Published online before print March 22, 2005

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(Journal of Leukocyte Biology. 2005;77:975-983.)
© 2005 by Society for Leukocyte Biology

Inhibition of IKK down-regulates antigen + IgE-induced TNF production by mast cells: a role for the IKK-IB-NF-B pathway in IgE-dependent mast cell activation

Yongde Peng^*,1, Melanie R. Power^*, Bo Li^* and Tong-Jun Lin^*,,2

^* Departments of Microbiology and Immunology and
Pediatrics, Dalhousie University, Isaac Walton Killam Health Centre, Halifax, Nova Scotia, Canada

² Correspondence: IWK Health Centre, Department of Pediatrics, 5850 University Ave., Halifax, NS, Canada, B3K 6R8. E-mail: tong-jun.lin{at}dal.ca

Mast cells (MC) are major effector cells for allergic diseases. Cross-linking of immunoglobulin E (IgE) and its high-affinity receptor, FcRI, by antigen initiates a cascade of signaling events leading to nuclear factor (NF)-B activation and tumor necrosis factor (TNF) production. Here, we demonstrated that inhibition of inhibitor of B (IB) kinase (IKK) by a peptide IKK inhibitor or by four individual chemical IKK inhibitors including 15-deoxy-prostaglandin J₂, BMS-345541, SC-514, or sulindac significantly blocked IgE + trinitrophenyl (TNP)-induced TNF production by mouse bone marrow-derived MC (BMMC). Moreover, IgE + TNP induced a rapid phosphorylation of IKK but not IKKß in BMMC. IgE + TNP-induced phosphorylation of IKK was accompanied with phosphorylation and degradation of IB, subsequent NF-B activation, and TNF production. Inhibition of IKK by sulindac decreased IKK phosphorylation, IB phosphorylation and degradation, NF-B activation, and TNF production by BMMC. It is interesting that IgE + TNP stimulation also induced a prominent synthesis of IKK and IB. Inhibition of NF-B activity by pyrrolidine dithiocarbomate (PDTC) blocked IgE + TNP-induced IB synthesis. NF-B activity and TNF production were also inhibited when PDTC was used even after IgE + TNP stimulation, suggesting a potential role for the newly synthesized IB in MC activation. In addition, IgE + TNP-induced IKK and IB phosphorylation was inhibited by a protein kinase C (PKC) inhibitor Ro 31-8220. Taken together, our results support a role for the IKK-IB-NF-B pathway, which likely involves PKC in IgE-dependent TNF production by MC. Thus, IKK may serve as a new target for the regulation of MC function in allergy.

Key Words: Fc receptors • inflammation • allergy • protein kinases • signal transduction

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