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- Title
Prostaglandin I2 Signaling and Inhibition of Group 2 Innate Lymphoid Cell Responses.
- Authors
Weisong Zhou; Shinji Toki; Jian Zhang; Goleniewksa, Kasia; Newcomb, Dawn C.; Cephus, Jacqueline Y.; Dulek, Daniel E.; Bloodworth, Melissa H.; Stier, Matthew T.; Polosuhkin, Vasiliy; Gangula, Rama D.; Mallal, Simon A.; Broide, David H.; Stokes Peebles Jr, R.; Zhou, Weisong; Toki, Shinji; Zhang, Jian; Peebles, R Stokes Jr
- Abstract
<bold>Rationale: </bold>Group 2 innate lymphoid cells (ILC2s) robustly produce IL-5 and IL-13, cytokines central to the asthma phenotype; however, the effect of prostaglandin (PG) I2 on ILC2 function is unknown.<bold>Objectives: </bold>To determine the effect of PGI2 on mouse and human ILC2 cytokine expression in vitro and the effect of endogenous PGI2 and the PGI2 analog cicaprost on lung ILC2s in vivo.<bold>Methods: </bold>Flow-sorted bone marrow ILC2s of wild-type (WT) and PGI2 receptor-deficient (IP(-/-)) mice were cultured with IL-33 and treated with the PGI2 analog cicaprost. WT and IP(-/-) mice were challenged intranasally with Alternaria alternata extract for 4 consecutive days to induce ILC2 responses, and these were quantified. Prior to A. alternata extract, challenged WT mice were treated with cicaprost. Human flow-sorted peripheral blood ILC2s were cultured with IL-33 and IL-2 and treated with the PGI2 analog cicaprost.<bold>Measurement and Main Results: </bold>We demonstrate that PGI2 inhibits IL-5 and IL-13 protein expression by IL-33-stimulated ILC2s purified from mouse bone marrow in a manner that was dependent on signaling through the PGI2 receptor IP. In a mouse model of 4 consecutive days of airway challenge with an extract of A. alternata, a fungal aeroallergen associated with severe asthma exacerbations, endogenous PGI2 signaling significantly inhibited lung IL-5 and IL-13 protein expression, and reduced the number of lung IL-5- and IL-13-expressing ILC2s, as well as the mean fluorescence intensity of IL-5 and IL-13 staining. In addition, exogenous administration of a PGI2 analog inhibited Alternaria extract-induced lung IL-5 and IL-13 protein expression, and reduced the number of lung IL-5- and IL-13-expressing ILC2s and the mean fluorescence intensity of IL-5 and IL-13 staining. Finally, a PGI2 analog inhibited IL-5 and IL-13 expression by human ILC2s that were stimulated with IL-2 and IL-33.<bold>Conclusions: </bold>These results suggest that PGI2 may be a potential therapy to reduce the ILC2 response to protease-containing aeroallergens, such as Alternaria.
- Subjects
ANIMAL experimentation; CELLULAR signal transduction; FUNGI; INTERLEUKINS; LUNGS; LYMPHOCYTES; MICE; PROSTACYCLIN; RESEARCH funding; IN vitro studies; PHARMACODYNAMICS; PHYSIOLOGY
- Publication
American Journal of Respiratory & Critical Care Medicine, 2016, Vol 193, Issue 1, p31
- ISSN
1073-449X
- Publication type
journal article
- DOI
10.1164/rccm.201410-1793OC