scholarly journals Glucocorticoid receptor modulators CpdX and CpdX-D3 exhibit the same in vivo antiinflammatory activities as synthetic glucocorticoids

2019 ◽  
Vol 116 (28) ◽  
pp. 14191-14199 ◽  
Author(s):  
Guoqiang Hua ◽  
Naimah Zein ◽  
François Daubeuf ◽  
Pierre Chambon
Keyword(s):  
Glucocorticoid Receptor ◽  
Lung Inflammation ◽  
Antiinflammatory Activity ◽  
Inflammatory Diseases ◽  
Collagen Induced Arthritis ◽  
Allergic Lung Inflammation ◽  
Dust Mite ◽  
Receptor Modulators ◽  
Synthetic Glucocorticoids

We previously reported that the nonsteroidal compound CpdX, which was initially characterized 20 y ago as a possible gestagen and, shortly afterward, as a possible drug for treatments of inflammatory diseases, selectively triggers the NFκB/AP1-mediated tethered indirect transrepression function of the glucocorticoid receptor (GR), and could therefore be a selective glucocorticoid receptor agonistic modulator (SEGRAM). We now demonstrate that, upon administration to the mouse, CpdX and one of its deuterated derivatives, CpdX-D3, repress as efficiently as a synthetic glucocorticoid (e.g., Dexamethasone) an induced skin atopic dermatitis, an induced psoriasis-like inflammation, a house dust mite (HDM)-induced asthma-like allergic lung inflammation, a collagen-induced arthritis, an induced ulcerative colitis, and an ovalbumin-induced allergic conjunctivitis. Interestingly, in the cases of an HDM-induced asthma-like allergic lung inflammation and of a collagen-induced arthritis, the CpdX antiinflammatory activity was selectively exerted by one of the two CpdX enantiomers, namely, CpdX(eA) or CpdX-D3(eA).

scholarly journals Essential role of TNF receptor superfamily 25 (TNFRSF25) in the development of allergic lung inflammation

2008 ◽  
Vol 205 (5) ◽  
pp. 1037-1048 ◽  
Author(s):  
Lei Fang ◽  
Becky Adkins ◽  
Vadim Deyev ◽  
Eckhard R. Podack
Keyword(s):  
Lung Inflammation ◽  
Tumor Necrosis Factor Receptor ◽  
Nkt Cells ◽  
Dominant Negative ◽  
Th2 Cytokine ◽  
Early Signal ◽  
Allergic Lung Inflammation ◽  
Necrosis Factor

We identify the tumor necrosis factor receptor superfamily 25 (TNFRSF25)/TNFSF15 pair as critical trigger for allergic lung inflammation, which is a cardinal feature of asthma. TNFRSF25 (TNFR25) signals are required to exert T helper cell 2 (Th2) effector function in Th2-polarized CD4 cells and co-stimulate interleukin (IL)-13 production by glycosphingolipid-activated NKT cells. In vivo, antibody blockade of TNFSF15 (TL1A), which is the ligand for TNFR25, inhibits lung inflammation and production of Th2 cytokines such as IL-13, even when administered days after airway antigen exposure. Similarly, blockade of TNFR25 by a dominant-negative (DN) transgene, DN TNFR25, confers resistance to lung inflammation in mice. Allergic lung inflammation–resistant, NKT-deficient mice become susceptible upon adoptive transfer of wild-type NKT cells, but not after transfer of DN TNFR25 transgenic NKT cells. The TNFR25/TL1A pair appears to provide an early signal for Th2 cytokine production in the lung, and therefore may be a drug target in attempts to attenuate lung inflammation in asthmatics.

Effect of the oral thrombin inhibitor dabigatran on allergic lung inflammation induced by repeated house dust mite administration in mice

2015 ◽  
Vol 309 (8) ◽  
pp. L768-L775 ◽  
Author(s):  
Johannes D. de Boer ◽  
Lea C. Berkhout ◽  
Sacha F. de Stoppelaar ◽  
Jack Yang ◽  
Roelof Ottenhoff ◽  
...  
Keyword(s):  
House Dust ◽  
House Dust Mite ◽  
Lung Inflammation ◽  
Exposure Model ◽  
Thrombin Inhibitor ◽  
Lung Pathology ◽  
Coagulation Activation ◽  
Allergic Lung Inflammation ◽  
Dust Mite ◽  
Asthma Patients

Asthma is a chronic disease of the airways; asthma patients are hampered by recurrent symptoms of dyspnoea and wheezing caused by bronchial obstruction. Most asthma patients suffer from chronic allergic lung inflammation triggered by allergens such as house dust mite (HDM). Coagulation activation in the pulmonary compartment is currently recognized as a feature of allergic lung inflammation, and data suggest that coagulation proteases further drive inflammatory mechanisms. Here, we tested whether treatment with the oral thrombin inhibitor dabigatran attenuates allergic lung inflammation in a recently developed HDM-based murine asthma model. Mice were fed dabigatran (10 mg/g) or placebo chow during a 3-wk HDM airway exposure model. Dabigatran treatment caused systemic thrombin inhibitory activity corresponding with dabigatran levels reported in human trials. Surprisingly, dabigatran did not lead to inhibition of HDM-evoked coagulation activation in the lung as measured by levels of thrombin-antithrombin complexes and D-dimer. Repeated HDM administration caused an influx of eosinophils and neutrophils into the lungs, mucus production in the airways, and a T helper 2 response, as reflected by a rise in bronchoalveolar IL-4 and IL-5 levels and a systemic rise in IgE and HDM-IgG1. Dabigatran modestly improved HDM-induced lung pathology ( P < 0.05) and decreased IL-4 levels ( P < 0.01), without influencing other HDM-induced responses. Considering the limited effects of dabigatran in spite of adequate plasma levels, these results argue against clinical evaluation of dabigatran in patients with asthma.

