Early Growth Response-1 Regulates Lipopolysaccharide-induced Suppressor of Cytokine Signaling-1 Transcription

Mostecki, Justin; Showalter, Brian M.; Rothman, Paul B.

doi:10.1074/jbc.m408938200

Cited by 39 publications

(36 citation statements)

References 55 publications

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“…These findings are in accord with previous reports identifying Col1a2 as one of the genes showing elevated expression in mouse synovial fibroblasts stably transfected with Egr-1 (53). The proximal region of the human COL1A2 promoter harbors two GC-rich sequences similar to consensus Egr-1 binding EBS elements found in the promoters of other Egr-1-inducible genes (54,55).…”

Section: Discussionsupporting

confidence: 82%

The Early-Immediate Gene EGR-1 Is Induced by Transforming Growth Factor-β and Mediates Stimulation of Collagen Gene Expression

Chen

Ning

Ishida

et al. 2006

Journal of Biological Chemistry

152

156

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Section: Discussionsupporting

confidence: 82%

The Early-Immediate Gene EGR-1 Is Induced by Transforming Growth Factor-β and Mediates Stimulation of Collagen Gene Expression

Chen

Ning

Ishida

et al. 2006

Journal of Biological Chemistry

152

156

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“…We show in this study that post-selection cytokine-mediated survival is affected in Egr2 mutant mice, and that expression of Socs1, which must be downregulated to allow the cytokine survival pathway to function [30], is regulated by Egr2. Interestingly, Egr1 has previously been shown to bind to cognate sites within the human Socs1 promoter and to positively regulate Socs1 expression in macrophages [37]. As one of the binding sites is conserved in the murine promoter, it is possible that Egr2 is able to bind to the Socs1 promoter directly and repress its activity, perhaps in combination with a member of the cofactor family of Nab proteins (for example, see [38]).…”

Section: Discussionmentioning

confidence: 99%

Early growth response 2 regulates the survival of thymocytes during positive selection

2009

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The early growth response (Egr) transcription factor family regulates multiple steps during T-cell development. We examine here the role played by Egr2 in positive selection. In double-positive cells, Egr2 is upregulated immediately following TCR ligation, and its expression requires both the MAPK and calcineurin signaling pathways. Inducible transgenic and knockout mice were generated to cause gain-or loss-of-function of Egr2 in double-positive cells, and had reciprocal effects; more mature single-positive cells were made when Egr2 was overexpressed, and fewer when Egr2 was absent. These defects were associated with changes in the survival of positively selected cells rather than perturbation of positive selection or immediate post-selection signaling. The survival function of Egr2 at least partly depends upon its ability to activate the cytokine-mediated survival pathway, likely through negative regulation of both the IL-7R and suppressor of cytokine signaling 1 (Socs1), the molecular switch whose downregulation normally results in restored responsiveness to cytokine signaling following selection. While gain of Egr2 caused a decrease in Socs1 mRNA, loss of Egr2 resulted in downregulation of IL-7R, upregulation of Socs1, and inhibition of Stat5 phosphorylation and IL-7-mediated survival post-selection. Therefore, expression of Egr2 following positive selection links the initial TCR signaling event to subsequent survival of signaled cells. , and Egr3 is also required for the post-b-selection proliferative burst to occur [12]. These transcription factors are also induced rapidly following ligation of the abTCR, both during thymocyte selection [15] and in mature T cells responding to antigen-MHC, where Egr1 has a role in upregulation of IL2 transcription [16], and Egr2 and Egr3 are required for induction of anergy [17,18], and regulate expression of FasL [19,20]. Through its control of self-tolerance, Egr2 has also been implicated in the development of late-onset autoimmune disease [21] and is required for the development and maturation of NKT cells [22].Upregulation of Egr proteins during positive selection is dependent upon the Ras/MAPK pathway [13]. Egr proteins are direct transcriptional targets of ternary complex factor Sap-1, which is itself a substrate of Erk and essential for positive selection [23]. In addition, Egr2 and Egr3 are regulated by calcineurin signaling, likely via NFAT [13,20,22]. Both Egr1 and Egr3 have roles in positive selection. Egr1 overexpression enhances positive selection of cells with low affinity TCR [24]. Conversely, Egr1-deficient mice have impaired positive selection [25]; although the initial TCR signal is transduced, cells stall at the DP to SP transition, resulting in a numerical decrease in CD4 and CD8 SP. Animals doubly deficient for both Egr1 and Egr3 have a similar but more marked selection phenotype, and CD8 differentiation is significantly impaired [14]. For both Egr1 and Egr3, the principal reason for the alterations in SP cell number is a change in the cells' susceptibi...

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“…It is described that NFAT, activated via Dectin-1, is responsible for the induction of egr, another family of transcription factors that, in turn, can bind to the promoter of IL-10, which is upregulated by C-type lectin receptor (CLR) engagement (28). Moreover, egr 1 transcription factor has been found to bind to the SOCS1 promoter (41). However, we were not able to ascertain any contribution of NFAT to the expression of SOCS1.…”

Section: Discussionmentioning

confidence: 99%

Dectin-1 Stimulation Induces Suppressor of Cytokine Signaling 1, Thereby Modulating TLR Signaling and T Cell Responses

Eberle

Dalpke

2012

The Journal of Immunology

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Suppressor of cytokine signaling (SOCS) proteins serve as negative regulators of cytokine receptor signaling. However, SOCS proteins are not only induced via the JAK/STAT pathway, but are also transcribed on triggering of pattern recognition receptors such as TLRs. We now show that SOCS1 can also be induced by the non-TLR pattern recognition receptor Dectin-1 in murine bone marrow-derived dendritic cells and macrophages (BMMs). The C-type lectin Dectin-1 binds to yeasts and signals either in an autonomous manner or can be triggered in combination with TLRs. In our study, SOCS1 was expressed independently of any TLR engagement as a direct target gene of the Dectin-1 ligand Zymosan. Induction of SOCS1 was mediated by a novel pathway encompassing the tyrosine kinases Src and Syk that activated the downstream kinase proline-rich tyrosine kinase 2. Proline-rich tyrosine kinase 2, in turn, caused activation of the MAPK ERK, thereby triggering SOCS1 induction. SOCS1 did not modulate Dectin-1 signaling but affected TLR signaling, leading to decreased and abbreviated NF-κB activation in BMMs triggered by TLR9. Furthermore, IL-12 and IL-10 secretion were inhibited by SOCS1. We additionally observed that IL-17–producing Th cells were clearly increased by SOCS1 in BMMs. Our results show that SOCS1 is expressed via a new, NF-κB–independent pathway in Dectin-1–triggered murine BMMs and influences TLR cross talk and T cell priming.

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Early Growth Response-1 Regulates Lipopolysaccharide-induced Suppressor of Cytokine Signaling-1 Transcription

Cited by 39 publications

References 55 publications

The Early-Immediate Gene EGR-1 Is Induced by Transforming Growth Factor-β and Mediates Stimulation of Collagen Gene Expression

The Early-Immediate Gene EGR-1 Is Induced by Transforming Growth Factor-β and Mediates Stimulation of Collagen Gene Expression

Early growth response 2 regulates the survival of thymocytes during positive selection

Dectin-1 Stimulation Induces Suppressor of Cytokine Signaling 1, Thereby Modulating TLR Signaling and T Cell Responses

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