title: Ability of Interleukin-33- and Immune Complex-Triggered Activation of Human Mast Cells to Down-Regulate Monocyte-Mediated Immune Responses.
abstract: OBJECTIVE
  Mast cells have been implicated in the pathogenesis of rheumatoid arthritis (RA). In particular, their activation by interleukin-33 (IL-33) has been linked to the development of arthritis in animal models. The aim of this study was to evaluate the functional responses of human mast cells to IL-33 in the context of RA.
  
  
  METHODS
  Human mast cells were stimulated with IL-33 combined with plate-bound IgG or IgG anti-citrullinated protein antibodies (ACPAs), and their effects on monocyte activation were evaluated. Cellular interactions of mast cells in RA synovium were assessed by immunofluorescence analysis, and the expression of messenger RNA (mRNA) for mast cell-specific genes was evaluated in synovial biopsy tissue from patients with early RA who were naive to treatment with disease-modifying antirheumatic drugs.
  
  
  RESULTS
  IL-33 induced the up-regulation of Fcγ receptor type IIa and enhanced the activation of mast cells by IgG, including IgG ACPAs, as indicated by the production of CXCL8/IL-8. Intriguingly, mast cell activation triggered with IL-33 and IgG led to the release of mediators such as histamine and IL-10, which inhibited monocyte activation. Synovial mast cells were found in contact with CD14+ monocyte/macrophages. Finally, mRNA levels of mast cell-specific genes were inversely associated with disease severity, and IL-33 mRNA levels showed an inverse correlation with the levels of proinflammatory markers.
  
  
  CONCLUSIONS
  When human mast cells are activated by IL-33, an immunomodulatory phenotype develops, with human mast cells gaining the ability to suppress monocyte activation via the release of IL-10 and histamine. These findings, together with the presence of synovial mast cell-monocyte interactions and the inverse association between the expression of mast cell genes at the synovial level and disease activity, suggest that these newly described mast cell-mediated inhibitory pathways might have a functional relevance in the pathogenesis of RA.
authors.affiliation: Leiden University Medical Center, Leiden, The Netherlands, University of Naples Federico II, Naples, Italy, and William Harvey Research Institute and Barts and The London School of Medicine and Dentistry, Queen Mary University of London, London, UK.
authors.forename: Felice
authors.initials: F
authors.lastname: Rivellese
authors.affiliation: Leiden University Medical Center, Leiden, The Netherlands.
authors.forename: Jolien
authors.initials: J
authors.lastname: Suurmond
authors.affiliation: Leiden University Medical Center, Leiden, The Netherlands.
authors.forename: Kim
authors.initials: K
authors.lastname: Habets
authors.affiliation: Leiden University Medical Center, Leiden, The Netherlands.
authors.forename: Annemarie L
authors.initials: AL
authors.lastname: Dorjée
authors.affiliation: Genentech Research and Early Development, South San Francisco, California.
authors.forename: Nandhini
authors.initials: N
authors.lastname: Ramamoorthi
authors.affiliation: Genentech Research and Early Development, South San Francisco, California.
authors.forename: Michael J
authors.initials: MJ
authors.lastname: Townsend
authors.affiliation: University of Naples Federico II, Naples, Italy.
authors.forename: Amato
authors.initials: A
authors.lastname: de Paulis
authors.affiliation: University of Naples Federico II, Naples, Italy.
authors.forename: Gianni
authors.initials: G
authors.lastname: Marone
authors.affiliation: Leiden University Medical Center, Leiden, The Netherlands.
authors.forename: Tom W J
authors.initials: TW
authors.lastname: Huizinga
authors.affiliation: William Harvey Research Institute and Barts and The London School of Medicine and Dentistry, Queen Mary University of London, London, UK.
authors.forename: Costantino
authors.initials: C
authors.lastname: Pitzalis
authors.affiliation: Leiden University Medical Center, Leiden, The Netherlands.
authors.forename: René E M
authors.initials: RE
authors.lastname: Toes
mesh_terms: D000328:Adult; D000368:Aged; D000936:Antigen-Antibody Complex / Q000276:immunology*; D001172:Arthritis, Rheumatoid / Q000276:immunology*; D001323:Autoantibodies / Q000276:immunology; D015536:Down-Regulation; D005260:Female; D015870:Gene Expression / Q000187:drug effects / Q000276:immunology; D006636:Histamine Release; D006801:Humans; D016753:Interleukin-10 / Q000276:immunology / Q000378:metabolism; D000067596:Interleukin-33; D016209:Interleukin-8 / Q000187:drug effects / Q000276:immunology; D007378:Interleukins / Q000276:immunology / Q000494:pharmacology*; D008264:Macrophages / Q000187:drug effects / Q000276:immunology; D008297:Male; D008407:Mast Cells / Q000187:drug effects* / Q000276:immunology / Q000378:metabolism; D008875:Middle Aged; D009000:Monocytes / Q000187:drug effects* / Q000276:immunology; D010456:Peptides, Cyclic; D012333:RNA, Messenger / Q000187:drug effects* / Q000378:metabolism; D017452:Receptors, IgG / Q000187:drug effects / Q000276:immunology; D013583:Synovial Membrane / Q000276:immunology; D015854:Up-Regulation
chemical_list: D000936:Antigen-Antibody Complex; D001323:Autoantibodies; C508606:CXCL8 protein, human; C445323:FCGR2A protein, human; C508609:IL10 protein, human; C506536:IL33 protein, human; D000067596:Interleukin-33; D016209:Interleukin-8; D007378:Interleukins; D010456:Peptides, Cyclic; D012333:RNA, Messenger; D017452:Receptors, IgG; C487763:cyclic citrullinated peptide; D016753:Interleukin-10