The TLR-2/TLR-6 agonist macrophage-activating lipopeptide-2 augments human NK cell cytotoxicity when PGE2 production by monocytes is inhibited by a COX-2 blocker

Christina Müller, Dejene M. Tufa, Debanjana Chatterjee, Peter F. Mühlradt, Reinhold E. Schmidt, Roland Jacobs

Research output: Contribution to journalArticlepeer-review

10 Scopus citations

Abstract

Macrophage-activating lipopeptide-2 (MALP-2) is a potent inducer of proinflammatory cytokine secretion by macrophages, monocytes, and dendritic cells. MALP-2 was reported to be involved in natural killer (NK) cell activation and ensuing tumor rejection. However, the mechanism of MALP-2-mediated NK cell activation remained unclear. Therefore, we studied the effects of MALP-2 on cultured human NK cells. We found that MALP-2 had no direct effect on NK cells. Instead, MALP-2 acted on monocytes and triggered the release of different molecules such as interleukin (IL)-1β, IL-6, IL-10, IL-12, IL-15, interferon gamma-induced protein (IP-10), and prostaglandin (PG)-E2. Our data show that monocyte-derived IP-10 could significantly induce NK cell cytotoxicity as long as the immunosuppression by PGE2 is specifically inhibited by cyclooxygenase (COX)-2 blockade. In summary, our results show that MALP-2-mediated stimulation of monocytes results in the production of several mediators which, depending on the prevailing conditions, affect the activity of NK cells in various ways. Hence, MALP-2 administration with concurrent blocking of COX-2 can be considered as a promising approach in MALP-2-based adjuvant tumor therapies.

Original languageEnglish (US)
Pages (from-to)1175-1184
Number of pages10
JournalCancer Immunology, Immunotherapy
Volume64
Issue number9
DOIs
StatePublished - Sep 21 2015

Bibliographical note

Funding Information:
The authors would like to extend their sincere appreciation to Sabine Buyny for her help with the chromium release assays. This work was supported by grants from the Deutsche Forschungsgemeinschaft (DFG): SFB738/A5, Hannover Biomedical Research School (HBRS), REBIRTH Cluster of Excellence, Niedersächsische Krebsgesellschaft e.V. The funding agencies had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript.

Publisher Copyright:
© 2015, Springer-Verlag Berlin Heidelberg.

Keywords

  • COX-2 upregulation
  • IP-10
  • MALP-2
  • Monocytes
  • NK cell activation
  • PGE2

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