A murine cellular model of necroinflammation displays RAGE-dependent cytokine induction that connects to hepatoma cell injury.

Abstract

Unresolved inflammation maintained by release of danger-associated molecular patterns, particularly high-mobility group box-1 (HMGB1), is crucial for hepatocellular carcinoma (HCC) pathogenesis. To further characterize interactions between leucocytes and necrotic cancerous tissue, a cellular model of necroinflammation was studied in which murine Raw 264.7 macrophages or primary splenocytes were exposed to necrotic lysates (N-lys) of murine hepatoma cells or primary hepatocytes. In comparison to those derived from primary hepatocytes, N-lys from hepatoma cells were highly active-inducing in macrophages efficient expression of inflammatory cytokines like C-X-C motif ligand-2 , tumor necrosis factor-α, interleukin (IL)-6 and IL-23-p19. This activity associated with higher levels of HMGB1 in hepatoma cells and was curbed by pharmacological blockage of the receptor for advanced glycation end product (RAGE)/HMGB1 axis or the mitogen-activated protein kinases ERK1/2 pathway. Analysis of murine splenocytes furthermore demonstrated that N-lys did not comprise of functionally relevant amounts of TLR4 agonists. Finally, N-lys derived from hepatoma cells supported inflammatory splenic Th17 and Th1 polarization as detected by IL-17, IL-22 or interferon-γ production. Altogether, a straightforward applicable model was established which allows for biochemical characterization of immunoregulation by HCC necrosis in cell culture. Data presented indicate a remarkably inflammatory capacity of necrotic hepatoma cells that, at least partly, depends on the RAGE/HMGB1 axis and may shape immunological properties of the HCC microenvironment.

• Authors: Malte Bachmann, Laura Lamprecht, Sina Gonther, Josef Pfeilschifter, Heiko Mühl
• Journal: Journal of cellular and molecular medicine (J Cell Mol Med) Vol. 24 Issue 18 Pg. 10356-10366 (09 2020) ISSN: 1582-4934 [Electronic] England
• PMID: 32697038 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't)
• Copyright: © 2020 The Authors. Journal of Cellular and Molecular Medicine published by Foundation for Cellular and Molecular Medicine and John Wiley & Sons Ltd.

Chemical References

• Cytokines
• Receptor for Advanced Glycation End Products

Topics

• Animals
• Carcinoma, Hepatocellular (immunology, metabolism, pathology)
• Cytokines (metabolism)
• Humans
• Immunomodulation
• Inflammation (pathology)
• Liver Neoplasms (immunology, metabolism, pathology)
• MAP Kinase Signaling System
• Macrophage Activation
• Macrophages (metabolism)
• Male
• Mice
• Mice, Inbred C57BL
• Models, Biological
• Necrosis
• RAW 264.7 Cells
• Receptor for Advanced Glycation End Products (metabolism)
• Spleen (pathology)