Thymoquinone attenuates proinflammatory responses in lipopolysaccharide-activated mast cells by modulating NF-kappaB nuclear transactivation

Gazzar, Mohamed A. El; Mezayen, Rabab El; Nicolls, Mark R.; Dreskin, Stephen C.

doi:10.1016/j.bbagen.2007.01.002

Cited by 70 publications

(56 citation statements)

References 60 publications

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“…These genes were either previously described as recruiting HP1 proteins to their promoters [1,4,6,20,21] or appeared in an earlier array analysis as regulated by HP1c [22]. RT-qPCR data revealed negative regulation of these genes upon DYRK1A depletion, confirming the array data.…”

Section: Dyrk1a Shares Target Genes With Hp1 Proteinssupporting

confidence: 76%

DYRK1A phoshorylates histone H3 to differentially regulate the binding of HP1 isoforms and antagonize HP1‐mediated transcriptional repression

et al. 2014

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Heterochromatin protein 1 (HP1) proteins are chromatin-bound transcriptional regulators. While their chromodomain binds histone H3 methylated on lysine 9, their chromoshadow domain associates with the H3 histone fold in a region involved in chromatin remodeling. Here, we show that phosphorylation at histone H3 threonine 45 and serine 57 within this latter region differentially affects binding of the three mammalian HP1 isoforms HP1a, HP1b and HP1c. Both phosphorylation events are dependent on the activity of the DYRK1A kinase that antagonizes HP1-mediated transcriptional repression and participates in abnormal activation of cytokine genes in Downs syndrome-associated megakaryoblastic leukemia.

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Section: Dyrk1a Shares Target Genes With Hp1 Proteinssupporting

confidence: 76%

DYRK1A phoshorylates histone H3 to differentially regulate the binding of HP1 isoforms and antagonize HP1‐mediated transcriptional repression

et al. 2014

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“…TQ has been shown to inhibit NF-nB activation in a rat model of brain and spinal cord experimental autoimmune encephalomyelitis (55) and induced by lipopolysaccharide in mast cells (56) and advanced glycation end products in proximal tubular epithelial cells (57); however, none of these reports described the mechanism by which TQ suppresses NF-nB activation. We investigated in detail how TQ inhibits the NF-nB activation pathway.…”

Section: Discussionmentioning

confidence: 96%

Targeting Nuclear Factor-κB Activation Pathway by Thymoquinone: Role in Suppression of Antiapoptotic Gene Products and Enhancement of Apoptosis

Sethi

Ahn

Aggarwal

2008

Molecular Cancer Research

291

218

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Thymoquinone (TQ), derived from the medicinal plant Nigella sativa, exhibits antiinflammatory and anticancer activities through mechanism(s) that is not fully understood. Because numerous effects modulated by TQ can be linked to interference with the nuclear factor-KB (NF-KB) signaling, we investigated in detail the effect of this quinone on NF-KB pathway. As examined by DNA binding, we found that TQ suppressed tumor necrosis factor -induced NF-KB activation in a dose-and time-dependent manner and inhibited NF-KB activation induced by various carcinogens and inflammatory stimuli. The suppression of NF-KB activation correlated with sequential inhibition of the activation of IKBA kinase, IKBA phosphorylation, IKBA degradation, p65 phosphorylation, p65 nuclear translocation, and the NF-KB -dependent reporter gene expression. TQ specifically suppressed the direct binding of nuclear p65 and recombinant p65 to the DNA, and this binding was reversed by DTT. However, TQ did not inhibit p65 binding to DNA when cells were transfected with the p65 plasmid containing cysteine residue 38 mutated to serine. TQ also down-regulated the expression of NF-KB -regulated antiapoptotic (IAP1, IAP2, XIAP Bcl-2, Bcl-xL, and survivin), proliferative (cyclin D1, cyclooxygenase-2, and c-Myc), and angiogenic (matrix metalloproteinase-9 and vascular endothelial growth factor) gene products. This led to potentiation of apoptosis induced by tumor necrosis factor and chemotherapeutic agents. Overall, our results indicate that the anticancer and antiinflammatory activities previously assigned to TQ may be mediated in part through the suppression of the NF-KB activation pathway, as shown here, and thus may have potential in treatment of myeloid leukemia and other cancers.

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“…In LPS-activated RBL-2H3 cells, thymoquinone at concentration of 10 μM suppressed the production of Th2-associated cytokines IL-5 and IL-13 (but not IL-10), which play a role in the pathogenesis of allergic inflammation [11] and the production of TNF- [12]. Thymoquinone inhibited IL-5 and IL-13 cytokine production by blocking GATA transcription factor expression and binding to the cytokine gene promoter [11] and TNF-production by modulating nuclear transactivation of NF-B [12]. Thymoquinone suppressed NF-B activation through modulation of the p65 subunit of NF-B and inhibition of IKK also in human chronic myeloid leukaemia cells KBM-5 [14].…”

Section: Discussionmentioning

confidence: 99%

Effect of Thymoquinone on Mouse Dendritic Cells

Xuân¹,

Shumilina²,

Qadri³

et al. 2010

Cell Physiol Biochem

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Thymoquinone, a component of Nigella sativa is known to confer protection against tumour growth due to stimulation of tumour cell apoptosis. Moreover, thymoquinone has remarkable anti-inflammatory potency. Surprisingly, despite its powerful influence on inflammation and its immunomodulatory effects, little is known about its effect on dendritic cells (DCs), key players in the regulation of innate and adaptive immunity. DC maturation and cytokine release is triggered by bacterial components such as lipopolysaccharides (LPS). The present study explored whether thymoquinone modifies LPS-induced DC maturation, survival and cytokine release. To this end, mouse bone marrow derived DCs were treated with LPS and different concentrations of thymoquinone and the surface expression of CD11c, CD86, MHCII, CD54 and CD40 was determined by FACS analysis, the formation of the interleukins 10 (IL-10) and 12 (IL-12p70) as well as TNF-α by ELISA, caspase activation by FITC-labelled antibodies (FACS), cell membrane scrambling by annexin V binding (FACS) and Akt and ERK1/2 phosphorylation by Western blotting. LPS increased the percentage of CD11c⁺CD86⁺, CD11c⁺MHCII⁺, CD11c⁺CD40⁺ and CD11c⁺CD54⁺ cells and stimulated the release of IL-10, IL-12p70 and TNF-α. These effects were blunted by thymoquinone in a concentration dependent manner (1-20 µM). Moreover, LPS decreased and thymoquinone increased caspase 3 and caspase 8 activation and annexin V binding. Moreover, LPS-induced phosphorylation of prosurvival kinases Akt and ERK1/2 was abrogated by thymoquinone. In conclusion, thymoquinone compromises the maturation, cytokine release and survival of DCs.

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Thymoquinone attenuates proinflammatory responses in lipopolysaccharide-activated mast cells by modulating NF-kappaB nuclear transactivation

Cited by 70 publications

References 60 publications

DYRK1A phoshorylates histone H3 to differentially regulate the binding of HP1 isoforms and antagonize HP1‐mediated transcriptional repression

DYRK1A phoshorylates histone H3 to differentially regulate the binding of HP1 isoforms and antagonize HP1‐mediated transcriptional repression

Targeting Nuclear Factor-κB Activation Pathway by Thymoquinone: Role in Suppression of Antiapoptotic Gene Products and Enhancement of Apoptosis

Effect of Thymoquinone on Mouse Dendritic Cells

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