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01-09-2015 | Original Article

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

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

Published in: Cancer Immunology, Immunotherapy | Issue 9/2015

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.

Embree J, Embil J (1980) Mycoplasmas in diseases of humans. Can Med Assoc J 123:105–111PubMedCentralPubMed

Cunha CB (2010) The first atypical pneumonia: the history of the discovery of Mycoplasma pneumoniae. Infect Dis Clin North Am 24:1–5CrossRefPubMed

Viscardi R, Hasday J (2009) Role of Ureaplasma species in neonatal chronic lung disease: epidemiologic and experimental evidence. Pediatr Res 65:84R–90RPubMedCentralCrossRefPubMed

Hartmann M (2009) Genital mycoplasmas. J Dtsch Dermatol Ges 7:371–377PubMed

McGowin CL, Annan RS, Quayle AJ et al (2012) Persistent Mycoplasma genitalium infection of human endocervical epithelial cells elicits chronic inflammatory cytokine secretion. Infect Immun 80:3842–3849PubMedCentralCrossRefPubMed

Yang J, Hooper W (2002) Regulation of proinflammatory cytokines in human lung epithelial cells infected with Mycoplasma pneumoniae. Infect Immun 70:3649–3655PubMedCentralCrossRefPubMed

Huang S, Li J, Wu J (2001) Mycoplasma infections and different human carcinomas. World J Gastroenterol 7:266–269PubMed

Manhart LE, Mostad SB, Baeten JM et al (2008) High Mycoplasma genitalium organism burden is associated with shedding of HIV-1 DNA from the cervix. J Infect Dis 197:733–736PubMedCentralCrossRefPubMed

Schneider C (2004) Tumour suppression induced by the macrophage activating lipopeptide MALP-2 in an ultrasound guided pancreatic carcinoma mouse model. Gut 53:355–361PubMedCentralCrossRefPubMed

10.

Shingu K, Kruschinski C, Lührmann A et al (2003) Intratracheal macrophage-activating lipopeptide-2 reduces metastasis in the rat lung. Am J Respir Cell Mol Biol 28:316–321CrossRefPubMed

11.

Schmidt J, Welsch T, Jäger D et al (2007) Intratumoural injection of the toll-like receptor-2/6 agonist “macrophage-activating lipopeptide-2” in patients with pancreatic carcinoma: a phase I/II trial. Br J Cancer 97:598–604PubMedCentralCrossRefPubMed

12.

Kaufmann A, Mühlradt PF, Gemsa D, Sprenger H (1999) Induction of cytokines and chemokines in human monocytes by Mycoplasma fermentans-derived lipoprotein MALP-2. Infect Immun 67:6303–6308PubMedCentralPubMed

13.

Mühlradt PF, Kiess M, Meyer H et al (1997) Isolation, structure elucidation, and synthesis of a macrophage stimulatory lipopeptide from Mycoplasma fermentans acting at picomolar concentration. J Exp Med 185:1951–1958PubMedCentralCrossRefPubMed

14.

Takeuchi O, Kawai T, Mühlradt P (2001) Discrimination of bacterial lipoproteins by Toll-like receptor 6. Int Immunol 13:933–940CrossRefPubMed

15.

Garcia J (1998) A Mycoplasma fermentans-derived synthetic lipopeptide induces AP-1 and NF-kB activity and cytokine secretion in macrophages via the activation of mitogen-activated protein kinase pathways. J Biol Chem 273:34391–34398CrossRefPubMed

16.

Deiters U, Mühlradt P (1999) Mycoplasmal lipopeptide MALP-2 induces the chemoattractant proteins macrophage inflammatory protein 1α (MIP-1α), monocyte chemoattractant protein 1, and MIP-2 and promotes leukocyte infiltration in mice. Infect Immun 67:3390–3398PubMedCentralPubMed

17.

Link C, Gavioli R, Ebensen T et al (2004) The Toll-like receptor ligand MALP-2 stimulates dendritic cell maturation and modulates proteasome composition and activity. Eur J Immunol 34:899–907CrossRefPubMed

18.

Shimizu T, Kida Y, Kuwano K (2005) A dipalmitoylated lipoprotein from Mycoplasma pneumoniae activates NF-kB through TLR1, TLR2, and TLR6. J Immunol 175:4641–4646CrossRefPubMed

19.

Jacobs R, Hintzen G, Kemper A et al (2001) CD56^bright cells differ in their KIR repertoire and cytotoxic features from CD56^dim NK cells. Eur J Immunol 31:3121–3127CrossRefPubMed

20.

Adib-Conquy M, Scott-Algara D, Cavaillon J-M, Souza-Fonseca-Guimaraes F (2014) TLR-mediated activation of NK cells and their role in bacterial/viral immune responses in mammals. Immunol Cell Biol 92:256–262CrossRefPubMed

21.

Sawahata R, Shime H, Yamazaki S et al (2011) Failure of mycoplasma lipoprotein MALP-2 to induce NK cell activation through dendritic cell TLR2. Microbes Infect 13:350–358CrossRefPubMed

22.

Akao Y, Ebihara T, Masuda H et al (2009) Enhancement of antitumor natural killer cell activation by orally administered Spirulina extract in mice. Cancer Sci 100:1494–1501CrossRefPubMed

23.

Azuma M, Sawahata R, Akao Y et al (2010) The peptide sequence of diacyl lipopeptides determines dendritic cell TLR2-mediated NK activation. PLoS ONE 5:1–12CrossRef

24.

