title: Failure of mycoplasma lipoprotein MALP-2 to induce NK cell activation through dendritic cell TLR2.
abstract: Macrophage-activating lipopeptide 2 (MALP-2), a mycoplasmal diacylated lipopeptide with palmitic acid moiety (Pam2), activates Toll-like receptor (TLR) 2 to induce inflammatory cytokines. TLR2 is known to mature myeloid dendritic cells (mDC) to drive mDC contact-mediated natural killer (NK) cell activation. Here we tested if MALP-2 activates NK cells through stimulation of TLR2 on mDC. Although synthetic MALP-2 with 6 or 14 amino acids (a.a.) stretch (designated as s and f) matured mDC to induce IL-6, IL-12p40 and TNF-α to a similar extent, they far less activated NK cells than Pam2CSK4, a positive control of 6 a.a.-containing diacyl lipopeptide. MALP-2s and f were TLR2/6 agonists and activate the MyD88 pathway similar to Pam2CSK4, but MALP-2s having the CGNNDE sequence acted on mDC TLR2 to barely induce external NK activation. Even the s form, with slightly high induction of IL-6 compared to the f form, barely induced in vivo growth retardation of NK-sensitive implant tumor. Pam2CSK4 and MALP-2 have the common lipid moiety but different peptides, which are crucial for NK cell activation. The results infer that MALP-2 is applicable to a cytokine inducer but not to an adjuvant for antitumor NK immunotherapy.
authors.affiliation: Department of Microbiology and Immunology, Graduate School of Medicine, Hokkaido University, N-15 W-7, Kita-ku, Sapporo 060-8638,Japan.
authors.forename: Ryoko
authors.initials: R
authors.lastname: Sawahata
authors.forename: Hiroaki
authors.initials: H
authors.lastname: Shime
authors.forename: Sayuri
authors.initials: S
authors.lastname: Yamazaki
authors.forename: Norimitsu
authors.initials: N
authors.lastname: Inoue
authors.forename: Takashi
authors.initials: T
authors.lastname: Akazawa
authors.forename: Yukari
authors.initials: Y
authors.lastname: Fujimoto
authors.forename: Koichi
authors.initials: K
authors.lastname: Fukase
authors.forename: Misako
authors.initials: M
authors.lastname: Matsumoto
authors.forename: Tsukasa
authors.initials: T
authors.lastname: Seya
mesh_terms: D000818:Animals; D000970:Antineoplastic Agents / Q000493:pharmacokinetics*; D002454:Cell Differentiation / Q000187:drug effects; D045744:Cell Line, Tumor; D003713:Dendritic Cells / Q000166:cytology / Q000187:drug effects*; D005260:Female; D057809:HEK293 Cells; D006801:Humans; D007694:Killer Cells, Natural / Q000187:drug effects*; D055666:Lipopeptides / Q000494:pharmacology*; D008213:Lymphocyte Activation / Q000187:drug effects*; D008546:Melanoma, Experimental / Q000503:physiopathology; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D009174:Mycoplasma / Q000737:chemistry; D053594:Myeloid Differentiation Factor 88 / Q000378:metabolism; D051195:Toll-Like Receptor 2 / Q000276:immunology*; D051216:Toll-Like Receptor 6 / Q000276:immunology; D014183:Transplantation, Heterologous
chemical_list: D000970:Antineoplastic Agents; D055666:Lipopeptides; D053594:Myeloid Differentiation Factor 88; C552442:S-(2,3-bis(palmitoyloxy)propyl)cysteine; D051195:Toll-Like Receptor 2; D051216:Toll-Like Receptor 6; C106335:macrophage stimulatory lipopeptide 2