Introduction: The IKK/NF-kappaB pathway is activated very early in acute pancreatitis (AP). The
role of specific subunits of this pathway in AP however remains unclear so far. In
particular, the role of the atypical Bcl-3 protein which resides predominantly in
the nucleus and is not degraded upon NF-kappaB activation has not been addressed.
Material and methods: Using Bcl-3 deficient mice (Bcl3–/–
), local damage and the systemic complications of AP were analyzed. Bone marrow transplantation
experiments of Bcl3–/–
and control mice were performed to scrutinize the role of Bcl-3 in vivo.
Results: Our data showed that Bcl-3 is up-regulated in AP. Its genetical inhibition resulted
in a deteriorated form of AP and high lethality, although NF-kappaB activity was not
different. Proinflammatory chemokines and cytokines were dramatically increased in
Bcl3–/–
mice in vivo and in vitro. Bone marrow transplantation experiments revealed a central role of Bcl-3 in acinar
and not in myeloid cells. In Bcl3–/–
mice, anti-inflammatory p50 homodimers diminished due to increased ubiquitination
and proteasomal mediated degradation.
Conclusion: Our study addresses the role of Bcl-3 in pancreatitis for the first time demonstrating
that Bcl-3 ameliorates acute pancreatitis and inhibits lethality. Mechanistically,
Bcl-3 inhibits p50 ubiquitination and proteasomal mediated degradation thus repressing
transcription of proinflammatory factors in AP.
