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The Signal Transduction Pathway of CD23 (FcRIIb) Targets IB Kinase¹

Rosa M. Ten^2,*, Melissa J. McKinstry^*, Sergey A. Trushin, Susana Asin and Carlos V. Paya

^* Division of Allergy and Department of Immunology, Mayo Clinic, Rochester, MN 55902

Alveolar macrophages play a crucial role in initiating the inflammatory response in allergic asthma through the cross-linking of the low affinity IgE receptors (FcRIIb or CD23) by IgE-allergen immunocomplexes. We have previously shown that CD23 cross-linking in monocytes and U937 cells targets IB, leading to the activation of the transcription factor NF-B. We demonstrate in this paper that CD23-initiated signaling in U937 cells leads to hyperphosphorylation of IB at Ser³²/Ser³⁶ residues. Overexpression of a dominant-negative IB transgene containing mutations at Ser³²/Ser³⁶ completely inhibits degradation of IB, NF-B activation, and gene transcription that follows CD23 cross-linking. Investigation of the second messengers mediating the CD23-dependent activation of NFB demonstrates that IB kinases (IKKs) but not p90^rsk are selectively activated following CD23 cross-linking and mediates the phosphorylation of IB. Cotransfection experiments with an IKKß negative dominant completely inhibit CD23 induced NFB activation. Furthermore, the activation of tyrosine kinase(s) by CD23 is required for the induction of IKK activity, IB degradation, and NF-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 IB at the N-terminal domain (Ser³²/Ser³⁶), inducing its degradation, NF-B activation and gene transcription.

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