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Impaired B cell development and function in the absence of IkappaBNS.

ABSTRACT: I?BNS has been identified as a member of the I?B family of NF-?B inhibitors, which undergoes induction upon TCR signaling. Mice carrying a targeted gene disruption of I?BNS demonstrate dysregulation of cytokines in T cells, macrophages, and dendritic cells. I?BNS mediates both positive and negative gene regulation, depending on individual cell type and/or cytokine. In this study, we demonstrate an additional role for I?BNS in the B cell lineage. B cells from I?BNS knockout (KO) mice were impaired in proliferative responses to LPS and anti-CD40. IgM and IgG3 Igs were drastically reduced in the serum of I?BNS KO mice, although I?BNS KO B cells exhibited a higher level of surface IgM than that found in wild-type mice. Switching to IgG3 was significantly reduced in I?BNS KO B cells. The in vitro induction of plasma cell development demonstrated that progression to Ab-secreting cells was impaired in I?BNS KO B cells. In agreement with this finding, the number of Ab-secreting cells in the spleens of I?BNS KO mice was reduced and production of Ag-specific Igs was lower in I?BNS KO mice after influenza infection as compared with wild-type mice. Additionally, I?BNS KO mice lacked B1 B cells and exhibited a reduction in marginal zone B cells. Thus, I?BNS significantly impacts the development and functions of B cells and plasma cells.

SUBMITTER: Touma M

PROVIDER: S-EPMC3348541 | biostudies-literature | 2011 Oct

REPOSITORIES: biostudies-literature

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Impaired B cell development and function in the absence of IkappaBNS.

Touma Maki M Keskin Derin B DB Shiroki Fumiko F Saito Ibuki I Koyasu Shigeo S Reinherz Ellis L EL Clayton Linda K LK

Journal of immunology (Baltimore, Md. : 1950) 20110907 8

IκBNS has been identified as a member of the IκB family of NF-κB inhibitors, which undergoes induction upon TCR signaling. Mice carrying a targeted gene disruption of IκBNS demonstrate dysregulation of cytokines in T cells, macrophages, and dendritic cells. IκBNS mediates both positive and negative gene regulation, depending on individual cell type and/or cytokine. In this study, we demonstrate an additional role for IκBNS in the B cell lineage. B cells from IκBNS knockout (KO) mice were impaire ...[more]

PMID: 21900180

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Project description:Glutathione (GSH) is a critical endogenous antioxidant that protects against intracellular oxidative stress. As such, pathological alterations in GSH levels are linked to a myriad of diseases including cancer, neurodegeneration and cataract. The rate limiting step in GSH biosynthesis is catalyzed by the glutamate cysteine ligase catalytic subunit (GCLC). The high expression of GCLC in the lens supports the synthesis of millimolar concentrations of GSH in this tissue. Herein, we describe the morphological consequences of deleting (knocking out) Gclc from surface ectoderm-derived ocular tissues (using the Le-Cre transgene; Gclc KO) which includes an overt microphthalmia phenotype and severely disrupted formation of multiple ocular structures (i.e., cornea, iris, lens, retina). Controlling for the Le-Cre transgene revealed that the deletion of Gclc significantly exacerbated the microphthalmia phenotype in Le-Cre hemizygous mice and resulted in dysregulated gene expression that was unique to only the lenses of KO mice. We further characterized the impaired lens development by conducting an RNA-seq experiment on KO and Gclc control (CON) mouse lens at the day of birth. RNA-sequencing revealed significant differences between Gclc knockout (KO) and Gclc control (CON) lenses, including down-regulation of crystallins and lens fiber cell identity genes, and up-regulation of lens epithelial cell identity genes. In addition, genes related to the immune system (e.g., immune system process, inflammatory response, neutrophil chemotaxis) were upregulated, and genes related to eye/lens development were downregulated. TRANSFAC analysis of differentially expressed genes (DEGs) in the lens of Gclc KO mice implicated PAX6 as a key upstream regulator of Gclc KO sensitive genes. This was further supported by a strong positive correlation between the transcriptomes of the lenses of Gclc KO and Pax6 KO mice. Strikingly, the dysregulation of PAX6-regulated genes in Gclc KO mice was observed despite no change in the ocular localization of PAX6 or decrease in the expression of PAX6 in the lens. In vitro experiments demonstrated that suppression of intracellular GSH concentrations resulted in impairment of PAX6 transactivation activity. Taken together, the present results elucidate a novel mechanism wherein intracellular GSH concentrations may modulate PAX6 activity.

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Impaired B cell development and function in the absence of IkappaBNS.

Publications

Impaired B cell development and function in the absence of IkappaBNS.

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