Analysis of the function of GADD34 in innate immune response and inflammation-induced colon cancer

2017 Fiscal Year Final Research Report

• Project/Area Number: 15K01708
• Research Category: Grant-in-Aid for Scientific Research (C)
• Allocation Type: Multi-year Fund
• Section: 一般
• Research Field: Applied health science
• Research Institution: Nagoya University
• Principal Investigator: Ito Sachiko 名古屋大学, 医学系研究科, 講師 (70447845)
• Project Period (FY): 2015-04-01 – 2018-03-31
• Keywords: GADD34 / ERストレス / TLR4シグナル / 炎症 / 炎症関連大腸癌

Outline of Final Research Achievements

In this study, we analyzed the function of GADD34 in inflammatory responses against bacterial infections. We found that GADD34-deficiency enhanced tissue destruction, cell death and pro-inflammatory cytokine expression in LPS-induced acute liver injury. GADD34 inhibited hepatic apoptosis through down-regulating the eIF2α-ATF4-CHOP pathway. Then GADD34 inhibited TLR4 signaling through dephosphorylation of IKKβ, and attenuated pro-inflammatory cytokine production in macrophages. Further, we analyzed the function of GADD34 in colitis associated cancer. We found that GADD34 promoted tumor formation induced by AOM/DSS. DSS induced the expression of GADD34. GADD34 upregulated the production of IL-6 induced by DSS in colon tissue and the proliferation of epithelial cells by activation of the IL-6 /STAT3 pathway. These results indicated that GADD34 promoted AOM/DSS-induced carcinogenesis by enhancing IL-6 production from myeloid cells and subsequent STAT3 activation in epithelial cells.

Free Research Field

免疫学