Induction of BAFF expression by IFN-γ via JAK/STAT signaling pathways in human intestinal epithelial cells

Woo, Sun-Je; Im, Jino; Jeon, Jun Ho; Kang, Seong-Gil; Lee, Mi-Hee; Yun, Cheol‐Heui; Moon, Eun‐Yi; Song, Man Ki; Kim, Hong-Hee; Han, Seung Hyun

doi:10.1189/jlb.0412210

Cited by 28 publications

(28 citation statements)

References 27 publications

(36 reference statements)

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“…3B). Importantly, this ISRE site was not identified by two previous studies on the BAFF promoter (15,16). In contrast with Woo et al (16), we did not identify any conserved GAS site in the BAFF promoter (20).…”

Section: Identification Of a Novel Isre Site In The Baff Promotercontrasting

confidence: 99%

“…Earlier studies of the BAFF promoter have indeed reported g activated sites (GAS) and ISRE sites, but importantly these sites are not conserved and were not functionally validated by mutational analysis (15,16). This could be because sequence conservation of the identified TFBS was not considered or because updated position weight matrix-based prediction tools were not used for TFBS prediction.…”

Section: Identification Of a Novel Isre Site In The Baff Promotermentioning

confidence: 98%

“…In contrast with Woo et al (16), we did not identify any conserved GAS site in the BAFF promoter (20). This could be because Woo et al (16) did not consider sequence conservation while predicting TFBS.…”

Section: Identification Of a Novel Isre Site In The Baff Promotermentioning

confidence: 99%

“…Understanding how the expression of BAFF is related to the activity of the type I IFN system in SLE and pSS might give important clues to the underlying mechanisms of these diseases. Two previous reports have analyzed the promoter of the BAFF gene and identified putative transcription factor binding sites (TFBS) in the proximal promoter region (15,16). Woo et al (16) identified a putative IFN-stimulated response element (ISRE) site but failed to validate it by mutational analysis; furthermore, the reported ISRE site is not conserved between species, indicating that it is a nonfunctional site.…”

mentioning

confidence: 99%

“…Two previous reports have analyzed the promoter of the BAFF gene and identified putative transcription factor binding sites (TFBS) in the proximal promoter region (15,16). Woo et al (16) identified a putative IFN-stimulated response element (ISRE) site but failed to validate it by mutational analysis; furthermore, the reported ISRE site is not conserved between species, indicating that it is a nonfunctional site. Surprisingly, Moon et al (15) did not identify any ISRE site in the promoter of BAFF.…”

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confidence: 99%

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The Expression of BAFF Is Controlled by IRF Transcription Factors

Sjöstrand

Johansson

Aqrawi

et al. 2016

The Journal of Immunology

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Patients with systemic lupus erythematosus (SLE) and primary Sjögren’s syndrome (pSS) are typically characterized by the presence of autoantibodies and an IFN-signature. The strength of the IFN-signature positively correlates with disease severity, suggesting that type I IFNs are active players in these diseases. BAFF is a cytokine critical for development and proper selection of B cells, and the targeting of BAFF has emerged as a successful treatment strategy of SLE. Previous reports have suggested that BAFF expression is directly induced by type I IFNs, but the precise mechanism for this remains unknown. In this article, we demonstrate that BAFF is a bona fide ISG and that IFN regulatory factors (IRFs) control the expression of BAFF. We identify IRF1 and IRF2 as positive regulators of BAFF transcription and IRF4 and IRF8 as potent repressors; in addition, we have mapped the precise binding site for these factors in the BAFF promoter. IFN-β injections induced BAFF expression mainly in neutrophils and monocytes, and BAFF expression in neutrophils from pSS patients strongly correlated with the strength of the IFN-signature. In summary, we show that BAFF expression is directly induced by type I IFNs via IRF1 and IRF2, whereas IRF4 and IRF8 are negative regulators of BAFF expression. These data suggest that type I IFN blockade in SLE and pSS patients will lead to downregulation of BAFF and a consequential reduction of autoreactive B cell clones and autoantibodies.

