IκB kinase β inhibitor, IMD-0354, prevents allergic asthma in a mouse model through inhibition of CD4+ effector T cell responses in the lung-draining mediastinal lymph nodes

Maślanka, Tomasz; Otrocka-Domagała, Iwona; Zuśka-Prot, Monika; Mikiewicz, Mateusz; Przybysz, Jagoda; Jasiecka, Agnieszka; Jaroszewski, Jerzy Jan

doi:10.1016/j.ejphar.2016.02.023

Cited by 10 publications

(10 citation statements)

References 35 publications

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“…Overall, our study showed that inhibition of IKKb in vivo using IMD-0354 during 3-day unloading prevented IjBa degradation in soleus muscle, but failed to diminish expression of MuRF1 and MAFbx ubiquitin ligases and muscle atrophy. The review of all available publications where IMD-0354 was used in animal models showed that this inhibitor does not have indirect or systemic effects with negative consequences for the health of the animals (Maslanka et al 2016;Zhou et al 2016). Therefore, we do not think that our observations are due to the systemic effects of IMD-0354 during unloading.…”

Section: Transcription Factors Of Nf-jb Pathwaymentioning

confidence: 83%

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Paradoxical effect of IKKβ inhibition on the expression of E3 ubiquitin ligases and unloading-induced skeletal muscle atrophy

et al. 2017

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We tested whether NF‐κB pathway is indispensable for the increase in expression of E3‐ligases and unloading‐induced muscle atrophy using IKKβ inhibitor IMD‐0354. Three groups of rats were used: nontreated control (C), 3 days of unloading/hindlimb suspension with (HS+IMD) or without (HS) IMD‐0354. Levels of IκBα were higher in HS+IMD (1.16‐fold) and lower in HS (0.82‐fold) when compared with C group. IMD‐0354 treatment during unloading: had no effect on loss of muscle mass; increased mRNA levels of MuRF1 and MAFbx; increased level of pFoxO3; and had no effect on levels of Bcl‐3, p105, and p50 proteins. Our study for the first time showed that inhibiting IKK β in vivo during 3‐day unloading failed to diminish expression of ubiquitin ligases and prevent muscle atrophy.

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Section: Transcription Factors Of Nf-jb Pathwaymentioning

confidence: 83%

“…The review of all available publications where IMD‐0354 was used in animal models showed that this inhibitor does not have indirect or systemic effects with negative consequences for the health of the animals (Maslanka et al. 2016; Zhou et al. 2016).…”

Section: Discussionmentioning

confidence: 99%

Paradoxical effect of IKKβ inhibition on the expression of E3 ubiquitin ligases and unloading-induced skeletal muscle atrophy

et al. 2017

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“…Peripheral blood (PB) was drawn from the inferior vena cava into heparinized tubes. Erythrocytes were removed as it was previously described [18]. Crystallizable fragment (Fc) receptors were blocked using anti-FcγR monoclonal antibody (mAb) (clone: 2.4G2) for 15 min on ice.…”

Section: Methodsmentioning

confidence: 99%

CD25+CD127+Foxp3- Cells Represent a Major Subpopulation of CD8+ T Cells in the Eye Chambers of Normal Mice

et al. 2017

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The aim of this study has been to determine whether eye chambers constitute part of the normal migratory pathway of naive CD4+ and CD8+ T cells in mouse and if natural CD4+CD25+Foxp3+ and CD8+CD25+Foxp3+ regulatory T cells are present within these eye compartments. To this aim, the cells obtained from aqueous humor (AH) of normal mice were phenotyped in terms of the expression CD4, CD8, CD25, CD127 and transcription factor Foxp3. The mean percentage of CD8+ T cells in the total AH lymphocyte population was as high as 28.69%; the mean percentage of CD8high and CD8low cells in this population was 34.09% and 65.91%, respectively. The presence of cells with the regulatory phenotype, i.e. CD25+Foxp3+ cells, constituted only 0.32% of CD8+ T cell subset. Regarding the expression of CD25, AH CD8+ T cells were an exceptional population in that nearly 85% of these cells expressed this molecule without concomitant Foxp3 expression. Despite having this phenotype, they should not be viewed as activated cells because most of them co-expressed CD127, which indicates that they are naive lymphocytes. With regard to the markers applied in the present research, CD8+CD25+CD127+Foxp3- T cells represent the most numerous subset of AH CD8+ cells. The results suggest that eye chambers in mice are an element in the normal migratory pathway of naive CD8+ T cells. The study presented herein demonstrated only trace presence of CD4+ cells in the eye chambers, as the mean percentage of these cells was just 0.56. Such selective and specific homing of CD8+ and CD4+ cells to the eye chambers is most clearly engaged in the induction and maintenance of ocular immune privilege.

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“…In fact, P2X1 receptor blockade may contribute to or even be a causative for the observed cardioprotective, 45 anti-cancer, 71 anti-proliferative, 47 and antiinflammatory effects. 72 We synthesized a series of 56 salicylanilide derivatives and analogues, including 15 new compounds, which have not been previously described in the literature. Variations of substituents and linker modification around the salicyanilide scaffold were extensively explored.…”

Section: ■ Conclusionmentioning

confidence: 99%

Discovery and Structure Relationships of Salicylanilide Derivatives as Potent, Non-acidic P2X1 Receptor Antagonists

et al. 2020

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Antagonists for the ATP-gated ion channel receptor P2X1 have potential as antithrombotics and for treating hyperactive bladder and inflammation. In this study, salicylanilide derivatives were synthesized based on a screening hit. P2X1 antagonistic potency was assessed in 1321N1 astrocytoma cells stably transfected with the human P2X1 receptor by measuring inhibition of the ATP-induced calcium influx. Structure–activity relationships were analyzed, and selectivity versus other P2X receptor subtypes was assessed. The most potent compounds, N-[3,5-bis(trifluoromethyl)phenyl]-5-chloro-2-hydroxybenzamide (1, IC50 0.0192 μM) and N-[3,5-bis(trifluoromethyl)phenyl]-4-chloro-2-hydroxybenzamide (14, IC50 0.0231 μM), displayed >500-fold selectivity versus P2X2 and P2X3, and 10-fold selectivity versus P2X4 and P2X7 receptors, and inhibited collagen-induced platelet aggregation. They behaved as negative allosteric modulators, and molecular modeling studies suggested an extracellular binding site. Besides selective P2X1 antagonists, compounds with ancillary P2X4 and/or P2X7 receptor inhibition were discovered. These compounds represent the first potent, non-acidic, allosteric P2X1 receptor antagonists reported to date.

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IκB kinase β inhibitor, IMD-0354, prevents allergic asthma in a mouse model through inhibition of CD4+ effector T cell responses in the lung-draining mediastinal lymph nodes

Cited by 10 publications

References 35 publications

Paradoxical effect of IKKβ inhibition on the expression of E3 ubiquitin ligases and unloading-induced skeletal muscle atrophy

Paradoxical effect of IKKβ inhibition on the expression of E3 ubiquitin ligases and unloading-induced skeletal muscle atrophy

CD25+CD127+Foxp3- Cells Represent a Major Subpopulation of CD8+ T Cells in the Eye Chambers of Normal Mice

Discovery and Structure Relationships of Salicylanilide Derivatives as Potent, Non-acidic P2X1 Receptor Antagonists

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