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1.
Immune Netw ; 20(2): e19, 2020 Apr.
Artigo em Inglês | MEDLINE | ID: mdl-32395371

RESUMO

Sestrin2 (Sesn2), a metabolic regulator, accumulates in response to a diverse array of cellular stresses. Sesn2 regulates cellular metabolism by inhibiting the mammalian target of rapamycin complex 1 through the AMP-activated protein kinase (AMPK) signaling pathway. Recently, researchers reported that Sesn2 regulates the differentiation and function of innate immune cells and T cells; however, the role of Sesn2 in B cells is largely unknown. In this study, we investigated the role of Sesn2 in Ig class switching and Ig production in mouse B cells. We observed that mouse B cells express Sesn2 mRNA. Interestingly, the expression of germline ε transcripts (GLTε) was selectively decreased in lipopolysaccharide-stimulated Sesn2 -/- splenocytes. Overexpression of Sesn2 increased GLTε promoter activity in B cells. In addition, AICAR (an activator of AMPK) selectively increased IL-4-induced GLTε expression and surface IgE (sIgE) expression in splenocytes. Furthermore, AICAR selectively enhanced IL-4-induced GLTε expression, sIgE expression, and IgE production by anti-CD40-stimulated B cells. We observed that ovalbumin (OVA)-specific IgE concentration was reduced in OVA-challenged Sesn2 -/- mice. Taken together, these results indicate that Sesn2-AMPK signaling selectively enhances IL-4-induced IgE class switching and IgE production by B cells, suggesting that this could be a therapeutic strategy targeting Sesn2 in IgE-mediated allergic diseases.

2.
Cell Immunol ; 338: 1-8, 2019 04.
Artigo em Inglês | MEDLINE | ID: mdl-30850088

RESUMO

Imiquimod (IMQ) is a selective toll-like receptor 7 (TLR7) agonist. TLR7 activation leads to the production of IFN-γ and pro-inflammatory cytokines by innate immune cells. However, the role of TLR7 in B cells is not fully understood. In this study, we investigated the direct effect of in vitro stimulation with IMQ on Ab production and isotype switching in B cells. IMQ selectively diminished IL-4-induced IgE and IgG1 production in anti-CD40-activated mouse B cells. IMQ also inhibited germline ε transcripts (GLTε)/GLTγ1 and post-switch ε transcripts (PSTε)/PSTγ1 expression, while enhancing GLTγ2c and PSTγ2c expression in anti-CD40/IL-4-stimulated B cells. Interestingly, IMQ abrogated IL-4-induced circle transcripts ε-γ1 (CTε-γ1) expression, indicative of sequential switching from IgG1 to IgE. Furthermore, IMQ repressed IL-4-induced surface IgE/IgG1 expression while increasing surface IgG2c expression. The selective inhibition of IgE synthesis was not due to IMQ-induced production of IFN-γ or IL-12 in the same culture. IMQ also enhanced BCL6 expression, a transcriptional repressor for the GLTε promoter, in anti-CD40/IL-4-stimulated B cells. In addition, BCL6 siRNA restored IMQ-mediated suppression of GLTε transcription. Therefore, these results indicate that TLR7 engagement by IMQ inhibits IL-4-induced GLTε transcription by enhancing BCL6 expression and inhibits IL-4-induced sequential switching from IgM to IgE via IgG1, thus resulting in the downregulation of IgE production by B cells.


Assuntos
Linfócitos B/fisiologia , Imiquimode/farmacologia , Imunoglobulina E/metabolismo , Proteínas Proto-Oncogênicas c-bcl-6/metabolismo , Receptor 7 Toll-Like/agonistas , Animais , Formação de Anticorpos , Antígenos CD40/metabolismo , Células Cultivadas , Regulação da Expressão Gênica , Switching de Imunoglobulina , Imunoglobulina E/genética , Imunoglobulina G/genética , Cadeias épsilon de Imunoglobulina/genética , Interleucina-4/metabolismo , Camundongos , Camundongos Endogâmicos C57BL , Proteínas Proto-Oncogênicas c-bcl-6/genética , RNA Interferente Pequeno/genética
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