The Transcription Factors Egr2 and Egr3 Are Essential for the Control of Inflammation and Antigen-Induced Proliferation of B and T Cells

Abstract

SummaryLymphocytes provide optimal responses against pathogens with minimal inflammatory pathology. However, the intrinsic mechanisms regulating these responses are unknown. Here, we report that deletion of both transcription factors Egr2 and Egr3 in lymphocytes resulted in a lethal autoimmune syndrome with excessive serum proinflammatory cytokines but also impaired antigen receptor-induced proliferation of B and T cells. Egr2- and Egr3-defective B and T cells had hyperactive signal transducer and activator of transcription-1 (STAT1) and STAT3 while antigen receptor-induced activation of transcription factor AP-1 was severely impaired. We discovered that Egr2 and/or Egr3 directly induced expression of suppressor of cytokine signaling-1 (SOCS1) and SOCS3, inhibitors of STAT1 and STAT3, and also blocked the function of Batf, an AP-1 inhibitor, in B and T cells. Thus, Egr2 and Egr3 regulate B and T cell function in adaptive immune responses and homeostasis by promoting antigen receptor signaling and controlling inflammation.

Acquired Initiating Mutations in Early Hematopoietic Cells of CLL Patients

“…EGR2 is a downstream target of the BCR and pre-BCR complexes, through an intracellular signaling cascade involving BRAF, ERK, ELK-SRF, and finally upregulation of EGR2 transcription (19). EGR2 plays an important role in the fine-tuning of early B-cell differentiation (19,24,36,37). Expression of a CLL BRAF mutant in murine progenitors induced abnormal B-cell maturation in mice, including low expression of IgM, a feature of human CLL.…”

Leukemic marrow infiltration reveals a novel role for Egr3 as a potent inhibitor of normal hematopoietic stem cell proliferation

“…Egr3 is an early response gene belonging to a family of zinc-finger transcription factors that also includes Egr1, Egr2, and Egr4. Egr1 controls HSC proliferation, 24 whereas Egr2 and Egr3 appear to be important for lymphocyte proliferation or activation 29,30 ; Egr1/2/3 were all highly expressed in the LKS 1 cells in the leukemic BM. Collectively, these results suggest a potential role for Egr3 in HSCs, which prompted us to further investigate its function in HSCs.…”

The Involvement of Cholesterol in Sepsis and Tolerance to Lipopolysaccharide Highlighted by the Transcriptome Analysis of Zebrafish (Danio rerio)

“…35 The up-modulation of other genes that limit the inflammatory process was also observed: IL10 (at 4 dpf), the inhibitor of NFKB (NFKBIA, the nuclear factor of kappa light polypeptide gene enhancer in B-cells inhibitor, alpha) and the early growth response 2 and 3 transcription factors (EGR2, 3) (at 6 dpf); these are essential for balancing and successfully controlling inflammation. 36 During the final process that leads to organ failure due to oxidative stress, tissue-damaging enzymes and apoptosis, several proteins were found to be up-modulated in the zebrafish transcriptome: the pyruvate dehydrogenase kinase isoenzyme 2 (PDK2) was up-modulated at 4 dpf and increases the concentration of lactate in mammals. Lactate concentration is a measure of tissue hypoxia and is sufficient for the diagnosis of septic shock.…”