Pyrin levels in human monocytes and monocyte derived macrophages regulate IL-1β processing and release (52.8)

Abstract

Abstract Macrophages and their precursors, monocytes, are key cells involved in the innate immune response. Although both monocytes and macrophages produce caspase-1, the key enzyme responsible for the processing of proIL-1β; macrophages are limited in their ability to process and release functional IL-1β. In this context, since mutations in the pyrin gene (MEFV) cause the inflammatory disorder familial Mediterranean fever, the protein pyrin is believed to regulate IL-1β. To determine whether variations in pyrin levels explain the difference between monocyte and macrophages in IL-1β processing and release, pyrin was studied in fresh human monocytes and monocyte derived macrophages. While fresh monocytes express pyrin protein and MEFV mRNA, monocyte derived macrophages have significantly less pyrin mRNA and protein. Since pyrin levels correlated with IL-1β processing, we asked whether pyrin may promote IL-1β processing and release. Pyrin induced IL-1β processing and release in a dose dependent fashion in HEK293 cells and pyrin overexpression in THP-1 cells confirmed the effect. Conversely, pyrin siRNA suppressed proIL-1β processing in both THP-1 cells and fresh human monocytes. In summary, pyrin expression and IL-1β processing and release is diminished upon the maturation of monocytes to macrophages. In the setting of endotoxin induced activation of mononuclear phagocytes, pyrin appears to augment IL-1β processing and release. Supported by grant NIH-NHLBI-HL40871 to MDW