is process by promoting hepatocyte survival. In low grade, chronic, inflammation promoted HCC models, hepatocytes with activated NF ?B produce cytokines and chemokines which activate Kupffer cells and recruit and activate other inflammatory cells and thereby maintain an inflammatory microenvironment. In both models, activated Kupffer Avasimibe CI-1011 cells produce cytokines and growth factors, such as IL 6, that are essential for the expansion of mutated hepatocytes and subsequent HCC development. Production of such cytokines by Kupffer cells is NF ?B dependent. npg IKK/NF ?B in liver myeloid cells promotes liver cancer development through IL 6 and liver inflammatory responses Different environmental challenges and stimuli are sensed by resident myeloid cells, which initiate an inflammatory response aimed to remove the insults and repair the injured tissue.
Activated Kupffer cells produce a panel of inflammatory cytokines and growth factors in an IKK/NF ?B dependent manner. In the BIX 02189 DEN model, where hepatocyte IKK/NF ?B signaling was found to inhibit HCC development, activation of IKK/NF ?B in Kupffer cells promotes tumor development. Deletion of IKK in liver myeloid cells in addition to hepatocytes diminished the production of proinflammatory cytokines, such as IL 6 and TNF, reduced liver compensatory proliferation and strongly inhibited DEN induced HCC development. Deletion of IKK in Kupffer cells was also found to inhibit the metastatic growth of Lewis lung carcinoma cells in liver.
The mechanism by which DEN administration leads to IKK/ NF ?B activation in Kupffer cells was found to depend on the release of IL 1 by necrotic hepatocytes which activates an MyD88 dependent signaling pathway upon binding to IL 1 receptor on Kupffer cells. Inhibition of IL 1R signaling or ablation of MyD88 was found to attenuate DEN induced HCC development. One of the most important NF ?B dependent cytokines that is produced by activated Kupffer cells is IL 6. Interestingly, DEN treated female mice which unlike male mice are resistant to DEN induced HCC development, produce less IL 6 than similarly treated male mice. IL 6 is a major STAT3 activator in liver and male mice lacking IL 6 exhibit reduced DEN induced STAT3 activation and are as protected from HCC development as wild type female. These results suggest that the striking male preference in HCC development in both human and mice may be due to differential IL 6 production.
Whereas IL 6 ablation abolishes the male bias in DEN induced HCC development, ovariectomy enhances IL 6 production and augments HCC induction in female mice. It is likely that genderspecific differences in IL 6 expression also affect the incidence of human HCC, as serum IL 6 is higher after menopause and postmenopausal women display higher HCC incidence than premenopausal women. Moreover, expression of IL 6 is elevated in both liver cirrhosis and HCC and was recently found to correlate with rapid progression from viral hepatitis to HCC. Precise mechanisms by which elevated IL 6 promotes HCC development are not known, but some of IL 6 functions are likely mediated by activation of STAT3. STAT3 in liver cancer STAT3 signaling is turned on in human HCC STAT3 was first identified and cloned from mouse liver cDNA library in the study of IL 6 signaling. STAT