IL-18 production downstream of the Nlrp3 inflammasome confers protection against colorectal tumor formation.
Colorectal cancer is a leading cause of cancer-related deaths worldwide. Chronic inflammation is recognized as a predisposing factor for the development of colon cancer, but the molecular mechanisms linking inflammation and tumorigenesis have remained elusive. Recent studies revealed a crucial role for the NOD-like receptor protein Nlrp3 in regulating inflammation through the assembly of proinflammatory protein complexes termed inflammasomes. However, its role in colorectal tumor formation remains unclear. In this study, we showed that mice deficient for Nlrp3 or the inflammasome effector caspase-1 were highly susceptible to azoxymethane/dextran sodium sulfate-induced inflammation and suffered from dramatically increased tumor burdens in the colon. This was a consequence of markedly reduced IL-18 levels in mice lacking components of the Nlrp3 inflammasome, which led to impaired production and activation of the tumor suppressors IFN-γ and STAT1, respectively. Thus, IL-18 production downstream of the Nlrp3 inflammasome is critically involved in protection against colorectal tumorigenesis.
Zaki
Mohammad Hasan
MH
Department of Immunology, St. Jude Children's Research Hospital, Memphis, TN 38105, USA.
Vogel
Peter
P
Body-Malapel
Mathilde
M
Lamkanfi
Mohamed
M
Kanneganti
Thirumala-Devi
TD
D000818:Animals; D015153:Blotting, Western; D002352:Carrier Proteins / Q000276:immunology / Q000378:metabolism*; D002471:Cell Transformation, Neoplastic / Q000276:immunology* / Q000378:metabolism; D015179:Colorectal Neoplasms / Q000276:immunology / Q000378:metabolism*; D016207:Cytokines / Q000096:biosynthesis; D004797:Enzyme-Linked Immunosorbent Assay; D007249:Inflammation / Q000276:immunology / Q000378:metabolism; D020382:Interleukin-18 / Q000096:biosynthesis* / Q000276:immunology; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D000071199:NLR Family, Pyrin Domain-Containing 3 Protein; D020133:Reverse Transcriptase Polymerase Chain Reaction
D002352:Carrier Proteins; D016207:Cytokines; D020382:Interleukin-18; D000071199:NLR Family, Pyrin Domain-Containing 3 Protein; C492716:Nlrp3 protein, mouse