Doctor of Philosophy, Technische Universitat Munchen (2013)
Steven Artandi, Postdoctoral Faculty Sponsor
Interleukin-6 is an important pro-inflammatory cytokine strongly linked to the most burdened exocrine pancreatic diseases including acute pancreatitis, chronic pancreatitis and pancreatic cancer. However, its role in all these diseases is versatile and not completely defined. Several studies provided accumulating evidence that IL-6 is mainly involved in the JAK/STAT pathway activation promoting acute and chronic pancreatitis disease aggravation as well as pancreatic cancer initiation and progression. This review will focus on recent studies illustrating the role of IL-6 in acute and chronic pancreatitis and pancreatic oncogenesis. Further, a short overview of indicated disease pathologies will be given and the impact of IL-6 in JAK/STAT pathway, persistent STAT3 activation and cancer immunotherapy will be discussed.
View details for DOI 10.1016/j.smim.2014.01.002
View details for Web of Science ID 000333658600010
View details for PubMedID 24572992
Acute lung injury (ALI) is an inflammatory disease with a high mortality rate. Although typically seen in individuals with sepsis, ALI is also a major complication in severe acute pancreatitis (SAP). The pathophysiology of SAP-associated ALI is poorly understood, but elevated serum levels of IL-6 is a reliable marker for disease severity. Here, we used a mouse model of acute pancreatitis-associated (AP-associated) ALI to determine the role of IL-6 in ALI lethality. Il6-deficient mice had a lower death rate compared with wild-type mice with AP, while mice injected with IL-6 were more likely to develop lethal ALI. We found that inflammation-associated NF-?B induced myeloid cell secretion of IL-6, and the effects of secreted IL-6 were mediated by complexation with soluble IL-6 receptor, a process known as trans-signaling. IL-6 trans-signaling stimulated phosphorylation of STAT3 and production of the neutrophil attractant CXCL1 in pancreatic acinar cells. Examination of human samples revealed expression of IL-6 in combination with soluble IL-6 receptor was a reliable predictor of ALI in SAP. These results demonstrate that IL-6 trans-signaling is an essential mediator of ALI in SAP across species and suggest that therapeutic inhibition of IL-6 may prevent SAP-associated ALI.
View details for DOI 10.1172/JCI64931
View details for Web of Science ID 000315749400018
View details for PubMedID 23426178
The transcription factor nuclear factor-?B (NF-?B) (a heterodimer of NF-?B1p50 and RelA) is activated rapidly in acute pancreatitis (AP). However, it is not clear whether NF-?B promotes or protects against AP. We used the NF-?B inhibitor protein, inhibitor of ?B (I?B)?, to study the roles of NF-?B in the development of AP in mice.I?B? or the combination of I?B? and RelA selectively were deleted from pancreas of mice using the Cre/locus of cross-over P strategy; cerulein or L-arginine were used to induce AP. We performed microarray analyses of the I?B?- and RelA-deficient pancreata. DNA from healthy individuals and patients with acute or chronic pancreatitis were analyzed for variants in coding regions of alpha-1-antichymotrypsin.Mice with pancreas-specific deletion of I?B? had constitutive activation of RelA and a gene expression profile consistent with NF-?B activation; development of AP in these mice was attenuated and trypsin activation was impaired. However, AP was fully induced in mice with pancreas-specific deletion of I?B? and RelA. By using genome-wide expression analysis, we identified a cluster of NF-?B-regulated genes that might protect against the development of AP. The serine protease inhibitor 2A (Spi2a) was highly up-regulated in I?B?-deficient mice. Lentiviral-mediated expression of Spi2A reduced the development of AP in C57BL/6 and RelA-deficient mice. However, we did not correlate any variants of alpha-1-antichymotrypsin, the human homologue of Spi2a, with acute or chronic pancreatitis.Pancreas-specific deletion of I?B? results in nuclear translocation of RelA and reduces AP induction and trypsin activation in mice after administration of cerulein or L-arginine. Constitutive activation of RelA up-regulates Spi2A, which protects mice against the development of AP.
View details for DOI 10.1053/j.gastro.2012.09.058
View details for PubMedID 23041330
Little is known about how transcription factors might regulate pathogenesis of chronic pancreatitis (CP). We analyzed the in vivo role of RelA/p65, a component of the transcription factor nuclear factor (NF)-?B, in different cell types during development of CP in mice.RelA/p65 was functionally inactivated in the pancreas (rela?panc), in myeloid cells (rela?mye), or both (rela?panc,?mye) compartments using the Cre-loxP strategy. Experimental CP was induced with repetitive injections of cerulein over 6 weeks. Pancreata were investigated histologically and biochemically. We created an in vitro coculture assay of pancreatic stellate cells (PSC) and macrophages and performed gene arrays from pancreata and macrophages with functionally inactivated RelA/p65. Tissue samples from patients with CP were analyzed for matrix metalloproteinase (MMP) 10 expression.In contrast to their relaF/F littermates, rela?panc displayed typical signs of CP after long-term stimulation with cerulein. Numerous macrophages and activated ?-smooth muscle actin (SMA)-positive PSCs were detected. Additional inactivation of RelA/p65 in myeloid cells (rela?panc,?mye) attenuated fibrosis. In vitro, RelA/p65-deficient, lipopolysaccharide (LPS)-stimulated macrophages degraded fibronectin in cocultured PSCs. Using gene expression analysis, MMP-10 was identified as a candidate for this process. Recombinant MMP-10 degraded fibronectin in LPS-stimulated PSCs. In tissue samples from patients with CP, MMP-10 was up-regulated in myeloid cells.RelA/p65 functions in myeloid cells to promote pathogenesis of CP. In acinar cells, RelA/p65 protects against chronic inflammation, whereas myeloid RelA/p65 promotes fibrogenesis. In macrophage, MMP-10 functions as a RelA/p65-dependent, potentially antifibrogenic factor during progression of CP.
View details for DOI 10.1053/j.gastro.2011.06.087
View details for Web of Science ID 000295593700054
View details for PubMedID 21763242