Autophagy-dependent PELI3 degradation inhibits proinflammatory IL1B expression

Giegerich, Annika K.; Kuchler, Laura; Sha, Lisa K.; Knape, Tilo; Heide, Heinrich; Wittig, Ilka; Behrends, Christian; Brüne, Bernhard; Knethen, Andreas von

doi:10.4161/auto.32178

Cited by 61 publications

(52 citation statements)

References 61 publications

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“…Moreover, pro-IL-1β is ubiquinated by E2 conjugase UBE2L3 and subsequently degraded during chronic LPS stimulation (32). This observation is in line with several studies showing that when macrophages are treated with TLR ligands, pro-IL-1β is sequestered in autophagosomes for degradation (33, 34). Of note, we found that although increases in mRNA levels were similar between Il18 and Il1b in response to Poly(I:C) in WT BMDMs, upregulation of IL-1β protein levels was much less robust compared with that of IL-18 levels (Fig.…”

Section: Resultssupporting

confidence: 92%

Cutting Edge: Distinct Regulatory Mechanisms Control Proinflammatory Cytokines IL-18 and IL-1β

Zhu

Kanneganti

2017

The Journal of Immunology

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IL-18 and IL-1β, which are cytokines of the IL-1 family, are synthesized as precursor proteins and activated by the inflammasome via proteolytic processing. IL-1β is induced only in response to inflammatory stimuli, but IL-18 is constitutively expressed. However, how IL-18 and IL-1β expression is regulated by different inflammatory signals remains poorly studied. In this study, we found that IL-18 and IL-1β are differentially regulated. Despite being constitutively expressed, IL-18 expression was increased and sustained after stimulation of Toll-like receptors. In contrast, IL-1β was induced but not sustained after chronic treatment. Furthermore, type I IFN signaling was essential for induction of IL-18 and macrophages lacking type I IFN signaling were impaired in their ability to promote IL-18 induction. Thus, our findings reveal a fundamental difference in IL-18 and IL-1β regulation and uncover novel mechanisms that are relevant to the inflammatory settings where these proinflammatory cytokines play a critical role.

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Section: Resultssupporting

confidence: 92%

Cutting Edge: Distinct Regulatory Mechanisms Control Proinflammatory Cytokines IL-18 and IL-1β

Zhu

Kanneganti

2017

The Journal of Immunology

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“…Recent reports have described that inhibition of GSK-3β leads to a reduced expression of NF-κB target genes17. Therefore, we tested the mRNA expression of pro-inflammatory NF-κB target genes IL81819 and interleukin-1beta20 both expressed in HEK293 cells after transfection of the NEMO triple mutant. Indeed, reduced expression of mRNA in cells transfected with mutated NEMO in comparison to wild-type NEMO was determined (Fig.…”

Section: Resultsmentioning

confidence: 99%

GSK-3β controls NF-kappaB activity via IKKγ/NEMO

Medunjanin

Schleithoff

Fiegehenn

et al. 2016

Sci Rep

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The NF-κB signaling pathway is central for the innate immune response and its deregulation is found in multiple disorders such as autoimmune, chronic inflammatory and metabolic diseases. IKKγ/NEMO is essential for NF-κB activation and NEMO dysfunction in humans has been linked to so-called progeria syndromes, which are characterized by advanced ageing due to age-dependent inflammatory diseases. It has been suggested that glycogen synthase kinase-3β (GSK-3β) participates in NF-κB regulation but the exact mechanism remained incompletely understood. In this study, we identified NEMO as a GSK-3β substrate that is phosphorylated at serine 8, 17, 31 and 43 located within its N-terminal domain. The kinase forms a complex with wild-type NEMO while point mutations of NEMO at the specific serines abrogated GSK-3β binding and subsequent phosphorylation of NEMO resulting in its destabilization. However, K63-linked polyubiquitination was augmented in mutated NEMO explaining an increased binding to IKKα and IKKβ. Even IκBα was found degraded. Still, TNFα-stimulated NF-κB activation was impaired pointing towards an un-controlled signalling process. Our data suggest that GSK-3β is critically important for ordered NF-κB signalling through modulation of NEMO phosphorylation.

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“…Harris et al [44] found that rapamycin could significantly reduce the production of IL-1β in LPS-treated macrophages via the induction of autophagy. Further studies identified that autophagy downregulated the production of IL-1β in LPS-treated macrophages by targeting pro-IL-1β for lysosomal degradation, which could be positively regulated by the inhibition of mTOR signaling [45,46] . These findings highlight a protective mechanism of rapamycin in halting CKD progression by promoting autophagy in kidney macrophages, which may also partly explain the therapeutic effect of rapamycin on LPS-induced kidney fibrosis in our study.…”

Section: Discussionmentioning

confidence: 99%

Lipopolysaccharide Induces Chronic Kidney Injury and Fibrosis through Activation of mTOR Signaling in Macrophages

et al. 2015

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Background: Septic kidney injury is one of the most common complications in critically ill patients with a high risk of developing chronic kidney disease (CKD). Emerging data indicate that mammalian target of rapamyci (mTOR) signaling plays a major role in septic inflammation by regulating the immune response of macrophage. This study was designed to evaluate the role of mTOR signaling in kidney macrophages during endotoxemia-induced chronic kidney injury and subsequent fibrogenesis. Methods: Male C57BL/6 mice were used for all animal studies (n = 9 for each group). Lipopolysaccharide (LPS) was injected intraperitoneally (1 mg/kg) every 2 days to induce persistent endotoxemia. Rapamycin (1 mg/kg·day) was administered to a subgroup of mice 1 day prior to LPS treatment and continued to termination of the experiment. In ex-vivo experiment, RAW264.7 cells were cultured and treated with LPS (2 µg/ml) for 48 h while a subgroup of cells were incubated in the presence of rapamycin (50 nmol) for 2 h. Results: Continuous administration of LPS resulted in progressive macrophage infiltration, tubular injury and collagen deposition in mice kidneys. Rapamycin markedly ameliorated LPS-induced kidney pathological changes. Expression of pS6K was rarely observed in normal kidney macrophages, but significantly increased with time by LPS treatment. In ex-vivo study, LPS induced prominent production of IL-1β and MCP-1 in cultured RAW264.7 cells, which was significantly suppressed by rapamycin. Conclusion: Taken together, our findings show that endotoxemia results in activation of mTOR signaling in macrophages, leading to progressive kidney inflammatory injuries and subsequent fibrosis. Our study may reveal a mechanism involved in the development of sepsis-associated CKD and kidney fibrosis.

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Autophagy-dependent PELI3 degradation inhibits proinflammatory IL1B expression

Cited by 61 publications

References 61 publications

Cutting Edge: Distinct Regulatory Mechanisms Control Proinflammatory Cytokines IL-18 and IL-1β

Cutting Edge: Distinct Regulatory Mechanisms Control Proinflammatory Cytokines IL-18 and IL-1β

GSK-3β controls NF-kappaB activity via IKKγ/NEMO

Lipopolysaccharide Induces Chronic Kidney Injury and Fibrosis through Activation of mTOR Signaling in Macrophages

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