The transcriptional response of mouse spleen B cells to IL-4: Comparison to the response of human peripheral blood B cells

Abstract

The Th2 cytokine IL-4 triggers a signaling cascade which activates transcription by STAT6. The goals of the present study are to define the transcriptomic response of mouse spleen B cells (mSBC) to IL-4 used as single stimulus, its specificity compared to human peripheral blood B cells (hPBBC) and to mouse spleen T cells (mSTC), and the pathways affected. Oligonucleotide-based microarrays were performed using two references, the untreated sample and the cells cultured without IL-4, an experimental design which reduces the potential confounding effect of cellular stress during culture. Specificity was addressed by comparing the response of mSBC and our previously published study on hPBBC, of similar design, and a study by other authors on mSTC. We detected an mSBC-specific response (including novel genes, e.g., Sertad4, Lifr, Pmepa1, Epcam, Tbxas1; and common genes, e.g., Usp2, Cst7, Grtp1, and Casp6), an hPBBC-specific response (e.g., CCL17, MTCL1, GCSAM, HOMER2, IL2RA), and a common mSBC/hPBBC response (e.g., CISH, NFIL3, SOCS1, VDR, CDH1). In contrast, the mSBC and mSTC responses were largely divergent. Gene set enrichment analysis (GSEA) was applied for the first time to identify the pathways affected. Both in mSBC and hPBBC, IL-4 activated Myc, the transcriptional machinery itself, cell cycle, mitochondria and respiratory chain, ribosome, proteasome and antigen presentation, and Wnt signaling, and inhibited GPCR signaling. However, significant differences were found in histone demethylation, Nod signaling, and Rho signaling, which were downregulated in mSBC, and in chromatin condensation, which was downregulated in hPBBC. These findings may have therapeutic implications for the treatment of allergic diseases and parasitic infections.

Shared transcriptional profiles of atypical B cells suggest common drivers of expansion and function in malaria, HIV, and autoimmunity

“…Signature analysis was done as described previously (55). In addition to the bulk RNA-seq gene signatures generated in this study for (39), and signatures from cells treated with different cytokines (15,(56)(57)(58).…”

The role of DOCK10 in the regulation of the transcriptome and aging

“…Therefore, transcriptome changes in SBC fit well with what was previously known about DOCK10, i.e., its induction by IL-4 and its role as a GEF for Rac1 and Cdc42. Moreover, it is known that the EGF signaling pathway activates Rac1 and Cdc42 [26], and the IL-4 signaling pathway induces activation of the Rac1, Cdc42, and Wnt signaling pathways [27]. These findings suggest that DOCK10-mediated transcription of genes involved in the integrin, IL-4, Wnt, Rac1, and Cdc42 signaling pathways likely operates as a feedforward mechanism that acts downstream of DOCK10-mediated activation of Rac1 and Cdc42 and enhances the effects of DOCK10 on the cytoskeletal dynamics.

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PCR Array Technology in Biopsy Samples Identifies Up-Regulated mTOR Pathway Genes as Potential Rejection Biomarkers After Kidney Transplantation

“…The mTOR signaling pathway plays a significant role in immune and inflammatory reactions according to experimental findings ( 21 ), It indicates that the increased expression of inflammatory cytokines may be the result of abnormal mTOR activation. In this sense, our group has published the important role of inflammatory cytokines in kidney and liver transplant outcome ( 4 , 48 , 60 , 61 ). Logically, a cytokine analysis and real-time correlation analysis would actually prove the association of up-regulated expression of some of mTOR pathway genes.…”