Dimethyl itaconate inhibits TNF-α induced NF-κB signaling pathway in human epithelial cells
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Abstract Background: Dimethyl itaconate (DMI), a membrane-permeable derivative of itaconate, was found to moderate IL-17-IκBζ-induced skin pathology including psoriasis in mouse experiments . TNF-α induced NF-κB pathway, which controls a variety of immune and inflammatory responses, was also proven to play a crucial role as mediator in psoriasis. However, whether DMI interacts with the TNF-α induced NF-κB pathway remains unclear. Results: Here we show that DMI inhibits TNF-α induced NF-κB transcriptional activities in dose-dependent manner in several human cell lines using dual luciferase assay and blocks the NF-κB nuclear entry. Moreover, DMI potently inhibits IKKβ dependent phosphorylation and degradation of IκBα in TNF-α induced activation of NF-κB pathway. We also demonstrate that DMI covalently binds to cysteine residue in IKKβ, a key regulator in NF-κB pathway, to suppress IKKβ activation and inhibit the canonical NF-κB pathway. Conclusion Our study presents a new mechanism for DMI as an anti-inflammatory agent that may have therapeutic potentials in treating NF-κB related human inflammatory diseases. Our results also suggest that itaconate produced by endogenous IRG1 may regulate NF-κB at post translation modification level, and the IRG1-itaconate-NF-κB axis could be targeted as a novel strategy for the treatment of IRG1-NF-κB mediated diseases.Keywords:
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Type I interferons (IFNs) play critical roles in the host defense by modulating the expression of various genes via the IFN-dependent activation of STAT (signal transducers and activators of transcription) and NF-κB (nuclear factor kappa B) transcription factors. Previous studies established that IFNα/β activates NF-κB to promote cell survival through a PI-3K/Akt pathway, which involves serine phosphorylation and degradation of IκBα. We now describe a second pathway by which IFNs activate NF-κB that is independent of IκB degradation. This pathway involves NF-κB-inducing kinase (NIK) and the TNF-receptor associated factor-2 (TRAF-2), and results in IFNα/β induced processing of the p100/NF-κB2 precursor into p52. IFNα/β stimulates NF-κB DNA binding and NF-κB-dependent transcription. While expression of NIK and TRAF2 constructs causes NF-κB activation, expression of dominant negative NIK and TRAF2 constructs blocks IFN-promoted NF-κB activation and IFN-stimulated κB-dependent transcription, and IFNα/β induced processing of the p100/NF-κB2 precursor into p52. In contrast, PI-3K does not mediate IFNα/β induced p100 processing although PI3K is involved in the pathway resulting in IκBα degradation. Moreover, while IFN promotes cell survival in lymphoblastoid cells, expression of dominant negative NIK and TRAF2 constructs enhances IFN-induced apoptosis. Our results place for the first time NIK and TRAF2, previously shown to function in TNF signaling, within the IFN signal transduction pathway. Thus, IFN induces NF-κB activation to mediate IFN-dependent cell survival signals through a “canonical” pathway of IκBα proteolysis mediated by PI-3K/Akt and a “noncanonical” pathway of p100 processing mediated by NIK/TRAF.
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Type I interferons (IFNs) play critical roles in the host defense by modulating the expression of various genes via the IFN-dependent activation of signal transducers and activators of transcription and NF-kappaB (nuclear factor kappa B) transcription factors. Previous studies established that IFNalpha/beta activates NF-kappaB to promote cell survival through a phosphatidylinositol 3-kinase (PI3K)/Akt pathway, which involves serine phosphorylation and degradation of IkappaB alpha. We now describe a second pathway by which IFNs activate NF-kappaB that is independent of IkappaB degradation. This pathway involves NF-kappaB-inducing kinase (NIK) and the tumor necrosis factor receptor-associated factor-2 (TRAF2) and results in IFNalpha/beta-induced processing of the p100/NF-kappaB2 precursor into p52. IFNalpha/beta stimulates NF-kappaB DNA binding and NF-kappaB-dependent transcription. Whereas expression of NIK and TRAF2 constructs causes NF-kappaB activation, expression of dominant negative NIK and TRAF2 constructs blocks IFN-promoted NF-kappaB activation and IFN-stimulated kappaB-dependent transcription and IFNalpha/beta-induced processing of the p100/NF-kappaB2 precursor into p52. In contrast, PI3K does not mediate IFNalpha/beta-induced p100 processing, although PI3K is involved in the pathway resulting in IkappaB alpha degradation. Moreover, whereas IFN promotes cell survival in lymphoblastoid cells, expression of dominant negative NIK and TRAF2 constructs enhances IFN-induced apoptosis. Our results for the first time place NIK and TRAF2, previously shown to function in TNF signaling, within the IFN signal transduction pathway. Thus, IFN induces NF-kappaB activation to mediate IFN-dependent cell survival signals through a "canonical" pathway of IkappaB alpha proteolysis mediated by PI3K/Akt and a "noncanonical" pathway of p100 processing mediated by NIK/TRAF.
