title: 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.
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.
authors.affiliation: Department of Clinical Immunology and Rheumatology, Hannover Medical School, Carl-Neuberg-Str. 1, 30625, Hannover, Germany.
authors.forename: Christina
authors.initials: C
authors.lastname: Müller
authors.forename: Dejene M
authors.initials: DM
authors.lastname: Tufa
authors.forename: Debanjana
authors.initials: D
authors.lastname: Chatterjee
authors.forename: Peter F
authors.initials: PF
authors.lastname: Mühlradt
authors.forename: Reinhold E
authors.initials: RE
authors.lastname: Schmidt
authors.forename: Roland
authors.initials: R
authors.lastname: Jacobs
mesh_terms: D002478:Cells, Cultured; D052246:Cyclooxygenase 2 Inhibitors / Q000276:immunology / Q000494:pharmacology*; D015232:Dinoprostone / Q000037:antagonists & inhibitors* / Q000096:biosynthesis / Q000276:immunology; D006801:Humans; D007694:Killer Cells, Natural / Q000187:drug effects* / Q000276:immunology; D055666:Lipopeptides / Q000276:immunology / Q000494:pharmacology*; D009000:Monocytes / Q000187:drug effects* / Q000276:immunology; D015398:Signal Transduction; D051195:Toll-Like Receptor 2 / Q000819:agonists*; D051216:Toll-Like Receptor 6 / Q000819:agonists*
chemical_list: D052246:Cyclooxygenase 2 Inhibitors; D055666:Lipopeptides; C495342:TLR2 protein, human; C495368:TLR6 protein, human; D051195:Toll-Like Receptor 2; D051216:Toll-Like Receptor 6; C106335:macrophage stimulatory lipopeptide 2; D015232:Dinoprostone