title: IL-6 promotes an increase in human mast cell numbers and reactivity through suppression of suppressor of cytokine signaling 3.
abstract: IL-6, levels of which are reported to be increased in association with mastocytosis, asthma, and urticaria, is used in conjunction with stem cell factor to generate CD34(+) cell-derived primary human mast cell (HuMC) cultures. Despite these associations, the effects on and mechanisms by which prolonged exposure to IL-6 alters HuMC numbers and function are not well understood.
  
  
  
  We sought to study the effect of IL-6 on HuMC function, the mechanisms by which IL-6 exerts its effects, and the relationship of these findings to mastocytosis.
  
  
  
  HuMCs were cultured in stem cell factor with or without IL-6. Responses to FcεRI aggregation and expression of proteases and receptors, including the soluble IL-6 receptor (sIL-6R), were then quantitated. Epigenetic changes in suppressor of cytokine signaling 3 (SOCS3) were determined by using methylation-specific PCR. Serum samples from healthy control subjects and patients with mastocytosis were assayed for IL-6, tryptase, and sIL-6R.
  
  
  
  IL-6 enhanced mast cell (MC) proliferation, maturation, and reactivity after FcεRI aggregation. IL-6 reduced expression of SOCS3, which correlated with methylation of the SOCS3 promoter and increased expression and activation of signal transducer and activator of transcription 3. IL-6 also suppressed constitutive production of sIL-6R, and serum levels of sIL-6R were similarly reduced in patients with mastocytosis.
  
  
  
  IL-6 increases MC proliferation and formation of a more reactive phenotype enabled by suppressing proteolytic cleavage of sIL-6R from IL-6R and downregulation of the SOCS3 autoinhibitory pathway. We suggest IL-6 blockade might ameliorate MC-related symptoms and pathology in patients with MC-related diseases associated with increased IL-6 levels, including mastocytosis.
authors.affiliation: Laboratory of Allergic Diseases, National Institutes of Allergy and Infectious Diseases, Bethesda, Md. Electronic address: avanti.desai@nih.gov.
authors.forename: Avanti
authors.initials: A
authors.lastname: Desai
authors.affiliation: Laboratory of Allergic Diseases, National Institutes of Allergy and Infectious Diseases, Bethesda, Md.
authors.forename: Mi-Yeon
authors.initials: MY
authors.lastname: Jung
authors.affiliation: Laboratory of Allergic Diseases, National Institutes of Allergy and Infectious Diseases, Bethesda, Md.
authors.forename: Ana
authors.initials: A
authors.lastname: Olivera
authors.affiliation: Laboratory of Allergic Diseases, National Institutes of Allergy and Infectious Diseases, Bethesda, Md.
authors.forename: Alasdair M
authors.initials: AM
authors.lastname: Gilfillan
authors.affiliation: Laboratory of Allergic Diseases, National Institutes of Allergy and Infectious Diseases, Bethesda, Md.
authors.forename: Calman
authors.initials: C
authors.lastname: Prussin
authors.affiliation: Laboratory of Allergic Diseases, National Institutes of Allergy and Infectious Diseases, Bethesda, Md.
authors.forename: Arnold S
authors.initials: AS
authors.lastname: Kirshenbaum
authors.affiliation: Laboratory of Molecular Immunology, National Heart, Lung, and Blood Institute, National Institutes of Health, Bethesda, Md.
authors.forename: Michael A
authors.initials: MA
authors.lastname: Beaven
authors.affiliation: Laboratory of Allergic Diseases, National Institutes of Allergy and Infectious Diseases, Bethesda, Md.
authors.forename: Dean D
authors.initials: DD
authors.lastname: Metcalfe
mesh_terms: D002452:Cell Count; D049109:Cell Proliferation / Q000187:drug effects; D053818:Chymases / Q000378:metabolism; D019175:DNA Methylation; D006801:Humans; D015850:Interleukin-6 / Q000378:metabolism* / Q000494:pharmacology; D008407:Mast Cells / Q000187:drug effects / Q000276:immunology* / Q000378:metabolism*; D010766:Phosphorylation; D011401:Promoter Regions, Genetic; D011485:Protein Binding; D019009:Proto-Oncogene Proteins c-kit / Q000378:metabolism; D017455:Receptors, IgE / Q000378:metabolism; D019947:Receptors, Interleukin-6 / Q000378:metabolism; D015398:Signal Transduction / Q000187:drug effects; D000071223:Suppressor of Cytokine Signaling 3 Protein / Q000378:metabolism*
chemical_list: D015850:Interleukin-6; D017455:Receptors, IgE; D019947:Receptors, Interleukin-6; D000071223:Suppressor of Cytokine Signaling 3 Protein; D019009:Proto-Oncogene Proteins c-kit; D053818:Chymases
keywords: IL-6; Mast cells; mastocytosis; signal transducer and activator of transcription 3; stem cell factor; suppressor of cytokine signaling 3