The steroidogenic enzyme Cyp11a1 is essential for development of peanut-induced intestinal anaphylaxis - 30/10/13
Abstract |
Background |
Cytochrome P450, family 11, subfamily A, polypeptide 1 (Cyp11a1), a cytochrome P450 enzyme, is the first and rate-limiting enzyme in the steroidogenic pathway, converting cholesterol to pregnenolone. Cyp11a1 expression is increased in activated T cells.
Objectives |
We sought to determine the role of Cyp11a1 activation in the development of peanut allergy and TH cell functional differentiation.
Methods |
A Cyp11a1 inhibitor, aminoglutethimide (AMG), was administered to peanut-sensitized and challenged mice. Clinical symptoms, intestinal inflammation, and Cyp11a1 levels were assessed. The effects of Cyp11a1 inhibition on TH1, TH2, and TH17 differentiation were determined. Cyp11a1 gene silencing was performed with Cyp11a1-targeted short hairpin RNA.
Results |
Peanut sensitization and challenge resulted in diarrhea, inflammation, and increased levels of Cyp11a1, IL13, and IL17A mRNA in the small intestine. Inhibition of Cyp11a1 with AMG prevented allergic diarrhea and inflammation. Levels of pregnenolone in serum were reduced in parallel. AMG treatment decreased IL13 and IL17A mRNA expression in the small intestine without affecting Cyp11a1 mRNA or protein levels. In vitro the inhibitor decreased IL13 and IL17A mRNA and protein levels in differentiated TH2 and TH17 CD4 T cells, respectively, without affecting GATA3, retinoic acid–related orphan receptor γt (RORγt), or TH1 cells and IFNG and T-bet expression. Short hairpin RNA–mediated silencing of Cyp11a1 in polarized TH2 CD4 T cells significantly decreased pregnenolone and IL13 mRNA and protein levels.
Conclusion |
Cyp11a1 plays an important role in the development of peanut allergy, regulating peanut-induced allergic responses through effects on steroidogenesis, an essential pathway in TH2 differentiation. Cyp11a1 thus serves as a novel target in the regulation and treatment of peanut allergy.
Le texte complet de cet article est disponible en PDF.Key words : Cyp11a1, peanut allergy, TH2, TH17, CD4 T cells
Abbreviations used : AMG, CFP, Cyp11a1, GC, PE, RORγt, RT-PCR, shRNA
Plan
| Supported by National Institutes of Health grants T32 AI-07405 (to J.R.), AI-81878 and AI-98417 (to J.R.H.), and HL-36577 and AI-77609 (to E.W.G.). M.W. was supported by a fellowship from the Eugene F. and Easton M. Crawford Charitable Lead Unitrust. The content is solely the responsibility of the authors and does not necessarily represent the official views of the National Heart, Lung, and Blood Institute or the National Institutes of Health. |
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| Disclosure of potential conflict of interest: M. A. Seibold is a Board member for Genentech and has received in-kind support for beta testing of sequencing protocols from Life Technologies. J. R. Hagman has been supported by one or more grants from National Jewish Health and has received one or more payments for lecturing from or is on the speakers' bureau for the University of Chicago. The rest of the authors declare that they have no relevant conflicts of interest. |
Vol 132 - N° 5
P. 1174 - novembre 2013 Retour au numéro
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