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Sestrin2 Mediates IL-4-induced IgE Class Switching by Enhancing Germline ? Transcription in B Cells.

ABSTRACT: 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 ? transcripts (GLT?) was selectively decreased in lipopolysaccharide-stimulated Sesn2 -/- splenocytes. Overexpression of Sesn2 increased GLT? promoter activity in B cells. In addition, AICAR (an activator of AMPK) selectively increased IL-4-induced GLT? expression and surface IgE (sIgE) expression in splenocytes. Furthermore, AICAR selectively enhanced IL-4-induced GLT? 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.

SUBMITTER: Shim YS

PROVIDER: S-EPMC7192835 | biostudies-literature | 2020 Apr

REPOSITORIES: biostudies-literature

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Sestrin2 Mediates IL-4-induced IgE Class Switching by Enhancing Germline ε Transcription in B Cells.

Shim You-Sun YS Lee Solji S Park Hwan-Woo HW Park Seok-Rae SR

Immune network 20200120 2

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 ...[more]

PMID: 32395371

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Project description:Autophagy is a conserved catabolic process by which cytoplasmic components are delivered into lysosomes for degradation. Pigment epithelium‑derived factor (PEDF) has been reported to be associated with autophagy and can induce p53 expression; however, the mechanism relating PEDF with autophagy in endothelial cells remains poorly understood. The present study aimed to investigate the association between the PEDF‑p53‑sestrin pathway and autophagy in human umbilical vein endothelial cells (HUVECs). PEDF‑induced autophagy was examined by fluorescence microscopy and western blot analysis. p53 small interfering (si)RNA and sestrin2 siRNA were constructed and transfected into HUVECs prior to PEDF treatment. The protein expression levels of microtubule‑associated protein light chain 3 (LC3) I, LC3 II and p62 were evaluated by western blot analysis, and the mRNA expression levels of p53 and sestrin2 were determined using reverse transcription‑quantitative polymerase chain reaction analysis. The regulation of mechanistic target of rapamycin (mTOR) was reflected by p70S6 kinase (p70S6K) and eukaryotic translation initiation factor 4E‑binding protein 1 (4E‑BP1) protein expression levels, as determined by western blot analysis. PEDF could induce HUVEC autophagy by sequentially inducing p53 and sestrin2 expression, as observed by fluorescence microscopy and western blot analysis. Conversely, the induction of sestrin2 by PEDF was eliminated by p53 siRNA. In addition, p53 siRNA and sestrin2 siRNA could attenuate PEDF‑induced HUVEC autophagy. Inhibition of mTOR may be the mechanism responsible for PEDF‑induced autophagy; as p70S6K and 4E‑BP1 phosphorylation levels were significantly upregulated in p53 siRNA‑treated and sestrin2 siRNA‑treated groups. The findings of the present study indicated that PEDF may trigger autophagy in HUVECs by inducing p53 and sestrin2 expression, and inhibiting mTOR expression; these findings may contribute to the improved understanding of diseases, including cancer and atherosclerosis.

Dataset Information

Sestrin2 Mediates IL-4-induced IgE Class Switching by Enhancing Germline ? Transcription in B Cells.

Publications

Sestrin2 Mediates IL-4-induced IgE Class Switching by Enhancing Germline ε Transcription in B Cells.

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