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The anti-inflammatory mechanism of lucidone isolated from the fruits of Lindera erythrocarpa Makino was investigated. Our data indicate that lucidone significantly inhibits the production of NO and PGE2 autacoids in LPS-induced RAW 264.7 murine macrophage cells. Moreover, it also notably decreased the secretion of tumor necrosis factor-alpha (TNF-α). Consistent with these observations, the mRNA and protein expression levels of iNOS and COX-2 were also inhibited by lucidone in a dose-dependent manner. Lucidone also reduced the translocation of NF-κB induced by LPS, which is associated with the prevention of the degradation of I-κB, and subsequently decreased p65/p50 protein levels in the nucleus. Lucidone also inhibited NF-κB activation by impairing the binding of NF-κB to its cis-acting element. In addition, lucidone inhibited JNK and p38MAPKs signals, which are the most significant signals involved in NO, PGE2 and TNF-α production; NF-κB/AP-1 activation was also inhibited by lucidone. Taken together, the anti-inflammatory activity of lucidone might be caused by the inhibition of iNOS and COX-2 expressions through downregulation of NF-κB and AP-1 binding.
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Abstract Heat shock protein‐27 ( HSP 27) is a member of the small HSP family which has been linked to the nuclear factor‐kappa B ( NF ‐ κB ) signaling pathway regulating inflammatory responses. Clinical reports have suggested that low‐level light therapy/laser irradiation ( LLLT ) could be an effective alternative treatment to relieve inflammation during bacterial infection associated with periodontal disease. However, it remains unclear how light irradiation can modulate the NF ‐ κB signaling pathway. We examined whether or not 635 nm irradiation could lead to a modulation of the NF ‐ kB signaling pathway in HSP 27‐silenced cells and analyzed the functional cross‐talk between these factors in NF ‐ κB activation. The results showed that 635 nm irradiation led to a decrease in the HSP 27 phosphorylation, reactive oxygen species ( ROS ) generation, I‐κB kinase ( IKK )/inhibitor of κB ( IκB )/ NF ‐ κB phosphorylation, NF ‐ κB p65 translocation and a subsequent decrease in the COX ‐1/2 expression and prostaglandin ( PGE 2 ) release in lipopolysaccharide( LPS )‐induced human gingival fibroblast cells ( hGFs ). However, in HSP 27‐silenced hGFs , no obvious changes were observed in ROS generation, IKK / IκB / NF ‐ κB phosphorylation, NF ‐ κB p65 translocation, nor in COX ‐1/2 expression, or PGE 2 release. This could be a mechanism by which 635 nm irradiation modulates LPS ‐induced NF ‐ κB signaling pathway via HSP 27 in inflammation. Thus, HSP 27 may play a role in regulating the anti‐inflammatory response of LLLT .
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Objective To study the suppressing effect molecular mechanism of extract from seeds of Magnolia zenii.(ESMZ) on NF-κB and IκBα.Methods Human hepatoma cancer cell HepG2 was treated with ESMZ.Western blot analysis was used to detect phospho-IκBα and NF-κB protein.Results ESMZ had significant suppressing effect on the phosphorylation and degradation of IκBα,and it could effectively suppress gene transcription mediated by NF-κB in HepG2 cell.Conclusion ESMZ can play a role of anti-inflammation and anti-carcinogenesis in human hepatoma cancer HepG cell line,by suppressing the phosphorylation and degradation of IκBα,blocking NF-κB activation and then restraining COX-2.
