TNF suppresses acute intestinal inflammation by inducing local glucocorticoid synthesis

Noti, Mario; Corazza, Nadia; Mueller, Christoph; Berger, Barbara J.; Brunner, Thomas

doi:10.1084/jem.20090849

Cited by 151 publications

(185 citation statements)

References 32 publications

(56 reference statements)

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“…Although TNFα is considered clinically causative in IBD, mice deficient in TNFα exhibit enhanced intestinal inflammation during DSS colitis and 40% more deaths compared with no deaths in WT mice (28). Also, the absence of TNFα results in a lack of colonic glucocorticoid synthesis and there is exacerbation of DSS-induced colitis (29). TNFα-deficient mice also had increased infiltration of mucosal neutrophils and disruption of the epithelial cell layer (28).…”

Section: Protective Role For Tnfα In the Innate Response Of The Intesmentioning

confidence: 96%

Paradoxical effects of constitutive human IL-32γ in transgenic mice during experimental colitis

Choi

Bae

Hong

et al. 2010

Proc. Natl. Acad. Sci. U.S.A.

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Inflammatory cytokines mediate inflammatory bowel diseases (IBDs) and cytokine blocking therapies often ameliorate the disease severity. IL-32 affects inflammation by increasing the production of IL-1, TNFα, and several chemokines. Here, we investigated the role of IL-32 in intestinal inflammation by generating a transgenic (TG) mouse expressing human IL-32γ (IL-32γ TG). Although IL-32γ TG mice are healthy, constitutive serum and colonic tissue levels of TNFα are elevated. Compared with wild-type (WT) mice, IL-32γ TG mice exhibited a modestly exacerbated acute inflammation early following the initiation of dextran sodium sulfate (DSS)-induced colitis. However, after 6 d, there was less colonic inflammation, reduced tissue loss, and improved survival rate compared with WT mice. Associated with attenuated tissue damage, colonic levels of TNFα and IL-6 were significantly reduced in the IL-32γ TG mice whereas IL-10 was elevated. Cultured colon explants from IL-32γ TG mice secreted higher levels of IL-10 compared with WT mice and lower levels of TNFα and IL-6. Constitutive levels of IL-32γ itself in colonic tissues were significantly lower following DSS colitis. Although the highest level of serum IL-32γ occurred on day 3 of colitis, IL-32 was below constitutive levels on day 9. The ability of IL-32γ to increase constitutive IL-10 likely reduces TNFα, IL-6, and IL-32 itself accounting for less inflammation. In humans with ulcerative colitis (UC), serum IL-32 is elevated and colonic biopsies contain IL-32 in inflamed tissues but not in uninvolved tissues. Thus IL-32γ emerges as an example of how innate inflammation worsens as well as protects intestinal integrity.

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Section: Protective Role For Tnfα In the Innate Response Of The Intesmentioning

confidence: 96%

Paradoxical effects of constitutive human IL-32γ in transgenic mice during experimental colitis

Choi

Bae

Hong

et al. 2010

Proc. Natl. Acad. Sci. U.S.A.

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“…Locally produced GCs might also add to the overall effect (49). Accordingly, RU486, a known GC receptor antagonist, is capable of inducing a disruption of LPS tolerance in LPS-tolerized mice (50).…”

Section: Discussionmentioning

confidence: 99%

Glucocorticoid-Induced Leucine Zipper: A Critical Factor in Macrophage Endotoxin Tolerance

Hoppstädter

Kessler

Bruscoli

et al. 2015

The Journal of Immunology

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Induction of glucocorticoid-induced leucine zipper (GILZ) by glucocorticoids plays a key role in their anti-inflammatory action. In activated macrophages, GILZ levels are downregulated via tristetraprolin-mediated GILZ mRNA destabilization. To assess the functional significance of GILZ downregulation, we generated myeloid-specific GILZ knockout (KO) mice. GILZ-deficient macrophages displayed a higher responsiveness toward LPS, as indicated by increased TNF-α and IL-1β expression. This effect was due to an activation of ERK, which was significantly amplified in GILZ KO cells. The LPS-induced activation of macrophages is attenuated upon pretreatment of macrophages with low-dose LPS, an effect termed endotoxin tolerance. In LPS-tolerant macrophages, GILZ mRNA was stabilized, whereas ERK activation was strongly decreased. In contrast, GILZ KO macrophages exhibited a strongly reduced desensitization. To explore the contribution of GILZ expression in macrophages to endotoxin tolerance in vivo, we treated GILZ KO mice with repeated i.p. injections of low-dose LPS followed by treatment with high-dose LPS. LPS pretreatment resulted in reduced proinflammatory mediator expression upon high-dose LPS treatment in serum and tissues. In contrast, cytokine induction was preserved in tolerized GILZ KO animals. In summary, our data suggest that GILZ is a key regulator of macrophage functions.

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“…Importantly, it has been reported that the synthesis of bioactive GCs is not restricted to the adrenal glands, but extends to other extra-adrenal sources such as the skin, intestine, thymus, brain, and vascular endothelium (82,83). In addition, it has been postulated that TNF␣ promotes local steroidogenesis by directly inducing steroidogenic enzymes in intestinal epithelial cells (84,85). Therefore we investigated whether TNF␣ stimulates steroidogenesis in other organs besides the adrenal glands and whether this results in the observed TNF␣-mediated GR reduction in Adx mice.…”

Section: Discussionmentioning

confidence: 99%

Tumor Necrosis Factor Inhibits Glucocorticoid Receptor Function in Mice

Bogaert

Vandevyver

Dejager

et al. 2011

Journal of Biological Chemistry

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As glucocorticoid resistance (GCR) and the concomitant burden pose a worldwide problem, there is an urgent need for a more effective glucocorticoid therapy, for which insights into the molecular mechanisms of GCR are essential. In this study, we addressed the hypothesis that TNF␣, a strong pro-inflammatory mediator in numerous inflammatory diseases, compromises the protective function of the glucocorticoid receptor (GR) against TNF␣-induced lethal inflammation. Indeed, protection of mice by dexamethasone against TNF␣ lethality was completely abolished when it was administered after TNF␣ stimulation, indicating compromised GR function upon TNF␣ challenge. TNF␣-induced GCR was further demonstrated by impaired GR-dependent gene expression in the liver. Furthermore, TNF␣ down-regulates the levels of both GR mRNA and protein. However, this down-regulation seems to occur independently of GC production, as TNF␣ also resulted in downregulation of GR levels in adrenalectomized mice. These findings suggest that the decreased amount of GR determines the GR response and outcome of TNF␣-induced shock, as supported by our studies with GR heterozygous mice. We propose that by inducing GCR, TNF␣ inhibits a major brake on inflammation and thereby amplifies the pro-inflammatory response. Our findings might prove helpful in understanding GCR in inflammatory diseases in which TNF␣ is intimately involved.

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TNF suppresses acute intestinal inflammation by inducing local glucocorticoid synthesis

Cited by 151 publications

References 32 publications

Paradoxical effects of constitutive human IL-32γ in transgenic mice during experimental colitis

Paradoxical effects of constitutive human IL-32γ in transgenic mice during experimental colitis

Glucocorticoid-Induced Leucine Zipper: A Critical Factor in Macrophage Endotoxin Tolerance

Tumor Necrosis Factor Inhibits Glucocorticoid Receptor Function in Mice

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