Hepatic fibrosis is a consequence of a number of chronic liver pathologies including alcoholic liver disease, viral infection, and biliary outflow obstruction. Growing experimental evidence implicates the class of cytokines produced, specifically the T helper (Th) cytokine phenotype expressed, as a key regulator of the fibrotic response. Indeed, while Th1 type cytokines such as interferon gamma (IFNg) or interleukin (IL) 12 are associated with hepatitis and acute inflammation, expression of the Th2 type cytokines IL4, IL5, and IL13 drive fibrosis development. Moreover, it appears that during chronic liver diseases a switch occurs in which a balanced or perhaps Th1 -shifted cytokine response is replaced by an unbalanced Th2 predominated cytokine phenotype. Natural killer T (NKT) cells make up approximately 50% of the intrahepatic lymphocytes and are capable of producing both Th1 and Th2 type cytokines making them a potential regulator of the hepatic Th cytokine balance. The impact this cell population has on the hepatic fibrotic response is not known. It is hypothesized that NKT cells limit hepatocellular inflammation and promote hepatic fibrosis through production of key regulatory and pro-fibrotic Th2 type cytokines. Utilizing two well described models of hepatic fibrosis in rodents, carbon tetrachloride administration or bile duct ligation, and two mouse models of NKT cell deficiency, CD1d-/- mice and Ja281-/- mice, the role that NKT cells play in the fibrotic response will be evaluated. In the first aim, the direct consequence of a deficiency in hepatic NKT cells in the development of hepatic fibrogenesis will be determined. Furthermore, using in vitro cell coculture, the role of NKT cells and NKT cell derived factors in the activation primary hepatic stellate cells will also be examined. In the second aim, hepatic NKT cell populations will be exhaustively characterized prior to and during the development of hepatic fibrosis focusing on their Th cytokine phenotype.
The third aim will extend these findings and determine the role of NKT cell derived cytokines specifically using a novel adoptive transfer approach where NKT cell deficient mice are reconstituted with certain cytokine deficient NKT cells including IFNg deficient and IL4 deficient cells.
The final aim will address the role of IL12, a known inhibitor of NKT cell function and survival, in the development and progression of experimental fibrosis. Together, these studies will provide new insight into the mechanisms of T cell-mediated hepatic fibrosis.
| Morris, Niya L; Ippolito, Jill A; Curtis, Brenda J et al. (2015) Alcohol and inflammatory responses: summary of the 2013 Alcohol and Immunology Research Interest Group (AIRIG) meeting. Alcohol 49:1-6 |
| Kremer, Michael; Son, Gakuhei; Zhang, Kun et al. (2014) Smad3 signaling in the regenerating liver: implications for the regulation of IL-6 expression. Transpl Int 27:748-58 |
| Hines, Ian N; Hartwell, Hadley J; Feng, Yan et al. (2011) Insulin resistance and metabolic hepatocarcinogenesis with parent-of-origin effects in A×B mice. Am J Pathol 179:2855-65 |
| Kremer, Michael; Thomas, Emmanuel; Milton, Richard J et al. (2010) Kupffer cell and interleukin-12-dependent loss of natural killer T cells in hepatosteatosis. Hepatology 51:130-41 |
| Son, Gakuhei; Hines, Ian N; Lindquist, Jeff et al. (2009) Inhibition of phosphatidylinositol 3-kinase signaling in hepatic stellate cells blocks the progression of hepatic fibrosis. Hepatology 50:1512-23 |
