In summary, the stress-induced expression of MIC A/B and their recognition by diverse
NK LDK378 cells may serve as a mechanism for the detection of damaged (for example, by fatty infiltration during NASH), infected, or malignantly transformed cells.44 In our present study, MIC A/B transcripts were detected in significant levels in patients with biopsy-proven NASH following bariatric surgery for obesity. Consistent with the PCR data, immunohistochemical analysis revealed that immunoreactivity of hepatic NK cells and MIC A/B was also enhanced in the livers of these patients. Immunohistochemically, MIC A/B revealed a diffuse tissue staining pattern. Due to loss of cell membrane integrity upon tissue injury, these stress-induced ligands may be internalized upon cellular stress as observed during fatty infiltration of the liver in NASH patients. The exact mechanisms remain to be clarified by further studies. In order to exclude the possibility that MIC A/B are up-regulated by obesity, we furthermore investigated a cohort of patients with NAFL and could demonstrate that the number of hepatic NK cells and transcripts for MIC B were significantly decreased
in this study population, which was accompanied by lower degrees of liver injury, hepatocyte apoptosis, and fibrosis. see more Moreover, we found a significant positive correlation between MIC proteins and markers of disease severity in patients with NASH. Therefore, assessment of MIC A/B serum levels could be identified as a novel index to assess liver injury in NASH in a noninvasive fashion. Taken together, these results
indicate that MIC A/B are expressed on hepatocytes from patients with NASH and that their expression plays an important role in their susceptibility to NK cells during hepatic inflammation as mediated by fatty infiltration of the liver. Indeed, based on the crystal structure of the NKG2D-MIC A-complex, Zhang and colleagues synthesized 3 short peptides, mimicking functional α1 and 2 domain of MIC A, and demonstrated that MIC A–mimicking peptides might be useful for targeting the function of NK cells.45 Bay 11-7085 In addition, Jinushi et al.46 demonstrated that NK-induced cytolysis was completely abolished by antibody-mediated masking of MIC A/B. MIC molecules can also be released from the cell surface by the activity of metalloproteinases, which can be inhibited by addition of a broad-spectrum metalloproteinase inhibitor.47 Metalloproteinases are known to be involved in tissue inflammation and repair.48 We recently demonstrated in a mouse model of murine obstructive cholestasis that administration of CTS-1027—a broad-spectrum matrix metalloproteinase inhibitor—significantly decreased liver injury, hepatocyte apoptosis, and fibrosis.49 This drug has already entered clinical trials evaluating the anti-inflammatory and antifibrogenic properties in hepatitis C.