Interleukin-4 receptor signaling and its binding mechanism: A therapeutic insight from inhibitors tool box

Ul-Haq, Zaheer; Naz, Sehrish; Mesaik, M. Ahmed

doi:10.1016/j.cytogfr.2016.04.002

Cited by 72 publications

(52 citation statements)

References 214 publications

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“…Our results are consistent with previous studies which identified gene-gene interactions as a major component in the pathogenesis of asthma [18]. These results can be explained by the fact that these interleukins share many signaling pathways and some can cross activate others' receptors [19].…”

Section: Discussionsupporting

confidence: 83%

Genetic Susceptibility to Asthma and Genetic Interactions in the 5q31-q33 and 16p11 Regions in Sudanese Families

Osman¹,

Amin²,

Salah³

et al. 2018

Immunome Res

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Background: Asthma is a complex disorder with heterogeneous phenotypes attributed to the interactions of many genes and the environment. Numerous genetic studies have mapped asthma susceptibility genes to a region on chromosome 5q31-q33. This study aimed to determine the association of 10 candidate polymorphisms in IL-4, IL-5, IL-9, IL-13 and IL-4R genes in 5q31-q33 region with susceptibility to asthma in Sudanese families.

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Section: Discussionsupporting

confidence: 83%

Genetic Susceptibility to Asthma and Genetic Interactions in the 5q31-q33 and 16p11 Regions in Sudanese Families

Osman¹,

Amin²,

Salah³

et al. 2018

Immunome Res

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“…3). IL-4 signalling through the IL-4Rα/STAT6 pathway has been shown to promote Th2 cytokine production and in turn the polarisation of innate/ adaptive immune cells towards regulatory function [36,37]. IL-4 is also implicated in cancer-associated immune regulation within the tumour microenvironment to avoid immune clearance [38].…”

Section: And Esmmentioning

confidence: 99%

Operational immune tolerance towards transplanted allogeneic pancreatic islets in mice and a non-human primate

et al. 2019

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Aims/hypothesis Patients with autoimmune type 1 diabetes transplanted with pancreatic islets to their liver experience significant improvement in quality of life through better control of blood sugar and enhanced awareness of hypoglycaemia. However, longterm survival and efficacy of the intrahepatic islet transplant are limited owing to liver-specific complications, such as immediate blood-mediated immune reaction, hypoxia, a highly enzymatic and inflammatory environment and locally elevated levels of drugs including immunosuppressive agents, all of which are injurious to islets. This has spurred a search for new islet transplant sites and for innovative ways to achieve long-term graft survival and efficacy without life-long systemic immunosuppression and its complications. Methods We used our previously established approach of islet transplant in the anterior chamber of the eye in allogeneic recipient mouse models and a baboon model of diabetes, which were treated transiently with anti-CD154/CD40L blocking antibody in the peri-transplant period. Survival of the intraocular islet allografts was assessed by direct visualisation in the eye and metabolic variables (blood glucose and C-peptide measurements). We evaluated longitudinally the cytokine profile in the local microenvironment of the intraocular islet allografts, represented in aqueous humour, under conditions of immune rejection vs tolerance. We also evaluated the recall response in the periphery of the baboon recipient using delayed-type hypersensitivity (DTH) assay, and in mice after repeat transplant in the kidney following initial transplant with allogeneic islets in the eye or kidney. Results Results in mice showed >300 days immunosuppression-free survival of allogeneic islets transplanted in the eye or kidney. Notably, >70% of tolerant mice, initially transplanted in the eye, exhibited >400 days of graft survival after retransplant in the kidney without immunosuppression compared with~30% in mice that were initially transplanted in the kidney. Cytokine and DTH data provided evidence of T helper 2-driven local and peripheral immune regulatory mechanisms in support of operational immune tolerance towards the islet allografts in both models.

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“…In particular there is evidence that IL-4 is crucial for Th2-cell differentiation from naive T cells. In addition IL-4 causes isotype class-switching of B cells toward IgE synthesis and it is involved in mast-cell recruitment and airway hyperresponsivity (Herz et al, 1998; Ryzhov et al, 2004; Chung, 2015; Ul-Haq et al, 2016). However, on the other hand, there is evidence that IL-4 may also reduce the activation of memory CD8 T cells and their following differentiation in NK cells, affecting in this way the immune response to pathogens.…”

Section: Introductionmentioning

confidence: 99%

Salvinorin A Inhibits Airway Hyperreactivity Induced by Ovalbumin Sensitization

et al. 2017

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Salvinorin A, a neoclerodane diterpene isolated from Salvia divinorum, exerts a number of pharmacological actions which are not solely limited to the central nervous system. Recently it has been demonstrated that Salvinorin A inhibits acute inflammatory response affecting leukotriene (LT) production. Since LTs are potent lipid mediators implicated in allergic diseases, we evaluated the effect of Salvinorin A on allergic inflammation and on airways following sensitization in the mouse. Mice were sensitized with s.c. injection of ovalbumin (OVA) on days 1 and 8. Sensitized mice received on days 9 and 12 on the shaved dorsal surface air administration to induce the development of the air-pouches. On day 15 animals were challenged by injection of OVA into the air-pouch. Salvinorin A, administered (10 mg/kg) before each allergen exposure, significantly reduced OVA-induced LT increase in the air pouch. This effect was coupled to a reduction in cell recruitment and Th2 cytokine production. In another set of experiments, mice were sensitized with OVA and both bronchial reactivity and pulmonary inflammation were assessed. Salvinorin A abrogated bronchial hyperreactivity and interleukin (IL)-13 production, without effect on pulmonary inflammation. Indeed cell infiltration and peribronchial edema were still present following diterpenoid treatment. Similarly, pulmonary IL-4 and plasmatic IgE levels were not modulated. Conversely, Salvinorin A significantly reduced LTC4 production in the lung of sensitized mice. Finally mast cell activity was evaluated by means of toluidine blue staining. Data obtained evidenced that Salvinorin A significantly inhibited mast cell degranulation in the lung. Our study demonstrates that Salvinorin A inhibits airway hyperreactivity induced by sensitization by inhibition of LT production and mast cell degranulation. In conclusion Salvinorin A could represent a promising candidate for drug development in allergic diseases such as asthma.

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Interleukin-4 receptor signaling and its binding mechanism: A therapeutic insight from inhibitors tool box

Cited by 72 publications

References 214 publications

Genetic Susceptibility to Asthma and Genetic Interactions in the 5q31-q33 and 16p11 Regions in Sudanese Families

Genetic Susceptibility to Asthma and Genetic Interactions in the 5q31-q33 and 16p11 Regions in Sudanese Families

Operational immune tolerance towards transplanted allogeneic pancreatic islets in mice and a non-human primate

Salvinorin A Inhibits Airway Hyperreactivity Induced by Ovalbumin Sensitization

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