Interaction of NF-κB and NFAT with the Interferon-γ Promoter

Sica, Antonio; Dorman, Linda; Viggiano, Vincenzo; Cippitelli, Marco; Ghosh, Paritosh; Rice, Nancy R.; Young, Howard A.

doi:10.1074/jbc.272.48.30412

Cited by 412 publications

(327 citation statements)

References 53 publications

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“…Activated c-jun combines with c-fos to form AP-1. One of the genes transcriptionally regulated by AP-1 is the IFN␥ gene (38). Our data suggest that the AP-1 pathway is critically involved in arterial wall inflammation and, as a therapeutic target, is as important as the NF-B pathway.…”

Section: Discussionmentioning

confidence: 70%

Therapeutic effects of acetylsalicylic acid in giant cell arteritis

Weyand

Kaiser

Yang

et al. 2002

Arthritis & Rheumatism

141

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Objective. In giant cell arteritis (GCA), inflammatory lesions typically produce interferon-␥ (IFN␥)-and nuclear factor B (NF-B)-dependent monokines. Corticosteroids influence disease activity by repressing NF-B-dependent genes but have only marginal effects on IFN␥. The current study explored whether acetylsalicylic acid (ASA) had cytokine-repressing activity in GCA and could function as a steroid-sparing agent.Methods. Temporal artery-severe combined immunodeficiency (SCID) mouse chimeras were created by engrafting inflamed temporal arteries into SCID mice. Chimeras were treated with ASA, indomethacin, or dexamethasone for 3 weeks. Temporal artery grafts were harvested and cytokine message was semiquantified by polymerase chain reaction-enzyme-linked immunosorbent assay. The ability of dexamethasone and ASA to suppress IFN␥ and interleukin-1␤ (IL-1␤) messenger RNA and protein production was also tested in vitro using T cell clones and monocytes derived from patients with GCA. Drug-induced effects on the transcription factors NF-B and activator protein 1 (AP-1) were assessed by electrophoretic mobility shift assays (EMSAs).Results. At clinically relevant doses, 20-100 mg/kg, ASA was a highly effective inhibitor of cytokine transcription in temporal arteries. While dexamethasone preferentially targeted NF-B-regulated monokines, ASA acted predominantly by suppressing IFN␥. Indomethacin failed to reduce tissue IFN␥ transcription, which therefore excluded the inhibition of cyclooxygenases as a critical mechanism. IFN␥ production by T cell clones was highly sensitive to ASA-mediated suppression, whereas IL-1␤ production by lipopolysaccharide-stimulated monocytes responded primarily to dexamethasone. The combination of ASA and dexamethasone had synergistic effects. EMSAs demonstrated that ASA interfered with the formation of AP-1, whereas dexamethasone suppressed the nuclear translocation of NF-B.Conclusion. The results of this study provide evidence of the complementary action of ASA and corticosteroids in suppressing proinflammatory cytokines in the vascular lesions of GCA.

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Section: Discussionmentioning

confidence: 70%

Therapeutic effects of acetylsalicylic acid in giant cell arteritis

Weyand

Kaiser

Yang

et al. 2002

Arthritis & Rheumatism

141

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“…NF-‹ B was first described as necessary for inducible activation of the Th1 cytokine genes IL-2 [25][26][27] and IFN-+ [28,29]. Subsequently, NF-‹ B was found to participate in activation of many inflammatory cytokine genes and also other genes [20].…”

Section: Discussionmentioning

confidence: 99%

NF‐κB synergizes with NF‐AT and NF‐IL6 in activation of the IL‐4 gene in T cells

et al. 2004

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IL‐4 plays a pivotal role in the development of the Th2 cell mediated humoral immune response and causes IgE‐dependent allergic inflammatory diseases. Expression of IL‐4 in differentiated Th2 cells is regulated by transcription factors such as NF‐AT, AP‐1 and NF‐IL6. Recently, increasing evidence indicates that the pro‐inflammatory transcription factor NF‐κB may also participate inIL‐4 expression. In this study, we show that the IL‐4 promoter is synergistically activated by NF‐κB, NF‐AT and NF‐IL6 at the NF‐κB/NF‐AT/NF‐IL6 composite sites. In addition, we performed the chromatin immunoprecipitation technique to determine the functional relevance of NF‐κB in the activation of the IL‐4 gene in vivo. We demonstrate that NF‐κB binds to the IL‐4 promoter in vivo upon T cell activation. Inhibition of NF‐κB nuclear translocation in living cells blocked binding of NF‐κB to the IL‐4 promoter. The data provide first evidence that NF‐κB is directly involved in IL‐4 transcription.

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“…We show that IL-15 alone is a more potent up-regulator of IFN-␥ production compared with IL-21 in human NK and T cells. The IFN-␥ gene has multiple binding sites for different transcription factors including AP-1, NF-B, and NFAT, which all contribute to the activation of the IFN-␥ gene transcription in response to TCR and/or cytokine stimulation (2,28,29,35,36). In addition, the IFN-␥ gene has putative STAT binding sites in its promoter region as well as in the first and third intron of the IFN-␥ gene and IFN-␥ GAS residing in the promoter has two consensus binding sites for STATs (28).…”

Section: Discussionmentioning

confidence: 99%

IL-21 in Synergy with IL-15 or IL-18 Enhances IFN-γ Production in Human NK and T Cells

Strengell

Matikainen

Sirén

et al. 2003

The Journal of Immunology

353

292

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NK and T cell-derived IFN-γ is a key cytokine that stimulates innate immune responses and directs adaptive T cell response toward Th1 type. IL-15, IL-18, and IL-21 have significant roles as activators of NK and T cell functions. We have previously shown that IL-15 and IL-21 induce the expression of IFN-γ, T-bet, IL-12Rβ2, and IL-18R genes both in NK and T cells. Now we have studied the effect of IL-15, IL-18, and IL-21 on IFN-γ gene expression in more detail in human NK and T cells. IL-15 clearly activated IFN-γ mRNA expression and protein production in both cell types. IL-18 and IL-21 enhanced IL-15-induced IFN-γ gene expression. IL-18 or IL-21 alone induced a modest expression of the IFN-γ gene but a combination of IL-21 and IL-18 efficiently up-regulated IFN-γ production. We also show that IL-15 activated the binding of STAT1, STAT3, STAT4, and STAT5 to the regulatory sites of the IFN-γ gene. Similarly, IL-21 induced the binding of STAT1, STAT3, and STAT4 to these elements. IL-15- and IL-21-induced STAT1 and STAT4 activation was verified by immunoprecipitation with anti-phosphotyrosine Abs followed by Western blotting with anti-STAT1 and anti-STAT4 Abs. IL-18 was not able to induce the binding of STATs to IFN-γ gene regulatory sites. IL-18, however, activated the binding of NF-κB to the IFN-γ promoter NF-κB site. Our results suggest that both IL-15 and IL-21 have an important role in activating the NK cell-associated innate immune response.

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Interaction of NF-κB and NFAT with the Interferon-γ Promoter

Abstract: Interferon-␥ (IFN-␥

Cited by 412 publications

References 53 publications

Therapeutic effects of acetylsalicylic acid in giant cell arteritis

Therapeutic effects of acetylsalicylic acid in giant cell arteritis

NF‐κB synergizes with NF‐AT and NF‐IL6 in activation of the IL‐4 gene in T cells

IL-21 in Synergy with IL-15 or IL-18 Enhances IFN-γ Production in Human NK and T Cells

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