Abstract
Inhibitor of kappa B (IκB)-ζ transcription is rapidly induced by stimulation with TLR ligands and IL-1. Despite high IκBζ expression in inflammation sites, the association of IκBζ with host defence via systemic immune responses against bacterial infection remains unclear. Oral immunisation with a recombinant attenuated Salmonella vaccine (RASV) strain did not protect IκBζ-deficient mice against a lethal Salmonella challenge. IκBζ-deficient mice failed to produce Salmonella LPS-specific IgG, especially IgG2a, although inflammatory cytokine production and immune cell infiltration into the liver increased after oral RASV administration. Moreover, IκBζ-deficient mice exhibited enhanced splenic germinal centre reactions followed by increased total IgG production, despite IκBζ-deficient B cells having an intrinsic antibody class switching defect. IκBζ-deficient CD4+ T cells poorly differentiated into Th1 cells. IFN-γ production by CD4+ T cells from IκBζ-deficient mice immunised with RASV significantly decreased after restimulation with heat-killed RASV in vitro, suggesting that IκBζ-deficient mice failed to mount protective immune responses against Salmonella infection because of insufficient Th1 and IgG production. Therefore, IκBζ is crucial in protecting against Salmonella infection by inducing Th1 differentiation followed by IgG production.
Highlights
Inhibitor of kappa B (IκB)-ζ is a protein encoded by the NF-kappa-B inhibitor zeta (NFKBIZ) gene, and it contains ankyrin repeat domains and is a member of the IκB family of nuclear proteins[1,2,3]
We showed that oral administration of a recombinant attenuated Salmonella vaccine strain (RASV) in mice elicited sufficient immune responses, including LPS-specific Ab responses, to protect virulent Salmonella infection in wild-type mice[13,14,15]
We further assessed which components of the immune responses associated with IκBζ are critical to establishing protective immunity against Salmonella infection after oral RASV immunisation
Summary
Inhibitor of kappa B (IκB)-ζ is a protein encoded by the NF-kappa-B inhibitor zeta (NFKBIZ) gene, and it contains ankyrin repeat domains and is a member of the IκB family of nuclear proteins[1,2,3]. Activation of IκBζ in macrophages leads to IL-6 production, which is known to be mediated by the Myd[88] (myeloid differentiation primary response 88) adaptor molecule[4]. The depletion of IκBζ reduces the production of Myd88-dependent IL-6 production in various cell types, including macrophages, mouse embryonic fibroblasts, and epithelial cells. We showed that oral administration of a recombinant attenuated Salmonella vaccine strain (RASV) in mice elicited sufficient immune responses, including LPS-specific Ab responses, to protect virulent Salmonella infection in wild-type mice[13,14,15]. We further assessed which components of the immune responses associated with IκBζ are critical to establishing protective immunity against Salmonella infection after oral RASV immunisation
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