title: Spleen tyrosine kinase (Syk)-dependent calcium signals mediate efficient CpG-induced exocytosis of tumor necrosis factor α (TNFα) in innate immune cells.
abstract: Pattern recognition receptors expressed by cells of the innate immune system initiate the immune response upon recognition of microbial products. Activation of pattern recognition receptors result in the production and release of proinflammatory cytokines, including TNFα and IL-6. Because these cytokines promote disparate effector cell responses, understanding the signaling pathways involved in their regulation is critical for directing the immune response. Using macrophages and dendritic cells deficient in spleen tyrosine kinase (Syk), we identified a novel pathway by which TNFα trafficking and secretion are regulated by Syk following stimulation with CpG DNA. In the absence of PLCγ2, a Syk substrate, or the calcium-responsive kinase calcium calmodulin kinase II, CpG-induced TNFα secretion was impaired. Forced calcium mobilization rescued the TNFα secretion defect in Syk-deficient cells. In contrast to its effect on TNFα, Syk deficiency did not affect IL-6 secretion, suggesting that Syk-dependent signals participate in differential sorting of cytokines, thus tailoring the cytokine response. Our data report a novel pathway for TNFα regulation and provide insight into non-transcriptional mechanisms for shaping cytokine responses.
authors.affiliation: Division of Pediatric Rheumatology, Children's Hospital of Philadelphia, Philadelphia, Pennsylvania 19104, USA.
authors.forename: Sheila
authors.initials: S
authors.lastname: Rao
authors.forename: Xiaohong
authors.initials: X
authors.lastname: Liu
authors.forename: Bruce D
authors.initials: BD
authors.lastname: Freedman
authors.forename: Edward M
authors.initials: EM
authors.lastname: Behrens
mesh_terms: D000276:Adjuvants, Immunologic / Q000494:pharmacology*; D000818:Animals; D020013:Calcium Signaling / Q000187:drug effects* / Q000235:genetics / Q000276:immunology; D054732:Calcium-Calmodulin-Dependent Protein Kinase Type 2 / Q000235:genetics / Q000276:immunology / Q000378:metabolism; D002460:Cell Line; D005089:Exocytosis / Q000187:drug effects / Q000235:genetics / Q000276:immunology; D007113:Immunity, Innate / Q000187:drug effects / Q000235:genetics; D015850:Interleukin-6 / Q000235:genetics / Q000276:immunology / Q000378:metabolism; D047908:Intracellular Signaling Peptides and Proteins / Q000235:genetics / Q000276:immunology / Q000378:metabolism*; D008264:Macrophages / Q000276:immunology / Q000378:metabolism*; D051379:Mice; D008822:Mice, Transgenic; D009838:Oligodeoxyribonucleotides / Q000494:pharmacology*; D051966:Phospholipase C gamma / Q000235:genetics / Q000276:immunology / Q000378:metabolism; D011505:Protein-Tyrosine Kinases / Q000235:genetics / Q000276:immunology / Q000378:metabolism*; D000072377:Syk Kinase; D014409:Tumor Necrosis Factor-alpha / Q000235:genetics / Q000276:immunology / Q000378:metabolism*
chemical_list: D000276:Adjuvants, Immunologic; C408982:CPG-oligonucleotide; D015850:Interleukin-6; D047908:Intracellular Signaling Peptides and Proteins; D009838:Oligodeoxyribonucleotides; D014409:Tumor Necrosis Factor-alpha; D011505:Protein-Tyrosine Kinases; D000072377:Syk Kinase; C000606897:Syk protein, mouse; D054732:Calcium-Calmodulin-Dependent Protein Kinase Type 2; D051966:Phospholipase C gamma
keywords: Cytokine; Secretion; Signal Transduction; Toll-like Receptors (TLR); Tumor Necrosis Factor (TNF)