Amelioration of acute inflammation by systemic administration of a cell‐permeable peptide inhibitor of NF‐κB activation

Meglio, Paola Di; Ianaro, Angela; Ghosh, Sankar

doi:10.1002/art.20960

Cited by 84 publications

(73 citation statements)

References 24 publications

(39 reference statements)

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“…Moreover, kidneys from NBDtreated mice displayed less intranuclear NF-κB activity and NF-κB-regulated gene expression, along with an attenuation of diabetes-induced structural and functional abnormalities. These results are comparable to those reported with different cell-permeable NBD versions in animal models of acute inflammation [10,39], arthritis [38], inflammatory bowel disease [35], lung inflammation [40], muscular dystrophy [41], B cell lymphoma [42] and neuroinflammation [37].…”

Section: Resultssupporting

confidence: 87%

Peptide-based inhibition of IκB kinase/nuclear factor-κB pathway protects against diabetes-associated nephropathy and atherosclerosis in a mouse model of type 1 diabetes

et al. 2015

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Aims/hypothesis The canonical nuclear factor-κB (NF-κB) pathway mediated by the inhibitor of NF-κB kinase (IKK) regulates the transcription of inflammatory genes involved in the pathogenesis of diabetes, from the early phase to progression and final complications. The NF-κB essential modulator binding domain (NBD) contained in IKKα/β is essential for IKK complex assembly. We therefore investigated the functional consequences of targeting the IKK-dependent NF-κB pathway in the progression of diabetes-associated nephropathy and atherosclerosis.Methods Apolipoprotein E-deficient mice with diabetes induced by streptozotocin were treated with a cell-permeable peptide derived from the IKKα/β NBD region. Kidneys and aorta were analysed for morphology, leucocyte infiltrate, collagen, NF-κB activity and gene expression. In vitro studies were performed in renal and vascular cells. Results NBD peptide administration did not affect the metabolic severity of diabetes but resulted in renal protection, as evidenced by dose-dependent decreases in albuminuria, renal lesions (mesangial expansion, leucocyte infiltration and fibrosis), intranuclear NF-κB activity and proinflammatory and pro-fibrotic gene expression. Furthermore, peptide treatment limited atheroma plaque formation in diabetic mice by decreasing the content of lipids, leucocytes and cytokines and increasing plaque stability markers. This nephroprotective and anti-atherosclerotic effect was accompanied by a decline in systemic T helper 1 cytokines. In vitro, NBD peptide prevented IKK assembly/activation, p65 nuclear translocation, NF-κB-regulated gene expression and cell proliferation induced by either high glucose or inflammatory stimulation. Conclusions/interpretation Peptide-based inhibition of IKK complex formation attenuates NF-κB activation, suppresses inflammation and retards the progression of renal and vascular injury in diabetic mice, thus providing a feasible approach against diabetes inflammatory complications.

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Section: Resultssupporting

confidence: 87%

Peptide-based inhibition of IκB kinase/nuclear factor-κB pathway protects against diabetes-associated nephropathy and atherosclerosis in a mouse model of type 1 diabetes

et al. 2015

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“…This stresses the importance of NF-B signaling in IL-13-induced inflammatory diseases. Our results go in accord with other studies demonstrating down-regulatory effects of NF-B inhibitions on asthmatic inflammation (24 -28) and suppression of the inflammatory processes associated with other pathologies (31,37,50). In addition, individual NF-B-based interventions lead to the reduction of other aspects of IL-13-induced airway remodeling characteristic of asthma (51), such as airway wall thickening (Figs.…”

Section: Discussionsupporting

confidence: 92%

“…On day 8, mice were euthanized and BAL was performed as described. The optimal dose and route for WT-NBD administration were determined in the carrageenan-induced paw edema study (37).…”

Section: Experimental Protocolsmentioning

confidence: 99%

Inhibition of NF-κB Activation Reduces the Tissue Effects of Transgenic IL-13

Chapoval

Al-Garawi²,

Lora³

et al. 2007

The Journal of Immunology

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IL-13 is a major Th2 cytokine that is capable of inducing inflammation, excessive mucus production, airway hyperresponsiveness, alveolar remodeling, and fibrosis in the murine lung. Although IL-13 through its binding to IL-4Rα/IL-13Rα1 uses the canonical STAT6-signaling pathway to mediate these tissue responses, recent studies have demonstrated that other signaling pathways may also be involved. Previous studies from our laboratory demonstrated that IL-13 mediates its tissue effects by inducing a wide variety of downstream genes many of which are known to be regulated by NF-κB. As a result, we hypothesized that NF-κB activation plays a critical role in the pathogenesis of IL-13-induced tissue alterations. To test this hypothesis, we compared the effects of transgenic IL-13 in mice with normal and diminished levels of NF-κB activity. Three pharmacologic approaches were used to inhibit NF-κB including 1) PS1145, a small molecule inhibitor of IκBα kinase (IKK2), 2) antennapedia-linked NF-κB essential modulator-binding domain (NBD) peptide (wild-type NBD), and 3) an adenoviral construct expressing a dominant-negative version of IKK2. We also crossed IL-13-transgenic mice with mice with null mutations of p50 to generate mice that overproduced IL-13 in the presence and absence of this NF-κB component. These studies demonstrate that all these interventions reduced IL-13-induced tissue inflammation, fibrosis and alveolar remodeling. In addition, we show that both PS1145 and wild-type NBD inhibit lung inflammatory and structural cell apoptosis. PS1145 inhibits caspase activation and up-regulates inhibitor of apoptosis protein cellular-inhibitor of apoptosis protein 1 (c-IAP-1). Therefore, NF-κB is an attractive target for immunotherapy of IL-13-mediated diseases.

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“…In particular, introduction of a cellpermeable 10 amino-acid peptide corresponding to the NEMO-binding domain of IKKb can block both the binding of NEMO to IKK and induction of NF-kB canonical pathway by TNF (May et al, 2000). Moreover, this peptide has shown efficacy in mouse models of inflammation by both topical and systemic administration (May et al, 2000;di Meglio et al, 2005). Similarly, introduction of peptides corresponding to the region of NEMO including the coiled-coil-2 and leucine zipper, which are required for oligomerization of NEMO, can also block NF-kB activation (Agou et al, 2004).…”

Section: Inhibitors Of Ikk Complex Activitiesmentioning

confidence: 99%