Abstract
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.
Highlights
Toll-like receptors (TLRs) are a family of receptor proteins that can recognize structurally conserved motifs from microbes.[4]
As the only Traf family member which participates in signal transduction of the tumor necrosis factor (TNF) receptor superfamily and the interleukin[1] receptor (IL-1R)/TLR superfamily, Traf[6] has been demonstrated to be involved in regulating cell death, survival, and cellular responses to stress.[7]
Mouse acute pancreatitis (AP) was induced by caerulein injection for the acute edematous pancreatitis (AEP) model and additional LPS injection for the acute necrotizing pancreatitis (ANP) model
Summary
Toll-like receptors (TLRs) are a family of receptor proteins that can recognize structurally conserved motifs from microbes.[4]. A group of intracellular immune regulators, the suppressor of cytokine signaling (Socs) protein family, has been shown to negatively regulate TLR signaling via the modulation of signal transducer and activator of transcription (STAT) pathway.[12,13] There are eight members in the Socs family: Socs[1] to Socs[7] and cytokine-inducible Src homology 2 (SH2)-containing protein (Cis) They all have a central SH2 domain and a C-terminal conserved domain termed the Socs box.[14] The N-terminal domain varies in length, with shorter length in Socs[2] and CIS, and longer length in Socs[4]. Our current study aims to investigate the role of Traf[6] in different types of AP in vitro and in the mouse experiments, and to identify the potential regulatory mechanism on how the inflammation could progress from mild to severe type
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