OX40 blockade inhibits house dust mite driven allergic lung inflammation in mice and in vitro allergic responses in humans

2015 ◽  
Vol 45 (4) ◽  
pp. 1116-1128 ◽  
Author(s):  
Katie E. Burrows ◽  
Celine Dumont ◽  
Clare L. Thompson ◽  
Matthew C. Catley ◽  
Kate L. Dixon ◽  
...  
Keyword(s):  
House Dust ◽  
House Dust Mite ◽  
Lung Inflammation ◽  
Allergic Lung Inflammation ◽  
Dust Mite

In vivo hydroquinone exposure impairs allergic lung inflammation in rats

Toxicology ◽  
2007 ◽  
Vol 241 (1-2) ◽  
pp. 47-57 ◽  
Author(s):  
S.M.D. Macedo ◽  
S.C.M. Vaz ◽  
E.L.B. Lourenço ◽  
M. da Glória de Sousa ◽  
A.P. Ligeiro-Oliveira ◽  
...  
Keyword(s):  
Lung Inflammation ◽  
Allergic Lung Inflammation

scholarly journals MAFB surrogates the glucocorticoid receptor ability to induce tolerogenesis in dendritic cells

2021 ◽  
Author(s):  
Octavio Morante-Palacios ◽  
Laura Ciudad ◽  
Raphael Micheroli ◽  
Carlos de la Calle-Fabregat ◽  
Tianlu Li ◽  
...  
Keyword(s):  
Dendritic Cells ◽  
Immune Responses ◽  
Glucocorticoid Receptor ◽  
Inflammatory Diseases ◽  
Dna Demethylation ◽  
Regulatory Mechanisms ◽  
Cell Type ◽  
Cell Type Specific

Glucocorticoids (GCs) exert potent anti-inflammatory effects in immune cells through the glucocorticoid receptor (GR). Dendritic cells (DCs), central actors for coordinating immune responses, acquire tolerogenic properties in response to GCs. Tolerogenic DCs (tolDCs) have emerged as a potential treatment for various inflammatory diseases. To date, the underlying cell type-specific regulatory mechanisms orchestrating GC-mediated acquisition of immunosuppressive properties remain poorly understood. In this study, we investigated the transcriptomic and epigenomic remodeling associated with differentiation to DCs in the presence of GCs. Our analysis demonstrates a major role of MAFB in this process, in synergy with GR. GR and MAFB both interact with methylcytosine dioxygenase TET2 and bind to genomic loci that undergo specific demethylation in tolDCs. We also show that the role of MAFB is more extensive, binding to thousands of genomic loci in tolDCs. Finally, MAFB knockdown erases the tolerogenic properties of tolDCs and reverts the specific DNA demethylation and gene upregulation. The preeminent role of MAFB is also demonstrated in vivo for myeloid cells from synovium in rheumatoid arthritis following GC treatment. Our results imply that, once directly activated by GR, MAFB takes over the main roles to orchestrate the epigenomic and transcriptomic remodeling that define the tolerogenic phenotype.

Protease-activated receptor-2 deficient mice have reduced house dust mite-evoked allergic lung inflammation

2013 ◽  
Vol 20 (6) ◽  
pp. 618-625 ◽  
Author(s):  
J Daan de Boer ◽  
Cornelis van’t Veer ◽  
Ingrid Stroo ◽  
Anne J van der Meer ◽  
Alex F de Vos ◽  
...  
Keyword(s):  
House Dust ◽  
House Dust Mite ◽  
Lung Inflammation ◽  
Allergic Lung Inflammation ◽  
Dust Mite ◽  
Protease Activated Receptor 2 ◽  
Deficient Mice

scholarly journals The Extract of Chrysanthemum zawadskii var. latilobum Ameliorates Collagen-Induced Arthritis in Mice

2016 ◽  
Vol 2016 ◽  
pp. 1-12 ◽  
Author(s):  
A-Ram Kim ◽  
Hyuk Soon Kim ◽  
Do Kyun Kim ◽  
Jun Ho Lee ◽  
Young Hyo Yoo ◽  
...  
Keyword(s):  
Mechanism Of Action ◽  
Bone Erosion ◽  
Inflammatory Diseases ◽  
Osteoclast Differentiation ◽  
Human Rheumatoid Arthritis ◽  
Collagen Induced Arthritis ◽  
Mobility Shift ◽  
Chrysanthemum Zawadskii

Chrysanthemum zawadskii var. latilobum (CZ) has been used for beverage or tea and also as folk medicine for the remedy of diverse inflammatory diseases. Nevertheless, the therapeutic effect of CZ on arthritis remains to be unknown. In this paper we aim to investigate the CZ’s antiarthritic effect and mechanism of action both in vitro and in vivo. To assess CZ’s antiarthritic effect, mouse models of type II collagen-induced arthritis (CIA) were used. Mice were used to gauge clinical arthritis index and histopathological changes. Reverse transcriptase-polymerase chain reaction (RT-PCR), western blotting, electrophoretic mobility shift assay (EMSA), and other biological methods were adopted to measure CZ’s effect on arthritis and to understand the veiled mechanism of action. CZ greatly suppressed CIA, histopathological score, bone erosion, and osteoclast differentiation. Mechanistically, CZ inhibited the production of various inflammatory and arthritic mediators like inflammatory cytokines, matrix metalloproteinases (MMPs), and chemokines. Of note, CZ significantly suppressed the activation of the NF-κB pathway in vivo. CZ exerted an antiarthritic effect in CIA mice by curbing the production of crucial inflammatory and arthritis mediators. This study warrants further investigation of CZ for the use in human rheumatoid arthritis (RA).

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