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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

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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.

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Abbreviations

AIDS:

Acquired immunodeficiency syndrome

ANOVA:

Analysis of variance

COX:

Cyclooxygenase

ELISA:

Enzyme-linked immunosorbent assay

E:T:

Effector to target

FSC:

Forward scatter

HRP:

Horseradish peroxidase

IFN:

Interferon

IL:

Interleukin

IP:

Interferon-γ-induced protein

LU:

Lytic units

MALP:

Macrophage-activating lipopeptide

MIP:

Macrophage inflammatory protein

NF-κB:

Nuclear factor kappa-light-chain-enhancer of activated B cells

NK:

Natural killer

PBMCs:

Peripheral blood mononuclear cells

PBS:

Phosphate-buffered saline

PG:

Prostaglandin

RPMI:

Roswell Park Memorial Institute

SEM:

Standard error of the mean

SSC:

Side scatter

sTNFR:

Soluble tumor necrosis factor receptor

TLR:

Toll-like receptor

TNF:

Tumor necrosis factor

TNFR:

Tumor necrosis factor receptor

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Acknowledgments

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.

Conflict of interest

The authors have no financial, personal, or professional conflict of interest to declare.

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    Authors and Affiliations

    1. Department of Clinical Immunology and Rheumatology, Hannover Medical School, Carl-Neuberg-Str. 1, 30625, Hannover, Germany

      Christina Müller, Dejene M. Tufa, Debanjana Chatterjee, Reinhold E. Schmidt & Roland Jacobs

    2. MALP-Research, Schubertstrasse 5, 38114, Braunschweig, Germany

      Peter F. Mühlradt

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    1. Christina Müller
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    2. Dejene M. Tufa
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    3. Debanjana Chatterjee
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    4. Peter F. Mühlradt
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    5. Reinhold E. Schmidt
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    6. Roland Jacobs
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    Correspondence to Roland Jacobs.

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    Christina Müller and Dejene M. Tufa have contributed equally to this work.

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    Müller, C., Tufa, D.M., Chatterjee, D. et al. 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. Cancer Immunol Immunother 64, 1175–1184 (2015). https://doi.org/10.1007/s00262-015-1723-3

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