Functional analysis of the relevance of Bcl-3 and its interference with STAT3 in acute pancreatitis as an example of inflammation in the gastrointestinal tract

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The immune response in inflammatory diseases like acute pancreatitis (AP) is controlled by meticulous mechanisms. A dysfunctional regulation of these mechanisms leads to an excessive immune stimulation, termed as systemic inflammatory response syndrome (SIRS). SIRS links the local damage in the pancreas to systemic complications. During the last funding period, we identified the IL-6/STAT3 signaling pathway as a mediator in AP with SIRS and concomitant pancreatitis-associated lung injury. STAT3 dependent expression of SOCS3 regulates the signaling pathway in a negative feedback mechanism. Based on our preliminary experiments, Bcl-3 seems to have a similar function on the activation of the IL-6/STAT3 signaling pathway as SOCS3. Bcl-3, an atypical member of the IkappaB protein family, predominantly regulates binding of NF-kappaB dimers to DNA. While recent publications showed that Bcl-3 is interfering with STAT3 activation in acute inflammatory responses, its role in acute pancreatitis has not been investigated so far. Our preliminary results demonstrate that Bcl-3 is expressed in experimental and human AP. Similar to the loss of SOCS3, genetic inactivation of Bcl-3 in mice leads to an increase of STAT3 activation in the pancreas and an aggravation of experimental AP. In this funding period, we will analyze the role of Bcl-3 and its interaction with STAT3 activation in the inflammatory response model of AP by using genetically modified mice.