Intracellular Interleukin-1α Functionally Interacts with Histone Acetyltransferase Complexes

Buryskova, Miroslava; Pospíšek, Martin; Grothey, Arnhild; Simmet, Thomas; Burýšek, Ladislav

doi:10.1074/jbc.m306342200

Cited by 91 publications

(98 citation statements)

References 52 publications

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“…5, Pearson's coefficient 5 À0.1070.15). These data indicate that ATP depletion enhances the previously reported associations of IL-1a with p300, and with RNA splicing factors [13,22]. These enhanced interactions may be responsible for the immobilization of IL-1a-GFP that occurs after ATP-depletion and thus for IL-1a retention in the nucleus after necrotic cell death.…”

Section: Nuclear Retention Of Il-1a By Immobilizationsupporting

confidence: 56%

“…Instead, our data (Fig. 5) suggest that IL-1a retention in the nucleus is more likely to depend on previously reported interactions with other intranuclear proteins; p300 and RNA splicing factors [13,22].Unlike nuclear IL-1a-GFP, nuclear GFP is not retained by necrotic COS-7 cells (Fig. 3), and GFP remains freely mobile in ATP-depleted COS-7 nuclei (Fig.…”

supporting

confidence: 44%

Section: Discussionmentioning

confidence: 39%

“…IL-1a-GFP also colocalized partially with the histone acetyl transferase p300 (Fig. 5, Pearson's coefficient 5 0.6270.07), an intranuclear protein known to interact with IL-1a [22]. In contrast, IL-1a-GFP co-localized poorly with active transcription sites labeled with serine-2-phosphorylated C-terminal domain repeat RNA polymerase II (PolII0, Fig.…”

Section: Nuclear Retention Of Il-1a By Immobilizationmentioning

confidence: 97%

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Nuclear retention of IL‐1α by necrotic cells: A mechanism to dampen sterile inflammation

2009

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Sterile inflammation is a host response to tissue injury that is mediated by damage-associated molecular patterns released from dead cells. Sterile inflammation worsens damage in a number of injury paradigms. The pro-inflammatory cytokine IL-1a is reported to be a damage-associated molecular pattern released from dead cells, and it is known to exacerbate brain injury caused by stroke. In the brain, IL-1a is produced by microglia, the resident brain macrophages. We found that IL-1a is actively trafficked to the nuclei of microglia, and hence tested the hypothesis that trafficking of IL-1a to the nucleus would inhibit its release following necrotic cell death, limiting sterile inflammation. Microglia subjected to oxygenglucose deprivation died via necrosis. Under these conditions, microglia expressing nuclear IL-1a released significantly less IL-1a than microglia with predominantly cytosolic IL-1a. The remaining IL-1a was immobilized in the nuclei of the dead cells. Thus, nuclear retention of IL-1a may serve to limit inflammation following cell death.Key words: IL-1a . Microglia . Necrosis . Nuclear retention . Sterile inflammation Supporting Information available online IntroductionSterile inflammation is a host response to tissue injury that can exacerbate the initial insult [1]. Intracellular molecules released from necrotic cells act as damage-associated molecular patterns (DAMP), signaling to the innate immune system that tissue injury has occurred [2]. IL-1a, a pro-inflammatory member of the IL-1 cytokine family [3], has recently been identified as a DAMP released from necrotic cells [4]. In addition, necrotic cell DAMP are reported to stimulate IL-1a production by immune cells, which further exacerbates sterile inflammation [1]. Experimental stroke in rodents elicits an inflammatory response that markedly exacerbates brain injury [5]. IL-1a is a key contributor to this injury, and its genetic ablation (along with IL-1b, a related cytokine) causes a 70% reduction in the brain injury caused by stroke [6].In the brain after injury (e.g. stroke, hemorrhage, trauma), IL-1 family cytokines are produced by microglia, the resident brain macrophages [7]. IL-1a is produced in the cytosol as a 31-kDa protein that, following release from necrotic cells, activates the type I IL-1 receptor on responsive cell membranes [8,9]. The Nterminal domain of IL-1a contains a nuclear localization sequence, which mediates active nuclear import [10,11]. IL-1a has been reported to act within the nucleus to regulate cytokine transcription and RNA splicing [12,13]. In this study we sought to test the hypothesis that IL-1a nuclear import also inhibits IL-1a release following necrotic cell death. We report that IL-1a nuclear import and intranuclear retention reduce IL-1a release from necrotic microglia. Thus, IL-1a nuclear retention by necrotic cells may inhibit injury-induced inflammation. Results IL-1a nuclear localization is inhibited at high cell densityTo investigate the effects of IL-1a nuclear localization on IL-1a release after ne...

