Abstract
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 pancreatitisinducing 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.
| Original language | English (US) |
|---|---|
| Pages (from-to) | 563-577 |
| Number of pages | 15 |
| Journal | Journal of Cell Biology |
| Volume | 202 |
| Issue number | 3 |
| DOIs | |
| State | Published - 2013 |
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ASJC Scopus subject areas
- Cell Biology
Cite this
Macrophage-secreted cytokines drive pancreatic acinar-to-ductal metaplasia through NF-ΚB and MMPs. / Liou, Geou Yarh; Döppler, Heike; Necela, Brian; Krishna, Murli; Crawford, Howard C.; Raimondo, Massimo; Storz, Peter.
In: Journal of Cell Biology, Vol. 202, No. 3, 2013, p. 563-577.Research output: Contribution to journal › Article
}
TY - JOUR
T1 - Macrophage-secreted cytokines drive pancreatic acinar-to-ductal metaplasia through NF-ΚB and MMPs
AU - Liou, Geou Yarh
AU - Döppler, Heike
AU - Necela, Brian
AU - Krishna, Murli
AU - Crawford, Howard C.
AU - Raimondo, Massimo
AU - Storz, Peter
PY - 2013
Y1 - 2013
N2 - 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 pancreatitisinducing 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.
AB - 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 pancreatitisinducing 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.
UR - http://www.scopus.com/inward/record.url?scp=84884236200&partnerID=8YFLogxK
UR - http://www.scopus.com/inward/citedby.url?scp=84884236200&partnerID=8YFLogxK
U2 - 10.1083/jcb.201301001
DO - 10.1083/jcb.201301001
M3 - Article
C2 - 23918941
AN - SCOPUS:84884236200
VL - 202
SP - 563
EP - 577
JO - Journal of Cell Biology
JF - Journal of Cell Biology
SN - 0021-9525
IS - 3
ER -