title: Regulation of IL-17A production is distinct from IL-17F in a primary human cell co-culture model of T cell-mediated B cell activation.
abstract: Improper regulation of B cell responses leads to excessive production of antibodies and contributes to the development of autoimmune disease. T helper 17 (Th17) cells also drive the development of autoimmune disease, but the role of B cells in shaping Th17 cell-mediated immune responses, as well as the reciprocal regulation of B cell responses by IL-17 family cytokines, remains unclear. The aim of this study was to characterize the regulation of IL-17A and IL-17F in a model of T cell-dependent B cell activation. Stimulation of primary human B cell and peripheral blood mononuclear cell (BT) co-cultures with α-IgM and a non-mitogenic concentration of superantigens for three days promoted a Th17 cell response as evidenced by increased expression of Th17-related gene transcripts, including Il17f, Il21, Il22, and Il23r, in CD4 T cells, as well as the secretion of IL-17A and IL-17F protein. We tested the ability of 144 pharmacologic modulators representing 91 different targets or pathways to regulate IL-17A and IL-17F production in these stimulated BT co-cultures. IL-17A production was found to be preferentially sensitive to inhibition of the PI3K/mTOR pathway, while prostaglandin EP receptor agonists, including PGE2, increased IL-17A concentrations. In contrast, the production of IL-17F was inhibited by PGE2, but selectively increased by TLR2 and TLR5 agonists. These results indicate that IL-17A regulation is distinct from IL-17F in stimulated BT co-cultures and that this co-culture approach can be used to identify pathway mechanisms and novel agents that selectively inhibit production of IL-17A or IL-17F.
authors.affiliation: BioSeek, a division of DiscoveRx, Corp., South San Francisco, California, United States of America.
authors.forename: Andrew C
authors.initials: AC
authors.lastname: Melton
authors.forename: Jennifer
authors.initials: J
authors.lastname: Melrose
authors.forename: Liisa
authors.initials: L
authors.lastname: Alajoki
authors.forename: Sylvie
authors.initials: S
authors.lastname: Privat
authors.forename: Hannah
authors.initials: H
authors.lastname: Cho
authors.forename: Naomi
authors.initials: N
authors.lastname: Brown
authors.forename: Ana Marija
authors.initials: AM
authors.lastname: Plavec
authors.forename: Dat
authors.initials: D
authors.lastname: Nguyen
authors.forename: Elijah D
authors.initials: ED
authors.lastname: Johnston
authors.forename: Jian
authors.initials: J
authors.lastname: Yang
authors.forename: Mark A
authors.initials: MA
authors.lastname: Polokoff
authors.forename: Ivan
authors.initials: I
authors.lastname: Plavec
authors.forename: Ellen L
authors.initials: EL
authors.lastname: Berg
authors.forename: Alison
authors.initials: A
authors.lastname: O'Mahony
mesh_terms: D001402:B-Lymphocytes / Q000187:drug effects / Q000276:immunology* / Q000378:metabolism*; D015496:CD4-Positive T-Lymphocytes / Q000276:immunology / Q000378:metabolism; D002117:Calcitriol / Q000494:pharmacology; D002450:Cell Communication; D018920:Coculture Techniques; D006801:Humans; D016130:Immunophenotyping; D020381:Interleukin-17 / Q000235:genetics / Q000378:metabolism*; D008213:Lymphocyte Activation / Q000276:immunology*; D010641:Phenotype; D010879:Piperazines / Q000494:pharmacology; D061251:Primary Cell Culture; D020005:Propanols / Q000494:pharmacology; D015398:Signal Transduction / Q000187:drug effects; D006377:T-Lymphocytes, Helper-Inducer / Q000187:drug effects / Q000276:immunology* / Q000378:metabolism*; D058504:Th17 Cells / Q000276:immunology / Q000378:metabolism
chemical_list: C575715:1,1,1,3,3,3-hexafluoro-2-(2-fluoro-4'-((4-(pyridin-4-ylmethyl)piperazin-1-yl)methyl)-(1,1'-biphenyl)-4-yl)propan-2-ol; D020381:Interleukin-17; D010879:Piperazines; D020005:Propanols; D002117:Calcitriol