title: Spleen tyrosine kinase is important in the production of proinflammatory cytokines and cell proliferation in human mesangial cells following stimulation with IgA1 isolated from IgA nephropathy patients.
abstract: IgA immune complexes are capable of inducing human mesangial cell (HMC) activation, resulting in release of proinflammatory and profibrogenic mediators. The subsequent inflammation, cellular proliferation, and synthesis of extracellular matrix lead to the progression of IgA nephropathy (IgAN). Spleen tyrosine kinase (SYK) is an intracellular protein tyrosine kinase involved in cell signaling downstream of immunoreceptors. In this study, we determined whether SYK is involved in the downstream signaling of IgA1 stimulation in HMC, leading to production of proinflammatory cytokines/chemokines and cell proliferation. Incubation of HMC with IgA1 purified from IgAN patients significantly increased the synthesis of MCP-1 in a dose-dependent manner. There was also significantly increased production of IL-6, IL-8, IFN-γ-inducible protein-10, RANTES, and platelet-derived growth factor-BB. Stimulation of HMC with heat-aggregated IgA1 purified from IgAN patients induced significantly increased HMC proliferation. Both pharmacological inhibition of SYK and knockdown of SYK by small interfering RNA significantly reduced the synthesis of these mediators and inhibited HMC proliferation. Moreover, positive immunostaining for total and phospho-SYK in glomeruli of kidney biopsies from IgAN patients strongly suggests the involvement of SYK in the pathogenesis of IgAN. To our knowledge, we demonstrate, for the first time, the involvement of SYK in the downstream signaling of IgA1 stimulation in HMC and in the pathogenesis of IgAN. Hence, SYK represents a potential therapeutic target for IgAN.
authors.affiliation: Imperial College Kidney and Transplant Institute, Hammersmith Hospital, Imperial College London, London W12 0NN, United Kingdom. mkim@uhbs.ch
authors.forename: Min Jeong
authors.initials: MJ
authors.lastname: Kim
authors.forename: John P
authors.initials: JP
authors.lastname: McDaid
authors.forename: Stephen P
authors.initials: SP
authors.lastname: McAdoo
authors.forename: Jonathan
authors.initials: J
authors.lastname: Barratt
authors.forename: Karen
authors.initials: K
authors.lastname: Molyneux
authors.forename: Esteban S
authors.initials: ES
authors.lastname: Masuda
authors.forename: Charles D
authors.initials: CD
authors.lastname: Pusey
authors.forename: Frederick W K
authors.initials: FW
authors.lastname: Tam
mesh_terms: D049109:Cell Proliferation; D016207:Cytokines / Q000096:biosynthesis* / Q000502:physiology; D005922:Glomerulonephritis, IGA / Q000201:enzymology* / Q000276:immunology / Q000473:pathology; D006801:Humans; D007070:Immunoglobulin A / Q000097:blood / Q000302:isolation & purification / Q000502:physiology*; D018836:Inflammation Mediators / Q000378:metabolism* / Q000502:physiology; D047908:Intracellular Signaling Peptides and Proteins / Q000502:physiology*; D050527:Mesangial Cells / Q000201:enzymology / Q000276:immunology / Q000473:pathology*; D011505:Protein-Tyrosine Kinases / Q000502:physiology*; D015398:Signal Transduction / Q000276:immunology; D013154:Spleen / Q000201:enzymology* / Q000276:immunology / Q000473:pathology; D000072377:Syk Kinase
chemical_list: D016207:Cytokines; D007070:Immunoglobulin A; D018836:Inflammation Mediators; D047908:Intracellular Signaling Peptides and Proteins; D011505:Protein-Tyrosine Kinases; C000606896:SYK protein, human; D000072377:Syk Kinase