scholarly journals Macrophage-secreted cytokines drive pancreatic acinar-to-ductal metaplasia through NF-κB and MMPs

2013 ◽  
Vol 202 (3) ◽  
pp. 563-577 ◽  
Author(s):  
Geou-Yarh Liou ◽  
Heike Döppler ◽  
Brian Necela ◽  
Murli Krishna ◽  
Howard C. Crawford ◽  
...  
Keyword(s):  
Target Genes ◽  
Acinar Cells ◽  
Nuclear Factor Κb ◽  
Pancreatic Acinar Cells ◽  
Nuclear Factor ◽  
Signaling Mechanisms ◽  
Acinar To Ductal Metaplasia ◽  
Factor Α ◽  
Necrosis Factor

In response to inflammation, pancreatic acinar cells can undergo acinar-to-ductal metaplasia (ADM), a reprogramming event that induces transdifferentiation to a ductlike phenotype and, in the context of additional oncogenic stimulation, contributes to development of pancreatic cancer. The signaling mechanisms underlying pancreatitis-inducing ADM are largely undefined. Our results provide evidence that macrophages infiltrating the pancreas drive this transdifferentiation process. We identify the macrophage-secreted inflammatory cytokines RANTES and tumor necrosis factor α (TNF) as mediators of such signaling. Both RANTES and TNF induce ADM through activation of nuclear factor κB and its target genes involved in regulating survival, proliferation, and degradation of extracellular matrix. In particular, we identify matrix metalloproteinases (MMPs) as targets that drive ADM and provide in vivo data suggesting that MMP inhibitors may be efficiently applied to block pancreatitis-induced ADM in therapy.

Different modes of NF-κB/Rel activation in pancreatic lobules

2002 ◽  
Vol 283 (2) ◽  
pp. G270-G281 ◽  
Author(s):  
Hana Algül ◽  
Yusuke Tando ◽  
Michael Beil ◽  
Christoph K. Weber ◽  
Claus Von Weyhern ◽  
...  
Keyword(s):  
Oxidative Stress ◽  
Nuclear Factor Κb ◽  
Pancreatic Acinar Cells ◽  
Tubulin Polymerization ◽  
Nuclear Factor ◽  
Eukaryotic Transcription ◽  
Iκb Kinase ◽  
Factor Α ◽  
Transcription Factor Nuclear Factor ◽  
Necrosis Factor

The eukaryotic transcription factor nuclear factor-κB (NF-κB)/Rel is activated by a large variety of stimuli. It has been demonstrated that NF-κB/Rel is induced during the course of cerulein pancreatitis. Here, we show that NF-κB/Rel is differentially activated in pancreatic lobules. Cerulein induces NF-κB/Rel via activation of IκB kinase (IKK), which causes degradation of IκBα but not IκBβ. Tumor necrosis factor-α-mediated IKK activation leads to IκBα and IκBβ degradation. In contrast, oxidative stress induced by H2O2activates NF-κB/Rel independent of IKK activation and IκBα degradation; instead IκBα is phosphorylated on tyrosine. H2O2but not cerulein-mediated NF-κB/Rel activation can be blocked by stabilizing microtubules with Taxol. Inhibition of tubulin polymerization with nocodazole causes NF-κB/Rel activation in pancreatic lobules. These results propose three different pathways of NF-κB/Rel activation in pancreatic acinar cells. Furthermore, these data demonstrate that microtubules play a key role in IKK-independent NF-κB/Rel activation following oxidative stress.

IL-10-inducible Bcl-3 negatively regulates LPS-induced TNF-α production in macrophages

Blood ◽  
2003 ◽  
Vol 102 (12) ◽  
pp. 4123-4129 ◽  
Author(s):  
Hirotaka Kuwata ◽  
Yasuyuki Watanabe ◽  
Hiroyuki Miyoshi ◽  
Masahiro Yamamoto ◽  
Tsuneyasu Kaisho ◽  
...  
Keyword(s):  
Nuclear Translocation ◽  
Lentiviral Vector ◽  
Nuclear Factor Κb ◽  
Interleukin 10 ◽  
Nuclear Factor ◽  
Tnf Α ◽  
Factor Α ◽  
Necrosis Factor ◽  
Inducible Gene

Abstract Interleukin-10 (IL-10) plays an important role in prevention of chronic inflammation in vivo. However, the molecular mechanism by which IL-10 exerts its anti-inflammatory response is poorly understood. Here, we performed a microarray analysis and identified Bcl-3 as an IL-10-inducible gene in macrophages. Lentiviral vector-mediated expression of Bcl-3 inhibited lipopolysaccharide (LPS)-induced production of tumor necrosis factor α (TNF-α), but not IL-6, in macrophages. In Bcl-3-transduced and IL-10-pretreated macrophages, LPS-induced nuclear translocation of nuclear factor κB (NF-κB) p65 was not impaired. However, DNA binding by NF-κB p50/p65 was profoundly inhibited. Nuclear localization of Bcl-3 was associated with inhibition of LPS-induced TNF-α production. Overexpression of Bcl-3 suppressed activation of the TNF-α promoter, but not the IL-6 promoter. Bcl-3 interacted with NF-κB p50 and was recruited to the TNF-α promoter, but not the IL-6 promoter, indicating that Bcl-3 facilitates p50-mediated inhibition of TNF-α expression. Furthermore, Bcl-3-deficient macrophages showed defective IL-10-mediated suppression of LPS induction of TNF-α, but not IL-6. These findings suggest that IL-10-induced Bcl-3 is required for suppression of TNF-α production in macrophages. (Blood. 2003; 102:4123-4129)

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