title: MPLA shows attenuated pro-inflammatory properties and diminished capacity to activate mast cells in comparison with LPS.
abstract: BACKGROUND
  Monophosphoryl lipid A (MPLA), a nontoxic TLR4 ligand derived from lipopolysaccharide (LPS), is used clinically as an adjuvant in cancer, hepatitis, and malaria vaccines and in allergen-specific immunotherapy. Nevertheless, its cell-activating effects have not been analyzed in a comprehensive direct comparison including a wide range of different immune cells. Therefore, the objective of this study was the side-by-side comparison of the immune-modulating properties of MPLA and LPS on different immune cells.
  
  
  METHODS
  Immune-activating properties of MPLA and LPS were compared in human monocytes and mast cells (MCs), a mouse endotoxin shock model (ESM), and mouse bone marrow (BM)-derived myeloid dendritic cells (mDCs), T cells (TCs), B cells, and MCs.
  
  
  RESULTS
  In a mouse in vivo ESM and a human ex vivo monocyte activation test (MAT), MPLA induced the same cytokine secretion pattern as LPS (ESM: IL-6, IL-12, TNF-α; MAT: IL-1β, IL-6, TNF-α), albeit at lower levels. Mouse mDCs and ex vivo isolated B cells stimulated with MPLA required a higher threshold to induce TRIF-dependent cytokine secretion (IL-1β, IL-6, IL-10, and TNF-α) than did LPS-stimulated cells. In mDC:DO11.10 CD4 TC cocultures, stimulation with MPLA, but not with LPS, resulted in enhanced OVA-specific IL-4 and IL-5 secretion from DO11.10 CD4 TCs. Unexpectedly, in both human and mouse MCs, MPLA, unlike LPS, did not elicit secretion of pro-inflammatory cytokines.
  
  
  CONCLUSIONS
  Compared to LPS, MPLA induced a qualitatively similar, but less potent pro-inflammatory immune response, but was unable to activate human or mouse MCs.
authors.affiliation: Vice President's Research Group 1: Molecular Allergology, Paul-Ehrlich-Institut, Langen, Germany.
authors.forename: S
authors.initials: S
authors.lastname: Schülke
authors.affiliation: Vice President's Research Group 1: Molecular Allergology, Paul-Ehrlich-Institut, Langen, Germany.
authors.forename: A
authors.initials: A
authors.lastname: Flaczyk
authors.affiliation: Division of Allergology, Paul-Ehrlich-Institut, Langen, Germany.
authors.forename: L
authors.initials: L
authors.lastname: Vogel
authors.affiliation: Department of Pathology, Stanford University School of Medicine, Stanford, CA, USA.
authors.forename: N
authors.initials: N
authors.lastname: Gaudenzio
authors.affiliation: Research Institute of the McGill University Health Center, Montréal, QC, Canada.
authors.forename: I
authors.initials: I
authors.lastname: Angers
authors.affiliation: Division of Microbiology, Paul-Ehrlich-Institut, Langen, Germany.
authors.forename: B
authors.initials: B
authors.lastname: Löschner
authors.affiliation: Vice President's Research Group 1: Molecular Allergology, Paul-Ehrlich-Institut, Langen, Germany.
authors.forename: S
authors.initials: S
authors.lastname: Wolfheimer
authors.affiliation: Division of Microbiology, Paul-Ehrlich-Institut, Langen, Germany.
authors.forename: I
authors.initials: I
authors.lastname: Spreitzer
authors.affiliation: Research Institute of the McGill University Health Center, Montréal, QC, Canada.|Department of Medicine, McGill University, Montréal, QC, Canada.
authors.forename: S
authors.initials: S
authors.lastname: Qureshi
authors.affiliation: Department of Pathology, Stanford University School of Medicine, Stanford, CA, USA.
authors.forename: M
authors.initials: M
authors.lastname: Tsai
authors.affiliation: Department of Pathology, Stanford University School of Medicine, Stanford, CA, USA.
authors.forename: S
authors.initials: S
authors.lastname: Galli
authors.affiliation: Vice President's Research Group 1: Molecular Allergology, Paul-Ehrlich-Institut, Langen, Germany.
authors.forename: S
authors.initials: S
authors.lastname: Vieths
authors.affiliation: Vice President's Research Group 1: Molecular Allergology, Paul-Ehrlich-Institut, Langen, Germany.
authors.forename: S
authors.initials: S
authors.lastname: Scheurer
mesh_terms: D033942:Adaptor Proteins, Vesicular Transport / Q000235:genetics / Q000378:metabolism; D000818:Animals; D000941:Antigens / Q000276:immunology; D001402:B-Lymphocytes / Q000276:immunology / Q000378:metabolism; D016207:Cytokines / Q000096:biosynthesis; D003713:Dendritic Cells / Q000187:drug effects / Q000276:immunology / Q000378:metabolism; D004195:Disease Models, Animal; D004847:Epithelial Cells / Q000378:metabolism; D006801:Humans; D018836:Inflammation Mediators / Q000378:metabolism; D008050:Lipid A / Q000031:analogs & derivatives* / Q000276:immunology / Q000494:pharmacology; D008070:Lipopolysaccharides / Q000276:immunology* / Q000494:pharmacology; D008407:Mast Cells / Q000187:drug effects / Q000276:immunology* / Q000378:metabolism*; D051379:Mice; D018345:Mice, Knockout; D009000:Monocytes / Q000187:drug effects / Q000276:immunology / Q000378:metabolism; D012772:Shock, Septic / Q000235:genetics / Q000276:immunology / Q000378:metabolism; D018418:Th2 Cells / Q000276:immunology / Q000378:metabolism
chemical_list: D033942:Adaptor Proteins, Vesicular Transport; D000941:Antigens; D016207:Cytokines; D018836:Inflammation Mediators; D008050:Lipid A; D008070:Lipopolysaccharides; C476286:Ticam1 protein, mouse; C048436:monophosphoryl lipid A
keywords: adjuvant; allergy; lipopolysaccharide; mast cells; monophosphoryl lipid A