PT  - JOURNAL ARTICLE
AU  - Wu, Juan
AU  - Li, Jiaqi
AU  - Salcedo, Rosalba
AU  - Mivechi, Nahid F
AU  - Trinchieri, Giorgio
AU  - Horuzsko, Anatolij
TI  - The Pro-inflammatory Myeloid Cell Receptor TREM-1 Controls Kupffer Cell Activation and Development of Hepatocellular Carcinoma
AID  - 10.1158/0008-5472.CAN-12-0938
DP  - 2012 Jun 19
TA  - Cancer Research
PG  - canres.0938.2012
4099  - http://cancerres.aacrjournals.org/content/early/2012/06/19/0008-5472.CAN-12-0938.short
4100  - http://cancerres.aacrjournals.org/content/early/2012/06/19/0008-5472.CAN-12-0938.full
AB  - Chronic inflammation drives liver cancer pathogenesis, invasion and metastasis. Liver Kupffer cells (KC) have crucial roles in mediating the inflammatory processes that promote liver cancer but the mechanistic basis for their contributions are not fully understood. Here we show that expression of the pro-inflammatory myeloid cell surface receptor TREM-1 expressed by KC is a crucial factor in the development and progression of liver cancer. Deletion of the murine homolog Trem1 in mice attenuated hepatocellular carcinogenesis triggered by diethylnitrosamine (DEN). Trem1 deficiency attenuated KC activation by downregulating transcription and protein expression of IL-6, IL-1β, TNF, CCL2 and CXCL10. In addition, Trem1 ablation diminished activation of the p38, ERK1/2, JNK, MAPK and NF-κB signaling pathways in KC, resulting in diminished liver injury after DEN exposure. Adoptive transfer of wild-type KC to Trem1-deficient mice complemented these defects and reversed unresponsiveness to DEN-induced liver injury and malignant development. Together, our findings offer causal evidence that TREM-1 is a pivotal determinant of KC activation in liver carcinogenesis, deepening mechanistic insights into how chronic inflammation underpins the development and progression of liver cancer.