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Abstract Background: Dimethyl itaconate (DMI), a membrane-permeable derivative of itaconate, was found to moderate IL-17-IκBζ-induced skin pathology including psoriasis in mouse experiments . TNF-α induced NF-κB pathway, which controls a variety of immune and inflammatory responses, was also proven to play a crucial role as mediator in psoriasis. However, whether DMI interacts with the TNF-α induced NF-κB pathway remains unclear. Results: Here we show that DMI inhibits TNF-α induced NF-κB transcriptional activities in dose-dependent manner in several human cell lines using dual luciferase assay and blocks the NF-κB nuclear entry. Moreover, DMI potently inhibits IKKβ dependent phosphorylation and degradation of IκBα in TNF-α induced activation of NF-κB pathway. We also demonstrate that DMI covalently binds to cysteine residue in IKKβ, a key regulator in NF-κB pathway, to suppress IKKβ activation and inhibit the canonical NF-κB pathway. Conclusion Our study presents a new mechanism for DMI as an anti-inflammatory agent that may have therapeutic potentials in treating NF-κB related human inflammatory diseases. Our results also suggest that itaconate produced by endogenous IRG1 may regulate NF-κB at post translation modification level, and the IRG1-itaconate-NF-κB axis could be targeted as a novel strategy for the treatment of IRG1-NF-κB mediated diseases.
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The noncanonical nuclear factor-κB (NF-κB) signaling pathway mediates activation of the p52/RelB NF-κB complex and, thereby, regulates specific immunological processes. This NF-κB pathway relies on the inducible processing of NF-κB2 precursor protein, p100, as opposed to the degradation of IκBα in the canonical NF-κB pathway. A central signaling component of the noncanonical NF-κB pathway is NF-κB-inducing kinase (NIK), which functions together with a downstream kinase, IKKα (inhibitor of NF-κB kinase α), to induce phosphorylation-dependent ubiquitination and processing of p100. Under normal conditions, NIK is targeted for continuous degradation by a tumor necrosis factor (TNF) receptor-associated factor-3 (TRAF3)-dependent E3 ubiquitin ligase. In response to signals mediated by a subset of TNF receptor superfamily members, NIK becomes stabilized as a result of TRAF3 degradation, leading to the activation of noncanonical NF-κB. This review discusses both the historical perspectives and the recent progress in the regulation and biological function of the noncanonical NF-κB pathway.
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The nuclear factor-κB (NF-κB) transcription factors control many physiological processes including inflammation, apoptosis, and angiogenesis. In our search for NF-κB inhibitors from natural resources, we identified 4′,6-dihydroxy-4-methoxyisoaurone (ISOA) as an inhibitor of NF-κB activation from the seeds of Trichosanthes kirilowii. However, the mechanism by which ISOA inhibits NF-κB activation is not fully understood. In the present study, we demonstrated the effect of ISOA on NF-κB activation in TNF-α-stimulated HeLa cells. This compound suppressed NF-κB activation through the inhibition of IκB kinase (IKK) activation. ISOA also has an influence on upstream signaling of IKK through the inhibition of expression of adaptor proteins, TNF receptor-associated factor 2 (TRAF2) and receptor interacting protein 1 (RIP1). Consequently, ISOA blocked the phosphorylation and degradation of the inhibitor of NF-κB alpha (IκBα), and subsequent phosphorylation and nuclear translocation of p65. The suppression of NF-κB activation by ISOA led to the down-regulation of target genes involved in inflammation, proliferation, as well as potentiation of TNF-α-induced apoptosis. Taken together, this study extends our understanding on the mechanisms underlying the anti-inflammatory and anti-cancer activities of ISOA. Our findings provide new insight into the molecular mechanisms and a potential application of ISOA for inflammatory diseases as well as certain cancers.
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Abstract Background: Dimethyl itaconate (DMI), a membrane-permeable derivative of itaconate, was found to moderate IL-17-IκBζ-induced skin pathology including psoriasis in mouse experiments. TNF-α induced NF-κB pathway, which controls a variety of immune and inflammatory responses, was also proven to play a crucial role as mediator in psoriasis. However, whether DMI interacts with the TNF-α induced NF-κB pathway remains unclear. Results: Here we show that DMI inhibits TNF-α induced NF-κB transcriptional activities in dose-dependent manner in several human cell lines using dual luciferase assay and blocks the NF-κB nuclear entry. Moreover, DMI potently inhibits IKKβ dependent phosphorylation and degradation of IκBα in TNF-α induced activation of NF-κB pathway. We also demonstrate that DMI covalently binds to cysteine residue in IKKβ, a key regulator in NF-κB pathway, to suppress IKKβ activation and inhibit the canonical NF-κB pathway. Conclusion Our study presents a new mechanism for DMI as an anti-inflammatory agent that may have therapeutic potentials in treating NF-κB related human inflammatory diseases. Our results also suggest that itaconate produced by endogenous IRG1 may regulate NF-κB at post translation modification level, and the IRG1-itaconate-NF-κB axis could be targeted as a novel strategy for the treatment of IRG1-NF-κB mediated diseases.
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