Inhibition of IKK down-regulates antigen + IgE-induced TNF production by mast cells: a role for the IKK-IkappaB-NF-kappaB pathway in IgE-dependent mast cell activation.
Mast cells (MC) are major effector cells for allergic diseases. Cross-linking of immunoglobulin E (IgE) and its high-affinity receptor, FcepsilonRI, by antigen initiates a cascade of signaling events leading to nuclear factor (NF)-kappaB activation and tumor necrosis factor (TNF) production. Here, we demonstrated that inhibition of inhibitor of kappaB (IkappaB) kinase (IKK) by a peptide IKK inhibitor or by four individual chemical IKK inhibitors including 15-deoxy-prostaglandin J(2), 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 IKKalpha but not IKKbeta in BMMC. IgE + TNP-induced phosphorylation of IKKalpha was accompanied with phosphorylation and degradation of IkappaBalpha, subsequent NF-kappaB activation, and TNF production. Inhibition of IKK by sulindac decreased IKKalpha phosphorylation, IkappaBalpha phosphorylation and degradation, NF-kappaB activation, and TNF production by BMMC. It is interesting that IgE + TNP stimulation also induced a prominent synthesis of IKKalpha and IkappaBalpha. Inhibition of NF-kappaB activity by pyrrolidine dithiocarbomate (PDTC) blocked IgE + TNP-induced IkappaBalpha synthesis. NF-kappaB activity and TNF production were also inhibited when PDTC was used even after IgE + TNP stimulation, suggesting a potential role for the newly synthesized IkappaBalpha in MC activation. In addition, IgE + TNP-induced IKKalpha and IkappaBalpha phosphorylation was inhibited by a protein kinase C (PKC) inhibitor Ro 31-8220. Taken together, our results support a role for the IKK-IkappaB-NF-kappaB 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.
Peng
Yongde
Y
Department of Microbiology and Immunology, Dalhousie University, Isaac Walton Killam Health Centre, Halifax, Nova Scotia, Canada.
Power
Melanie R
MR
Li
Bo
B
Lin
Tong-Jun
TJ
D000818:Animals; D000941:Antigens / Q000276:immunology; D015536:Down-Regulation; D051550:I-kappa B Kinase; D020672:I-kappa B Proteins / Q000037:antagonists & inhibitors* / Q000378:metabolism; D007093:Imidazoles / Q000494:pharmacology; D007073:Immunoglobulin E / Q000276:immunology*; D008407:Mast Cells / Q000276:immunology*; D051379:Mice; D000072000:NF-KappaB Inhibitor alpha; D016328:NF-kappa B / Q000378:metabolism; D010455:Peptides / Q000494:pharmacology; D017346:Protein Serine-Threonine Kinases / Q000037:antagonists & inhibitors*; D011810:Quinoxalines / Q000494:pharmacology; D017455:Receptors, IgE / Q000502:physiology*; D013467:Sulindac / Q000494:pharmacology; D014301:Trinitrobenzenes / Q000276:immunology; D014409:Tumor Necrosis Factor-alpha / Q000235:genetics / Q000378:metabolism*
C471109:4(2'-aminoethyl)amino-1,8-dimethylimidazo(1,2-a)quinoxaline; D000941:Antigens; D020672:I-kappa B Proteins; D007093:Imidazoles; C467063:NBD peptide, mouse; D016328:NF-kappa B; C000606205:Nfkbia protein, mouse; D010455:Peptides; D011810:Quinoxalines; D017455:Receptors, IgE; D014301:Trinitrobenzenes; D014409:Tumor Necrosis Factor-alpha; D000072000:NF-KappaB Inhibitor alpha; D013467:Sulindac; D007073:Immunoglobulin E; D017346:Protein Serine-Threonine Kinases; C496564:Chuk protein, mouse; D051550:I-kappa B Kinase; C496562:Ikbkb protein, mouse; C496566:Ikbke protein, mouse