Dataset Information

Prostaglandins E2 signal mediated by receptor subtype EP2 promotes IgE production in vivo and contributes to asthma development.

ABSTRACT: Prostaglandins E2 (PGE2) has been shown to enhance IgE production by B cells in vitro. The physiological and pathological relevance of this phenomenon and the underlying molecular mechanism, however, remain to be elucidated. B cells from wild type and EP2-deficient mice were compared in culture for their responses to PGE2 in terms of IgE class switching and production. Ovalbumin (OVA)-induced asthma models were used to evaluate the impact of EP2-deficiency on IgE responses and the development of asthma. PGE2 promoted IgE class switching, generation of IgE(+) cells and secretion of IgE by B cells stimulated with LPS+IL4. These effects were much attenuated as a consequence of EP2 deficiency. Consistent with the in vitro data, EP2-deficient mice showed a markedly suppressed IgE antibody response and developed less pronounced airway inflammation in the OVA-induced asthma model. Mechanistic studies demonstrated that PGE2, in an EP2-depedent manner, enhanced STAT6 activation induced by IL-4, thereby promoting the expression of IgE germline and post switch transcripts and the transcription of activation-induced cytidine deaminase (AID). Collectively, these data support an important regulatory role of the PGE2-EP2-STAT6 signaling pathway in IgE response and allergic diseases.

SUBMITTER: Gao Y

PROVIDER: S-EPMC4744937 | biostudies-literature |

REPOSITORIES: biostudies-literature

ACCESS DATA

Similar Datasets

Project description:What is already known about this subjectOmalizumab is a humanized anti-IgE monoclonal antibody that binds and captures circulating IgE, preventing interaction with receptors on mast cells and basophils, thereby interrupting the allergic cascade. It has a well-characterized efficacy and safety profile in patients with asthma. While omalizumab is known to reduce serum free IgE concentrations, effects on total IgE and IgE production are less well characterized.What this study adds(i) Confirmation of prior hypotheses that IgE production can decrease with time when patients are given anti-IgE therapy; (ii) guidance on a biomarker, total IgE, which can be used to ascertain whether individual patients experience a change in their IgE production; and (iii) a way to assess whether patients' IgE production has been sufficiently down-regulated such that they may consider stopping anti-IgE therapy.AimTo determine whether excessive IgE production by patients with atopic allergic asthma decreases with omalizumab therapy.MethodsOmalizumab, free and total IgE data were obtained from an epidemiological study and six randomized, double-blind, placebo-controlled trials in patients with allergic asthma. The binding between omalizumab and IgE together with the production and elimination of IgE were modelled as previously, except that, in order to explain why total IgE was decreasing over a period of 5 years, the expression of IgE was allowed to change.ResultsThe prior constant IgE production model failed to converge on the data once long-term observations were included, whereas models allowing IgE production to decrease fitted. A feedback model indicated that, on average, IgE production decreased by 54% per year. This model was further developed with covariate searches indicating clinically small but statistically significant effects of age, gender, body mass index and race on some parameters. Model predictions were checked internally and externally against 3-5 year data from paediatric and adult atopic asthmatic patients and externally against extensive total IgE data from a long-duration (>1 year) phase 1 study which was not used in the model building.ConclusionsA pharmacokinetic-pharmacodynamic model incorporating omalizumab-IgE binding and feedback for control of IgE production indicates that omalizumab reduces production of IgE. This raises the possibility that indefinite treatment may not be required, only for perhaps a few years. After the initial accumulation, total IgE should provide a means to monitor IgE production and guide individual treatment decisions.

Dataset Information

Prostaglandins E2 signal mediated by receptor subtype EP2 promotes IgE production in vivo and contributes to asthma development.

Similar Datasets

OmicsDI is part of the ELIXIR infrastructure

Tweets