title: Role of calcium ionophore A23187-induced activation of IkappaB kinase 2 in mast cells.
abstract: BACKGROUND
  Mast cells are known to play a pivotal role in allergic diseases by releasing granules containing histamine and other preformed chemical mediators. Cross-linking of high-affinity receptors for IgE (FcεRI) on mast cells results in rapid increases in intracellular free calcium concentration [Ca(2+)]i and consequent activation of many transcription factors, including NFAT, NF-κB, JNK and CREB. Ca(2+) signaling is essential for many cellular activities such as proliferation, gene expression and degranulation in mast cells. In addition to Ca(2+) signaling, previous reports have shown that IkappaB kinase 2 (IKK2 or IKKβ), a central component of the IKK complex mediating NF-κB activation, also plays a crucial role in FcεRI-mediated degranulation and cytokine production. Moreover, it has been demonstrated that activation of PKCβ, a calcium-dependent PKC isoform, leads to IKK2 activation in many cell types. However, the roles of Ca(2+) signaling and PKCβ in the activation of IKK2 in mast cells remain largely unknown.
  
  
  METHODS
  We investigated the effect of PKC inhibitor Gö6976 on calcium ionophore A23187-induced activation of IKK2 in mast cells. We also examined the role of IKK2 in A23187-induced NF-κB-dependent gene induction, degranulation, proinflammatory cytokine production and extracellular signal-regulated kinases 1 and 2 (ERK1/2) activation by using IKK2-deficient (IKK2(-/-)) fetal liver-derived mast cells (FLMCs).
  
  
  RESULTS
  A23187 activated IKK2 and NF-κB even in the presence of Gö6976 in mast cells. A23187-induced degranulation, cytokine production and activation of ERK1/2 were diminished in IKK2(-/-) FLMCs compared to those in wild-type FLMCs.
  
  
  CONCLUSIONS
  Ca(2+)-IKK2 signaling is involved in the degranulation and cytokine production in activated mast cells by a mechanism independent of PKCβ.
authors.affiliation: Department of Allergy and Clinical Immunology, Graduate School of Medicine, Chiba University, Chiba, Japan.
authors.forename: Junichi
authors.initials: J
authors.lastname: Hosokawa
authors.forename: Kotaro
authors.initials: K
authors.lastname: Suzuki
authors.forename: Daiki
authors.initials: D
authors.lastname: Nakagomi
authors.forename: Tomohiro
authors.initials: T
authors.lastname: Tamachi
authors.forename: Hiroaki
authors.initials: H
authors.lastname: Takatori
authors.forename: Akira
authors.initials: A
authors.lastname: Suto
authors.forename: Hiroshi
authors.initials: H
authors.lastname: Nakajima
mesh_terms: D000001:Calcimycin / Q000494:pharmacology*; D061207:Calcium Ionophores / Q000494:pharmacology*; D020013:Calcium Signaling; D015550:Cell Degranulation / Q000276:immunology; D002478:Cells, Cultured; D016207:Cytokines / Q000096:biosynthesis; D004789:Enzyme Activation / Q000187:drug effects; D006801:Humans; D051550:I-kappa B Kinase / Q000378:metabolism*; D008407:Mast Cells / Q000187:drug effects* / Q000378:metabolism*; D019950:Mitogen-Activated Protein Kinase 1 / Q000378:metabolism; D048052:Mitogen-Activated Protein Kinase 3 / Q000378:metabolism; D010766:Phosphorylation / Q000187:drug effects; D011493:Protein Kinase C / Q000378:metabolism; D064546:Protein Kinase C beta; D017472:Receptors, Interleukin-1 / Q000378:metabolism; D047888:Receptors, Tumor Necrosis Factor, Type I / Q000378:metabolism
chemical_list: D061207:Calcium Ionophores; D016207:Cytokines; D017472:Receptors, Interleukin-1; D047888:Receptors, Tumor Necrosis Factor, Type I; D000001:Calcimycin; C496559:CHUK protein, human; D051550:I-kappa B Kinase; C496560:IKBKB protein, human; D011493:Protein Kinase C; D064546:Protein Kinase C beta; D019950:Mitogen-Activated Protein Kinase 1; D048052:Mitogen-Activated Protein Kinase 3