NLRP12 Suppresses Colon Inflammation and Tumorigenesis through the Negative Regulation of Noncanonical NF-魏B Signaling

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• 作者：Irving  ; C. Allen¹ ; Justin  ; E. Wilson¹ ; Monika Schneider² ; John  ; D. Lich¹ ; Reid  ; A. Roberts² ; Janelle  ; C. Arthur² ; Rita-Marie  ; T. Woodford³ ; Beckley  ; K. Davis¹ ; Joshua  ; M. Uronis⁴ ; Hans  ; H. Herfarth⁴ ; ⁵ ; Christian Jobin² ; ⁴ ; ⁶ ; Arlin  ; B. Rogers⁷ ; Jenny  ; P.-Y. Ting¹ ; ² ; ³ ; ⁴ ; ^{panyun@med.unc.edu}
• 刊名：Immunity
• 出版年：2012
• 期刊代码：40_10747613
• 类别：imm
• 出版时间：25 May, 2012
• 卷：36
• 期：5
• 页码：742-754
• 文件大小：1531 K

摘要

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Summary

In聽vitro data suggest that a subgroup of NLR proteins, including NLRP12, inhibits the transcription factor NF-魏B, although physiologic and disease-relevant evidence is largely missing. Dysregulated NF-魏B activity is associated with colonic inflammation and cancer, and we found Nlrp12^{鈭?鈭?/sup>} mice were highly susceptible to colitis and colitis-associated colon cancer. Polyps isolated from Nlrp12^{鈭?鈭?/sup>} mice showed elevated noncanonical NF-魏B activation and increased expression of target genes that were associated with cancer, including Cxcl13 and Cxcl12. NLRP12 negatively regulated ERK and AKT signaling pathways in affected tumor tissues. Both hematopoietic- and nonhematopoietic-derived NLRP12 contributed to inflammation, but the latter dominantly contributed to tumorigenesis. The noncanonical NF-魏B pathway was regulated upon degradation of TRAF3 and activation of NIK. NLRP12 interacted with both NIK and TRAF3, and Nlrp12^{鈭?鈭?/sup>} cells have constitutively elevated NIK, p100 processing to p52 and reduced TRAF3. Thus, NLRP12 is a checkpoint of noncanonical NF-魏B, inflammation, and tumorigenesis.