Ma X, You X, Zeng Y et al (2013) Mycoplasma fermentans MALP-2 induces heme oxygenase-1 expression via mitogen-activated protein kinases and Nrf2 pathways to modulate cyclooxygenase 2 expression in human monocytes. Clin Vaccine Immunol 20:827–834PubMedCentralCrossRefPubMed

25.

Knorr C, Marks D, Gerstberger R et al (2010) Peripheral and central cyclooxygenase (COX) products may contribute to the manifestation of brain-controlled sickness responses during localized inflammation induced by macrophage-activating lipopeptide-2 (MALP-2). Neurosci Lett 479:107–111CrossRefPubMed

26.

Choy H, Milas L (2003) Enhancing radiotherapy with cyclooxygenase-2 enzyme inhibitors: a rational advance? J Natl Cancer Inst 95:1440–1452CrossRefPubMed

27.

Simmons D, Botting R, Hla T (2004) Cyclooxygenase isozymes: the biology of prostaglandin synthesis and inhibition. Pharmacol Rev 56:387–437CrossRefPubMed

28.

Van Elssen CH, Vanderlocht J, Oth T et al (2011) Inflammation restraining effects of prostaglandin E2 on natural killer–dendritic cell (NK–DC) interaction are imprinted during DC maturation. Blood 118:2473–2482CrossRefPubMed

29.

Chatterjee D, Marquardt N, Tufa D et al (2014) Role of gamma-secretase in human umbilical-cord derived mesenchymal stem cell mediated suppression of NK cell cytotoxicity. Cell Commun Signal 12:63PubMedCentralCrossRefPubMed

30.

Tufa DM, Chatterjee D, Low HZ et al (2014) TNFR2 and IL-12 coactivation enables slanDCs to support NK-cell function via membrane-bound TNF-α. Eur J Immunol 44:3717–3728CrossRefPubMed

31.

Morr M, Takeuchi O, Akira S (2002) Differential recognition of structural details of bacterial lipopeptides by toll like receptors. Eur J Immunol 32:3337–3347CrossRefPubMed

32.

Schmidt R, MacDermott R, Bartley G (1985) Specific release of proteoglycans from human natural killer cells during target lysis. Nature 318:289–291CrossRefPubMed

33.

Bryant J, Day R (1992) Calculation of lytic units for the expression of cell-mediated cytotoxicity. J Immunol Methods 146:91–103CrossRefPubMed

34.

Maghazachi AA, Al-aoukaty A (1998) Chemokines activate natural killer cells through heterotrimeric G-proteins : implications for the treatment of AIDS and cancer. FASEB J 12:913–924PubMed

35.

Hornung V, Rothenfusser S, Britsch S et al (2002) Quantitative expression of toll-like receptor 1–10 mRNA in cellular subsets of human peripheral blood mononuclear cells and sensitivity to CpG oligodeoxynucleotides. J Immunol 168:4531–4537CrossRefPubMed

36.

Akazawa T, Ohashi T, Nakajima H et al (2014) Development of a dendritic cell-targeting lipopeptide as an immunoadjuvant that inhibits tumor growth without inducing local inflammation. Int J Cancer 135:2847–2856CrossRefPubMed

37.

De Heer P, Sandel MH, Guertens G et al (2008) Celecoxib inhibits growth of tumors in a syngeneic rat liver metastases model for colorectal cancer. Cancer Chemother Pharmacol 62:811–819PubMedCentralCrossRefPubMed

38.

Khan Z, Khan N, Tiwari RP et al (2011) Biology of COX-2: an application in cancer therapeutics. Curr Drug Targets 12:1082–1093CrossRefPubMed

39.

Sarkar FH, Adsule S, Li Y, Padhye S (2007) Back to the future: COX-2 inhibitors for chemoprevention and cancer therapy. Mini Rev Med Chem 7:599–608CrossRefPubMed

40.

Jinushi M, Komohara Y (2015) Tumor-associated macrophages as an emerging target against tumors: creating a new path from bench to bedside. Biochim Biophys Acta 1855:123–130PubMed

41.

Chanmee T, Ontong P, Konno K, Itano N (2014) Tumor-associated macrophages as major players in the tumor microenvironment. Cancers (Basel) 6:1670–1690CrossRef

42.

Wang W, Bergh A, Damber JE (2005) Cyclooxygenase-2 expression correlates with local chronic inflammation and tumor neovascularization in human prostate cancer. Clin Cancer Res 11:3250–3256CrossRefPubMed

43.

Grote K, Schuett H, Salguero G et al (2010) Toll-like receptor 2/6 stimulation promotes angiogenesis via GM-CSF as a potential strategy for immune defense and tissue regeneration. Blood 115:2543–2552CrossRefPubMed

44.

Deiters U, Barsig J, Tawil B, Mühlradt PF (2004) The macrophage-activating lipopeptide-2 accelerates wound healing in diabetic mice. Exp Dermatol 13:731–739CrossRefPubMed

45.

Martin GM, Stockfleth E (2012) Diclofenac sodium 3% gel for the management of actinic keratosis: 10+ years of cumulative evidence of efficacy and safety. J Drugs Dermatol 11:600–608PubMed

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
Authors: Christina Müller
Dejene M. Tufa
Debanjana Chatterjee
Peter F. Mühlradt
Reinhold E. Schmidt
Roland Jacobs
Publication date: 01-09-2015
Publisher: Springer Berlin Heidelberg
Published in: Cancer Immunology, Immunotherapy / Issue 9/2015
Print ISSN: 0340-7004
Electronic ISSN: 1432-0851
DOI: https://doi.org/10.1007/s00262-015-1723-3

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