Regulation of dendritic cell interleukin-12 secretion by tumour cell necrosis

H. Kandil, V. Bachy, D. J. Williams, R. Helmi, F. M. Gotch, Mohammad A.A. Ibrahim*

*Corresponding author for this work

Research output: Contribution to journalArticlepeer-review

5 Citations (Scopus)

Abstract

Dendritic cells (DCs) play a key role in the induction and regulation of antigen-specific immunity. Studies have shown that, similar to infection, cellular necrosis can stimulate DC maturation. However, the ability of necrotic cell death to modulate DC cytokine secretion has yet to be explored. We investigated the regulation of interleukin (IL)-12 secretion by human DCs in response to tumour cell necrosis in an in vitro culture model. Two human tumour cell lines (K562 and JAr) were induced to undergo necrosis using heat injury and repeated cycles of freezing and thawing. Both types of tumour cells tested in this study, when injured, induced secretion of monomeric IL-12p40 by monocyte-derived DCs. Furthermore, priming DCs with necrotic cells augmented IL-12p70 secretion significantly in conjunction with CD40 cross-linking. This was physiologically relevant because cell death-pulsed DCs were more potent than non-pulsed DCs at stimulating T cells to proliferate and secrete interferon (IFN)-γ. The Toll-like receptor 4 (TLR4) played a role in mediating the DC response to heat-killed, but not freeze/thaw-killed necrotic cells. For both methods of injury, proteins contributed to the effect of necrosis on dendritic cells, whereas DNA was involved in the effect of freeze/thawed cells only. These findings indicate that necrotic tumour cell death is not sufficient to induce bioactive IL-12p70, the Th1 promoting cytokine, but acts to augment its secretion via the CD40/CD40L pathway. The results also highlight that the mode of cell death may determine the mechanism of dendritic cell stimulation.

Original languageEnglish
Pages (from-to)54-64
Number of pages11
JournalClinical and Experimental Immunology
Volume140
Issue number1
DOIs
Publication statusPublished - Apr 2005

Keywords

  • Apoptosis
  • Cytokines
  • Dendritic cells
  • Human studies
  • Interleukins
  • Toll-like receptors

Fingerprint

Dive into the research topics of 'Regulation of dendritic cell interleukin-12 secretion by tumour cell necrosis'. Together they form a unique fingerprint.

Cite this