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Section: Identification Of a Novel Isre Site In The Baff Promotercontrasting

confidence: 99%

Section: Identification Of a Novel Isre Site In The Baff Promotermentioning

confidence: 98%

Section: Identification Of a Novel Isre Site In The Baff Promotermentioning

confidence: 99%

mentioning

confidence: 99%

mentioning

confidence: 99%

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The Expression of BAFF Is Controlled by IRF Transcription Factors

Sjöstrand

Johansson

Aqrawi

et al. 2016

The Journal of Immunology

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BAFF Regulates Follicular Helper T Cells and Affects Their Accumulation and Interferon‐γ Production in Autoimmunity

Coquery

Loo

Wade

et al. 2015

Arthritis & Rheumatology

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Objective T follicular helper (TFH) cells are critical for the development of protective antibodies via germinal center (GC) B-cell responses; however, uncontrolled TFH cell expansion activates autoreactive B-cells to produce antibodies that cause autoimmunity. The mechanisms that control TFH cell homeostasis remains largely unknown. The aim of this study was to determine the contribution of BAFF to TFH cell responses in autoimmunity. Methods We analyzed the properties of TFH cells in lupus-prone mice, sufficient or deficient in B-cell maturation antigen (BCMA). Adoptive transfer studies and mixed bone marrow chimeras were used to test BCMA signaling in T cells. We assessed BAFF stimulation of TFH cells through in vitro cell cocultures and in vivo depletion studies using flow cytometry. Results In Nba2 mice, TFH cells expressed the BAFF receptors BCMA and BR3, and accumulated in the spleen when BCMA was absent. BCMA deficiency in T cells promoted the expansion of TFH cells, GC formation, autoantibody production, and IFNγ production by TFH cells through BR3. IFNγ-producing TFH cells increased BAFF expression in dendritic cells. Blocking BAFF or IFNγ in vivo reduced TFH cell accumulation and improved autoimmunity in BCMA-deficient animals. Moreover, circulating TFH-like cells that expressed BR3 (but not BCMA) were elevated in SLE patients, which correlated with serum BAFF and IFNγ titers. Conclusion In Nba2 mice, BCMA negatively regulates TFH cell expansion whereas BAFF signaling through BR3 promotes TFH cell accumulation. Our work suggests the balance between BCMA and BR3 signaling in TFH cells serves as a checkpoint of immune tolerance.

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IFN‐γ stimulates CpG‐induced IL‐10 production in B cells via p38 and JNK signalling pathways

et al. 2018

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The production of IL-10, a potent immunosuppressive cytokine, must be strictly regulated to ensure a balanced immune response. IFN-γ, a key cytokine in multiple immune processes and pathologies, is known as an inhibitor of IL-10 production by monocytes and macrophages, but also has some regulatory functions. In the present study, we explored the role of IFN-γ on Toll-like receptor (TLR)-induced IL-10 production in murine peritoneal and spleen cells and in human peripheral blood mononuclear cells. IFN-γ inhibited IL-10 production induced by TLR2, TLR3, TLR4 and TLR7/8 agonists, but stimulated IL-10 production when cells were triggered with CpG oligodeoxynucleotides, a specific TLR9 agonist. The stimulatory effect of IFN-γ on TLR9-induced IL-10 was restricted to B cells. In line with the increased IL-10, B cells stimulated with CpG and IFN-γ profoundly inhibited CD4 T cell proliferation. Further research into the mechanisms involved, revealed that the mitogen-activated protein kinases p38 and JNK are essential players in this stimulatory effect, and that the phosphatase MKP1 - an inhibitor of p38 and JNK activity - is downregulated after combined stimulation with IFN-γ and CpG. Our data may represent a novel immunoregulatory role of IFN-γ in B cells after triggering of TLR9, by stimulating IL-10 production.

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Induction of BAFF expression by IFN-γ via JAK/STAT signaling pathways in human intestinal epithelial cells

Cited by 28 publications

References 27 publications

The Expression of BAFF Is Controlled by IRF Transcription Factors

The Expression of BAFF Is Controlled by IRF Transcription Factors

BAFF Regulates Follicular Helper T Cells and Affects Their Accumulation and Interferon‐γ Production in Autoimmunity

IFN‐γ stimulates CpG‐induced IL‐10 production in B cells via p38 and JNK signalling pathways

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