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Section: Nuclear Retention Of Il-1a By Immobilizationsupporting

confidence: 56%

supporting

confidence: 44%

Section: Discussionmentioning

confidence: 39%

Section: Nuclear Retention Of Il-1a By Immobilizationmentioning

confidence: 97%

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Nuclear retention of IL‐1α by necrotic cells: A mechanism to dampen sterile inflammation

2009

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“…In contrast, the IL-1 precursor is not cleaved by caspase 1, IL-1␣ is not secreted from cells, and only in severe disease can one detect serum IL-1␣, which may result from its release from dying cells. IL-1␣ remains intracellular, where it can function as a DNA binding transcription factor, and perhaps as an oncogene (34)(35)(36). As shown in Figure 3, the IL-1␣ precursor is biologically active when inserted into the cell's membrane, oriented in such a manner that it binds to the type I IL-1 receptor and initiates signal transduction (37).…”

Section: Why 2 Il-1s?mentioning

confidence: 99%

The many worlds of reducing interleukin‐1

Dinarello¹

2005

Arthritis & Rheumatism

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DNA demethylation at specific CpG sites in the IL1B promoter in response to inflammatory cytokines in human articular chondrocytes

Hashimoto¹,

Oreffo²,

Gibson³

et al. 2009

Arthritis & Rheumatism

147

153

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Objective. To determine whether changes in the DNA methylation status in the promoter region of the gene encoding interleukin-1␤ (IL-1␤) account for expression of IL1B messenger RNA (mRNA) after longterm treatment of human articular chondrocytes with inflammatory cytokines.Methods. IL-1␤, tumor necrosis factor ␣ (TNF␣) plus oncostatin M (OSM), or 5-azadeoxycytidine (5-azadC) was added twice weekly for 4-5 weeks to primary cultures of normal human articular chondrocytes derived from the femoral head cartilage of patients with a fracture of the femoral neck. Expression of MMP13, IL1B, TNFA, and DNMT1 was determined by SYBR Greenbased quantitative reverse transcription-polymerase chain reaction (RT-PCR) analysis of genomic DNA and total RNA extracted from the same sample before and after culture. Bisulfite modification was used to identify which CpG sites in the IL1B promoter showed differential methylation between IL1B-expressing and IL1B-nonexpressing cells. The percentages of cells that were methylated at that critical CpG site (-299 bp) were quantified by a method that depended on methylationsensitive restriction enzymes and real-time RT-PCR. Secretion of IL-1␤ into the culture media was assessed by enzyme-linked immunosorbent assay.Results. Healthy chondrocytes did not express IL1B mRNA, but the levels were increased 5-fold by treatment with 5-aza-dC and were increased 100-1,000-fold by treatment with TNF␣/OSM. The percentage CpG methylation was decreased by 5-aza-dC treatment but was reduced considerably more by IL-1␤ and was almost abolished by TNF␣/OSM. The mRNA was translated into protein in cytokine-treated chondrocytes.Conclusion. These novel findings indicate that inflammatory cytokines can change the DNA methylation status at key CpG sites, resulting in long-term induction of IL1B in human articular chondrocytes.

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Intracellular Interleukin-1α Functionally Interacts with Histone Acetyltransferase Complexes

Cited by 91 publications

References 52 publications

Nuclear retention of IL‐1α by necrotic cells: A mechanism to dampen sterile inflammation

Nuclear retention of IL‐1α by necrotic cells: A mechanism to dampen sterile inflammation

The many worlds of reducing interleukin‐1

DNA demethylation at specific CpG sites in the IL1B promoter in response to inflammatory cytokines in human articular chondrocytes

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