MyD88 inhibition amplifies dendritic cell capacity to promote pancreatic carcinogenesis via Th2 cells.
The transition of chronic pancreatic fibroinflammatory disease to neoplasia is a primary example of the paradigm linking inflammation to carcinogenesis. However, the cellular and molecular mediators bridging these entities are not well understood. Because TLR4 ligation can exacerbate pancreatic inflammation, we postulated that TLR4 activation drives pancreatic carcinogenesis. In this study, we show that lipopolysaccharide accelerates pancreatic tumorigenesis, whereas TLR4 inhibition is protective. Furthermore, blockade of the MyD88-independent TRIF pathway is protective against pancreatic cancer, whereas blockade of the MyD88-dependent pathway surprisingly exacerbates pancreatic inflammation and malignant progression. The protumorigenic and fibroinflammatory effects of MyD88 inhibition are mediated by dendritic cells (DCs), which induce pancreatic antigen-restricted Th2-deviated CD4(+) T cells and promote the transition from pancreatitis to carcinoma. Our data implicate a primary role for DCs in pancreatic carcinogenesis and illustrate divergent pathways in which blockade of TLR4 signaling via TRIF is protective against pancreatic cancer and, conversely, MyD88 inhibition exacerbates pancreatic inflammation and neoplastic transformation by augmenting the DC-Th2 axis.
Department of Surgery, New York University School of Medicine, New York, NY 10016, USA.
Atsuo
A
Ochi
Andrew H
AH
Nguyen
Andrea S
AS
Bedrosian
Harry M
HM
Mushlin
Saman
S
Zarbakhsh
Rocky
R
Barilla
Constantinos P
CP
Zambirinis
Nina C
NC
Fallon
Adeel
A
Rehman
Yuliya
Y
Pylayeva-Gupta
Sana
S
Badar
Cristina H
CH
Hajdu
Alan B
AB
Frey
Dafna
D
Bar-Sagi
George
G
Miller
D033942:Adaptor Proteins, Vesicular Transport / Q000378:metabolism; D000230:Adenocarcinoma / Q000378:metabolism / Q000473:pathology*; D000818:Animals; D015496:CD4-Positive T-Lymphocytes / Q000378:metabolism / Q000473:pathology; D003713:Dendritic Cells / Q000276:immunology / Q000378:metabolism*; D006801:Humans; D008297:Male; D051379:Mice; D008817:Mice, Mutant Strains; D053594:Myeloid Differentiation Factor 88 / Q000235:genetics / Q000378:metabolism*; D010190:Pancreatic Neoplasms / Q000378:metabolism / Q000473:pathology*; D050500:Pancreatitis, Chronic / Q000378:metabolism / Q000473:pathology; D018418:Th2 Cells / Q000276:immunology / Q000473:pathology*; D051197:Toll-Like Receptor 4 / Q000378:metabolism*
D033942:Adaptor Proteins, Vesicular Transport; D053594:Myeloid Differentiation Factor 88; D051197:Toll-Like Receptor 4; C507780:Myd88 protein, mouse; C476286:Ticam1 protein, mouse; C493487:Tlr4 protein, mouse