Alveolar macrophages play a crucial role in initiating the inflammatory res
ponse in allergic asthma through the cross-linking of the low affinity IgE
receptors (Fc epsilon RIIb or CD23) by IgE-allergen immunocomplexes. We hav
e previously shown that CD23 cross-linking in monocytes and U937 cells targ
ets 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 U
937 cells leads to hyperphosphorylation of I kappa B alpha at Ser(32)/Ser(3
6) residues. Overexpression of a dominant-negative I kappa B alpha transgen
e containing mutations at Ser(32)/Ser(36) completely inhibits degradation o
f I kappa B alpha, NF-kappa B activation, and gene transcription that follo
ws CD23 cross-linking. Investigation of the second messengers mediating the
CD23-dependent activation of NF kappa B demonstrates that I kappa B kinase
s (IKKs) but not p90(rsk) are selectively activated following CD23 cross-li
nking and mediates the phosphorylation of I kappa B alpha. Cotransfection e
xperiments with an IKK beta negative dominant completely inhibit CD23 induc
ed 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 deg
radation, and NF-kappa B nuclear translocation. Taken together, our results
show that CD23 cross-linking in the monocytic lineage induces tyrosine kin
ase activation followed by activation of IKK, which phosphorylates I kappa
B alpha at the N-terminal domain (Ser(32)/Ser(36)), inducing its degradatio
n, NF-kappa B activation and gene transcription.