IKK NBD peptide inhibits LPS induced pulmonary inflammation and alters sphingolipid metabolism in a murine model

Bismarck, Philipp von; Winoto-Morbach, Supandi; Herzberg, Mona; Uhlig, Ulrike; Schütze, Stefan; Lucius, Ralph; Krause, Martín

doi:10.1016/j.pupt.2012.03.002

Cited by 20 publications

(14 citation statements)

References 49 publications

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“…Previous mouse studies have demonstrated inhibitory effects of NBD peptide on NF-κB activity occurring between 24 and 48 hours after systemic administration [17], [18], [36]. The effects of NBD peptide on the phosphorylation status of IKK and IκBα were determined by immunoblot (Fig.…”

Section: Resultsmentioning

confidence: 99%

A Phase I Clinical Trial of Systemically Delivered NEMO Binding Domain Peptide in Dogs with Spontaneous Activated B-Cell like Diffuse Large B-Cell Lymphoma

Ndikuyeze

Gaurnier-Hausser

Patel³

et al. 2014

PLoS ONE

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Activated B-Cell (ABC) Diffuse Large B-Cell Lymphoma (DLBCL) is a common, aggressive and poorly chemoresponsive subtype of DLBCL, characterized by constitutive canonical NF-κB signaling. Inhibition of NF-κB signaling leads to apoptosis of ABC-DLBCL cell lines, suggesting targeted disruption of this pathway may have therapeutic relevance. The selective IKK inhibitor, NEMO Binding Domain (NBD) peptide effectively blocks constitutive NF-κB activity and induces apoptosis in ABC-DLBCL cells in vitro. Here we used a comparative approach to determine the safety and efficacy of systemic NBD peptide to inhibit constitutive NF-κB signaling in privately owned dogs with spontaneous newly diagnosed or relapsed ABC-like DLBCL. Malignant lymph nodes biopsies were taken before and twenty-four hours after peptide administration to determine biological effects. Intravenous administration of <2 mg/kg NBD peptide was safe and inhibited constitutive canonical NF-κB activity in 6/10 dogs. Reductions in mitotic index and Cyclin D expression also occurred in a subset of dogs 24 hours post peptide and in 3 dogs marked, therapeutically beneficial histopathological changes were identified. Mild, grade 1 toxicities were noted in 3 dogs at the time of peptide administration and one dog developed transient subclinical hepatopathy. Long term toxicities were not identified. Pharmacokinetic data suggested rapid uptake of peptide into tissues. No significant hematological or biochemical toxicities were identified. Overall the results from this phase I study indicate that systemic administration of NBD peptide is safe and effectively blocks constitutive NF-κB signaling and reduces malignant B cell proliferation in a subset of dogs with ABC-like DLBCL. These results have potential translational relevance for human ABC-DLBCL.

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Section: Resultsmentioning

confidence: 99%

A Phase I Clinical Trial of Systemically Delivered NEMO Binding Domain Peptide in Dogs with Spontaneous Activated B-Cell like Diffuse Large B-Cell Lymphoma

Ndikuyeze

Gaurnier-Hausser

Patel³

et al. 2014

PLoS ONE

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“…Hence, it is mandatory to cure innate immunity in CF patients and immunomodulatory agents are required to reduce the persistent inflammation that favours infection stabilization. From literature evidences it is clear that acute and chronic inflammation modulate sphingolipids and are, in turn, tuned by sphingolipid metabolites (2; 31; 39; 47). Accordingly, in CF human cells we showed: i) a basal higher amount of endogenously synthesized ceramide, that provides the cells with the ability to partially overcome the antiproliferative effect of sphingolipid de novo synthesis inhibition; ii) an increased expression of the rate limiting enzyme of sphingolipid de novo synthesis upon TNFα stimulation (Figure 2 B).…”

Section: Discussionmentioning

confidence: 99%

Anti-inflammatory action of lipid nanocarrier-delivered myriocin: therapeutic potential in cystic fibrosis

