Mechanisms involved in inflammatory development during
acute pancreatitis (AP) are largely vague, especially in the transformation of
acute edematous pancreatitis (AEP) into
acute necrotizing pancreatitis (
ANP). This current study aims to investigate the functions of
Traf6 in different AP models in vitro and in vivo, and to identify the possible regulatory mechanism in the progression of
inflammation from mild to severe. Our data revealed that the level of
Traf6 expression was significantly increased in the mild AP induced by
caerulein, and the upregulation of
Traf6 played a protective role in acinar cells against
caerulein-induced apoptosis. In contrast, only
Traf6 protein but not
mRNA was downregulated in the severe
ANP induced by combination treatment of
caerulein and LPS. Mechanistic studies showed that LPS upregulated the levels of Socs1 and Socs3 expressions in acinar cells, Socs1 and Socs3 interacted
Traf6 directly and degraded
Traf6 protein via polyubiquitination, thereby counteracted the protective function of
Traf6. In vivo study further showed that combination treatment of
caerulein and LPS failed to induce an
ANP model in the TLR4 knockout mice, and the level of
Traf6 expression in the pancreatic tissues remained the same as that from the
acute edematous pancreatitis (AEP) mouse. Taken together, our study reveals that
Traf6 functioned as a protective factor in the progression of AP, and LPS-induced Socs1 and Socs3 exacerbate mild AP to severe AP, which provides evidence for developing a new therapeutic target to combat AP.