Flagellin positively and negatively regulates IL‐1β expression via Ipaf and TLR5

IL‐1β plays a pivotal role in health/disease. Consequently, regulation of IL‐1β bioactivity is multi‐faceted including inflammasome‐mediated processing of pro‐IL‐1β to mature IL‐1β and production of secretory IL‐1 receptor antagonist (sIL‐1Ra), which blocks IL‐1β activity. We sought to define how IL‐1β bioactivity is regulated in response to bacterial flagellin. We examined production of IL‐1β and sIL‐1Ra in vitro, in intestinal epithelial cells (IEC), macrophages, and mice treated with flagellin. Exposure of macrophages to 10μg/ml flagellin did not induce typical activation markers (e.g. IL‐6) but resulted in internalization of flagellin and production of Il‐1β that was dependent on both Ipaf and caspace‐1, but not TLR5. Conversely, although quite responsive to flagellin, IEC neither internalized flagellin nor produced IL‐1β suggesting that, in vivo, flagellin‐induced IL‐1β production is mediated by macrophage Ipaf. In contrast, production of sIL‐Ra, in vivo, was mediated by TLR5 suggesting loss of TLR5 might result in excessive flagellin‐induced IL‐1β activity. In accordance, while administration of flagellin to mice lacks toxicity in WT mice, flagellin‐treated TLR5 −/− developed lasting inflammatory pathology. Thus, dual opposing regulation of flagellin‐induced Il‐1β activity by Ipaf and TLR5 mediates host defense while protecting against excessive inflammation.