title: Novel role for the N-terminus domain of the a2 isoform of vacuolar ATPase in interleukin-1beta production.
abstract: Interleukin-1beta (IL-1beta) is a mediator cytokine that is released by macrophages and epithelial cells in pregnancy and tumorigenesis before antigen recognition. a2V-ATPase is a protein expressed during pregnancy and tumorigenesis and has a novel role in immune regulation. It is expressed as a 70 kDa molecule in intracellular vesicles. Upon cell stimulation it migrates to the surface followed by the cleavage of a 20 kDa portion (a2 N-terminus domain, a2NTD). This study aimed to determine whether a2NTD could induce IL-1beta production in immune cells. Peripheral blood mononuclear cells (PMBC) were stimulated with a2NTD and analyzed for cytokine gene expression by gene arrays. Supernatants were analyzed for IL-1beta by enzyme-linked immunosorbent assay, and cells were analyzed for intracellular expression of IL-1alpha, IL-1beta, and TNF-alpha by flow cytometry. When PBMC were cultured with a2NTD, there was a 2.5-fold increase in IL1A and IL1B gene expression and no induction of TNF gene expression. There was a 72-fold increase in IL-1beta in supernatants of PBMC cultured with a2NTD. Finally, there was a 204-fold increase in intracellular expression of IL-1beta in monocytes incubated with a2NTD. These results indicate a regulatory role for a2NTD in IL-1 cytokine production and suggest a unique role for this molecule in inflammation.
authors.affiliation: Clinical Immunology Laboratory, Rosalind Franklin University of Medicine and Science, North Chicago, IL, USA.
authors.forename: Evangelos
authors.initials: E
authors.lastname: Ntrivalas
authors.forename: Richard
authors.initials: R
authors.lastname: Derks
authors.forename: Alice
authors.initials: A
authors.lastname: Gilman-Sachs
authors.forename: Joanne
authors.initials: J
authors.lastname: Kwak-Kim
authors.forename: Rita
authors.initials: R
authors.lastname: Levine
authors.forename: Kenneth
authors.initials: K
authors.lastname: Beaman
mesh_terms: D006801:Humans; D053583:Interleukin-1beta / Q000378:metabolism*; D007527:Isoenzymes / Q000378:metabolism; D007963:Leukocytes, Mononuclear / Q000166:cytology / Q000187:drug effects / Q000378:metabolism*; D017434:Protein Structure, Tertiary; D021122:Protein Subunits / Q000378:metabolism; D025262:Vacuolar Proton-Translocating ATPases / Q000378:metabolism*
chemical_list: D053583:Interleukin-1beta; D007527:Isoenzymes; D021122:Protein Subunits; D025262:Vacuolar Proton-Translocating ATPases