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...
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| Veröffentlicht in: | The Journal of immunology (1950) 2010-10, Vol.185 (8), p.4912-4920 |
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| container_title | The Journal of immunology (1950) |
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| creator | Zaki, Mohammad Hasan Vogel, Peter Body-Malapel, Mathilde Lamkanfi, Mohamed Kanneganti, Thirumala-Devi |
| description | 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. |
| doi_str_mv | 10.4049/jimmunol.1002046 |
| format | Article |
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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.</description><identifier>ISSN: 0022-1767</identifier><identifier>EISSN: 1550-6606</identifier><identifier>DOI: 10.4049/jimmunol.1002046</identifier><identifier>PMID: 20855874</identifier><language>eng</language><publisher>United States: Publisher : Baltimore : Williams & Wilkins, c1950-. 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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.</description><subject>Animals</subject><subject>Blotting, Western</subject><subject>Carrier Proteins - immunology</subject><subject>Carrier Proteins - metabolism</subject><subject>Cell Transformation, Neoplastic - immunology</subject><subject>Cell Transformation, Neoplastic - metabolism</subject><subject>Colorectal Neoplasms - immunology</subject><subject>Colorectal Neoplasms - metabolism</subject><subject>Cytokines - biosynthesis</subject><subject>Enzyme-Linked Immunosorbent Assay</subject><subject>Immunology</subject><subject>Inflammation - immunology</subject><subject>Inflammation - metabolism</subject><subject>Interleukin-18 - biosynthesis</subject><subject>Interleukin-18 - immunology</subject><subject>Life Sciences</subject><subject>Mice</subject><subject>Mice, Inbred C57BL</subject><subject>Mice, Knockout</subject><subject>NLR Family, Pyrin Domain-Containing 3 Protein</subject><subject>Reverse Transcriptase Polymerase Chain Reaction</subject><issn>0022-1767</issn><issn>1550-6606</issn><fulltext>true</fulltext><rsrctype>article</rsrctype><creationdate>2010</creationdate><recordtype>article</recordtype><sourceid>EIF</sourceid><recordid>eNpdkcFr2zAUxsXoWNNs952KbmUHZ0-yJMuXQQhbUwjbJXch21LjVrIyyU7pfz-FpKUd7_Dge9_vE-JD6CuBBQNWf3_ovZ-G4BYEgAITH9CMcA6FECAu0CyLtCCVqC7RVUoPACCAsk_okoLkXFZshh7vNgWReB9DN7VjHwbchachjdFoj4PF487g3y7uS9wP1mnvdQre4DYM1sR05EZz4vS97jOYTy7ErGmHx8mHiG2IXh8tn9FHq10yX857jra_fm5X62Lz5_ZutdwULafVWBjCOwBGhNZtQ6BjkjJpOama1kqhpa6FIYw0ojFU1IJzQUsrKmI6yWsuyzn6cYrdT403XWuGMWqn9rH3Oj6roHv1_jL0O3UfDqokwICWOeDbKWD3H7ZebtRRA1KXIs-BZO_N-bEY_k4mjcr3qTXO6cGEKSnJRVUBozw74eRsY0gpGvsaTUAd21Qvbapzmxm5fvuTV-ClvvIfyMGe2Q</recordid><startdate>20101015</startdate><enddate>20101015</enddate><creator>Zaki, Mohammad Hasan</creator><creator>Vogel, Peter</creator><creator>Body-Malapel, Mathilde</creator><creator>Lamkanfi, Mohamed</creator><creator>Kanneganti, Thirumala-Devi</creator><general>Publisher : Baltimore : Williams & Wilkins, c1950-. 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| subjects | Animals Blotting, Western Carrier Proteins - immunology Carrier Proteins - metabolism Cell Transformation, Neoplastic - immunology Cell Transformation, Neoplastic - metabolism Colorectal Neoplasms - immunology Colorectal Neoplasms - metabolism Cytokines - biosynthesis Enzyme-Linked Immunosorbent Assay Immunology Inflammation - immunology Inflammation - metabolism Interleukin-18 - biosynthesis Interleukin-18 - immunology Life Sciences Mice Mice, Inbred C57BL Mice, Knockout NLR Family, Pyrin Domain-Containing 3 Protein Reverse Transcriptase Polymerase Chain Reaction |
| title | IL-18 production downstream of the Nlrp3 inflammasome confers protection against colorectal tumor formation |
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