are suppressed by PGE2, and (iii) a group of genes not suppressed by PGE2. Collectively, our findings reveal the hitherto unknown immune regulatory system by PGE2 and damage-associated molecules, which may have clinical implications in inflammation and cancer.
Highlights
Dying or damaged cells that are not completely eradicated by the immune system release their intracellular components in the extracellular space
Several damage-associated molecules have been identified, we unexpectedly found that the supernatants from necrotic dead cells did not induce the tumor necrosis factor-α (TNF-α), a potent pro-inflammatory cytokine induced by the Tolllike receptors (TLRs) activation in peritoneal m acrophages[7]
The 11 canine tumor cell lines comprised of two breast cancer (CHMm and CTBm), three urothelial cell carcinoma (Sora, Love, Nene), three malignant melanoma (KMeC, Pu, LMeC), and three osteosarcoma (HOS, OOS, HMPOS) cell lines
Summary
Dying or damaged cells that are not completely eradicated by the immune system release their intracellular components in the extracellular space. Inhibition of PGE2 production by indomethacin, a potent inhibitor of cyclooxygenase (COX) enzymes, induces the expression of tumor necrosis factor (Tnf) mRNA in the necrotic tumor cell supernatants. These results comply with the previous observations reported in mouse cell lines. Various types of immune-activating damage-associated molecules have been identified, including high-mobility group box protein 1 (HMGB1), heat shock proteins (HSPs), S100 proteins (calcium-binding cytosolic proteins), interleukin (IL)-1A, IL-33, nucleic acids (NAs), adenosine triphosphate (ATP), and uric acids[3,4,5,6] Some of these are recognized by the TLRs and reportedly induce sterile inflammation[4].
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