The signal transduction pathway of CD23 (Fc epsilon RIIb) targets I kappa B kinase.
Alveolar macrophages play a crucial role in initiating the inflammatory response in allergic asthma through the cross-linking of the low affinity IgE receptors (Fc epsilon RIIb or CD23) by IgE-allergen immunocomplexes. We have previously shown that CD23 cross-linking in monocytes and U937 cells targets I kappa B alpha, leading to the activation of the transcription factor NF-kappa B. We demonstrate in this paper that CD23-initiated signaling in U937 cells leads to hyperphosphorylation of I kappa B alpha at Ser32/Ser36 residues. Overexpression of a dominant-negative I kappa B alpha transgene containing mutations at Ser32/Ser36 completely inhibits degradation of I kappa B alpha, NF-kappa B activation, and gene transcription that follows CD23 cross-linking. Investigation of the second messengers mediating the CD23-dependent activation of NF kappa B demonstrates that I kappa B kinases (IKKs) but not p90rsk are selectively activated following CD23 cross-linking and mediates the phosphorylation of I kappa B alpha. Cotransfection experiments with an IKK beta negative dominant completely inhibit CD23 induced NF kappa B activation. Furthermore, the activation of tyrosine kinase(s) by CD23 is required for the induction of IKK activity, I kappa B alpha degradation, and NF-kappa B nuclear translocation. Taken together, our results show that CD23 cross-linking in the monocytic lineage induces tyrosine kinase activation followed by activation of IKK, which phosphorylates I kappa B alpha at the N-terminal domain (Ser32/Ser36), inducing its degradation, NF-kappa B activation and gene transcription.
Ten
R M
RM
Division of Allergy and Department of Immunology, Mayo Clinic, Rochester, MN 55902, USA. ten.rosa@mayo.edu
McKinstry
M J
MJ
Trushin
S A
SA
Asin
S
S
Paya
C V
CV
D004268:DNA-Binding Proteins / Q000378:metabolism / Q000502:physiology; D006801:Humans; D051550:I-kappa B Kinase; D020672:I-kappa B Proteins; D007106:Immune Sera / Q000378:metabolism; D016297:Mutagenesis, Site-Directed; D000072000:NF-KappaB Inhibitor alpha; D016328:NF-kappa B / Q000037:antagonists & inhibitors / Q000378:metabolism; D010766:Phosphorylation; D017346:Protein Serine-Threonine Kinases / Q000235:genetics / Q000276:immunology / Q000378:metabolism*; D011505:Protein-Tyrosine Kinases / Q000378:metabolism; D017455:Receptors, IgE / Q000276:immunology / Q000378:metabolism / Q000502:physiology*; D019893:Ribosomal Protein S6 Kinases / Q000378:metabolism; D012694:Serine / Q000235:genetics / Q000378:metabolism; D015398:Signal Transduction / Q000276:immunology*; D020298:U937 Cells
D004268:DNA-Binding Proteins; C083487:I kappa B beta protein; D020672:I-kappa B Proteins; D007106:Immune Sera; D016328:NF-kappa B; C000606204:NFKBIA protein, human; D017455:Receptors, IgE; D000072000:NF-KappaB Inhibitor alpha; D012694:Serine; D011505:Protein-Tyrosine Kinases; D017346:Protein Serine-Threonine Kinases; D019893:Ribosomal Protein S6 Kinases; C496559:CHUK protein, human; D051550:I-kappa B Kinase; C496560:IKBKB protein, human; C496565:IKBKE protein, human