In:
The Journal of Immunology, The American Association of Immunologists, Vol. 198, No. 1_Supplement ( 2017-05-01), p. 64.1-64.1
Abstract:
Mutations in the gene encoding pyrin (MEFV) are associated with autoinflammatory disorder Familial Mediterranean Fever (FMF). A “FMF-knock-in” (FMF-KI) mouse strain that expresses chimeric pyrin protein with a V726A mutation (MefvV726A/V726A) was generated to model human FMF. This mouse strain exhibits an autoinflammatory disorder that is prevented by genetic deletion of IL-1 receptor (IL-1R) or apoptosis-associated speck-like protein containing a CARD (ASC). ASC-mediated cell death leads to the release of IL-1α and IL-1β, both of which signal through IL-1R. Further, caspase-1 and caspase-8 can interact with ASC to mediate secretion of IL-1 cytokines. The specific IL-1 cytokine instigating development of FMF and the enzymatic caspase involved in its secretion are currently unknown. In this study, we demonstrate that the autoinflammation observed in MefvV726A/V726A mice is specifically mediated by IL-1β and not IL-1α. Furthermore, the disorder is dependent on the caspase-1-ASC axis, while caspase-8 is dispensable. Concurrently, aberrant IL-1β release by MefvV726A/V726A monocytes in response to stimulation with lipopolysaccharide is also dependent on the caspase-1-ASC axis. In conclusion, our studies have uncovered a specific role for caspase-1-mediated IL-1β release in the manifestation of FMF.
Type of Medium:
Online Resource
ISSN:
0022-1767
,
1550-6606
DOI:
10.4049/jimmunol.198.Supp.64.1
Language:
English
Publisher:
The American Association of Immunologists
Publication Date:
2017
detail.hit.zdb_id:
1475085-5
detail.hit.zdb_id:
3056-9