Caretti

Bragonzi²,

Facchini³

et al. 2014

Biochimica et Biophysica Acta (BBA) - General Subjects

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Background Sphingolipids take part in immune response and can initiate and/or sustain inflammation. Various inflammatory diseases have been associated with increased ceramide content, and pharmacological reduction of ceramide diminishes inflammation damage in vivo. Inflammation and susceptibility to microbial infection are two elements in a vicious circle. Recently, sphingolipid metabolism inhibitors were used to reduce infection. Cystic Fibrosis (CF) is characterized by a hyper-inflammation and an excessive innate immune response, which fails to evolve into adaptive immunity and to eradicate acute infection. This results in chronic infections, lung damage, and patient morbidity. Indeed, ceramide content in mucosa airways is higher in CF mouse models and in patients than in control mice or healthy subjects. Methods The potential of the de novo ceramide synthesis inhibitor myriocin in CF therapy was investigated in cells and mice models. Results We treated CF human respiratory epithelial cells with myriocin, an inhibitor of the rate limiting enzyme involved in de novo ceramide synthesis Serine Palmitoyl Transferase (SPT). This treatment resulted in reduced basal, as well as TNFα -stimulated, inflammation. In turn, TNFα induced an increase in SPT in these cells, linking de novo synthesis of ceramide and inflammation in a noxious loop. Furthermore, myriocin-loaded nanocarrier, injected intratrachea prior to P.aeruginosa challenge, allowed a significant reduction of lung infection and reduced inflammation. Conclusion The presented data suggest that de novo sphingolipid synthesis is constitutively enhanced in CF mucosa and that it can be envisaged as pharmacological target for modulating inflammation and restoring effective innate immunity against acute infection. General significance Myriocin stands as a powerful immunomodulatory agent for inflammatory and infectious diseases.

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“…Selective NF-κB inhibition by IKKγ NEMO Binding Domain (IKK-NBD) inhibitory peptide as an experimental pharmacological tool has been the matter of the last decade. IKK-NBD is cell-permeable low molecular peptide which binds to the regulatory NEMO (NF-κB Essential Modulator) subunit of IKK (IκB kinase) complex, thus preventing IκBα (Inhibitor of κB α) protein phosphorylation and related NF-κB activation (von Bismarck et al 2012). Recently, its in vivo administration has been examined in connection with various disorders as from rat cerebral ischemia-reperfusion injury model (Desai et al 2010) through murine Duchenne muscular dystrophy (Reay et al 2011) to trial in dogs with Diffuse large B-Cell lymphoma (Habineza Ndikuyeze et al 2014).…”

Section: Vol 66mentioning

confidence: 99%

“…Recently, its in vivo administration has been examined in connection with various disorders as from rat cerebral ischemia-reperfusion injury model (Desai et al 2010) through murine Duchenne muscular dystrophy (Reay et al 2011) to trial in dogs with Diffuse large B-Cell lymphoma (Habineza Ndikuyeze et al 2014). In respiratory tract, IKK-NBD had favorable effect in the treatment of LPS-induced pulmonary inflammation in mice (von Bismarck et al 2012) and surfactant "fortifier" in lavage model of ARDS in newborn piglets (Ankermann et al 2005, von Bismarck et al 2007, von Bismarck et al 2009). Considering that meconium aspiration syndrome (MAS) unites main features of both these conditions, surfactant dysfunction and TLR4-mediated inflammation, we were interested if IKK-NBD "upgrade" of surfactant therapy would have an additional benefit in the treatment of experimental MAS.…”

Section: Vol 66mentioning

confidence: 99%

Selective Inhibition of NF-κB and Surfactant Therapy in Experimental Meconium-Induced Lung Injury

Kopincova

Mikolka²,

M³

et al. 2017

Physiol Res

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Meconium aspiration syndrome (MAS) in newborns is characterized mainly by respiratory failure due to surfactant dysfunction and inflammation. Previous meta-analyses did not prove any effect of exogenous surfactant treatment nor glucocorticoid administration on final outcome of children with MAS despite oxygenation improvement. As we supposed there is the need to intervene in both these fields simultaneously, we evaluated therapeutic effect of combination of exogenous surfactant and selective inhibitor of NF-κB (IKK-NBD peptide). Young New Zealand rabbits were instilled by meconium suspension and treated by surfactant alone or surfactant in combination with IKK-NBD, and oxygen-ventilated for 5 h. PaO2/FiO2, oxygenation index, oxygen saturation and ventilation efficiency index were evaluated every hour; post mortem, total and differential leukocyte counts were investigated in bronchoalveolar lavage fluid (BALF) and inflammatory, oxidative and apoptotic markers were assessed in lung tissue homogenates. Exogenous surfactant combined with IKK-NBD improved oxygenation, reduced neutrophil count in BALF and levels of IL-1β, IL-6, p38 MAPK and caspase 3 in comparison with surfactant-only therapy. It seems that inhibition of inflammation may be strong supporting factor in surfactant treatment of MAS.

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IKK NBD peptide inhibits LPS induced pulmonary inflammation and alters sphingolipid metabolism in a murine model

Cited by 20 publications

References 49 publications

A Phase I Clinical Trial of Systemically Delivered NEMO Binding Domain Peptide in Dogs with Spontaneous Activated B-Cell like Diffuse Large B-Cell Lymphoma

A Phase I Clinical Trial of Systemically Delivered NEMO Binding Domain Peptide in Dogs with Spontaneous Activated B-Cell like Diffuse Large B-Cell Lymphoma

Anti-inflammatory action of lipid nanocarrier-delivered myriocin: therapeutic potential in cystic fibrosis

Selective Inhibition of NF-κB and Surfactant Therapy in Experimental Meconium-Induced Lung Injury

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