Previous studies have shown macrophage expression of 11��-HSD1 in further information the context of distinct disease models of acute inflammation notably murine studies where macrophage 11��-HSD1 activity rapidly increases during the development of acute peritonitis [31]. Our human study in NASH has shown for the first time that macrophage 11��-HSD1 expression is specifically intense in a chronic inflammatory process. These results clearly lead to a number of exciting possibilities with respect to the role of 11��-HSD1 in steatohepatitis. With relevance to the inflammatory response it would be important to discern the phenotype of the response of these macrophages. Previous studies have shown that macrophage 11��-HSD1 expression is stimulated by IL-4 and IL-3 cytokines, both examples of Th2 cytokines that promote anti inflammatory responses.

In the peritonitis model referred to above, macrophage 11��-HSD1 expression was important in the induction of phagocytosis of apoptotic neutrophils [31]. However, treatment of a murine macrophage cell line with 11��-HSD1 inhibitors was able to reduce the proinflammatory cytokine response following lipopolysaccharide treatment [32]. Macrophage 11��-HSD1 mediated glucocorticoid production may therefore be a central mechanism to fine tune the phenotype of the inflammatory response. This may be to limit injury in chronic inflammation, and promote pro resolution mechanisms particularly in acute inflammation. The role of the differential activation of Type 1 (pro-inflammatory), and Type 2 (anti-inflammatory) macrophages in determining the outcome of liver inflammation has only recently been appreciated [33].

Increased hepatocyte 11��-HSD1 expression, particularly in periseptal areas would further directly expose inflamed septa to glucocorticoids. However overall increased hepatic glucocorticoid would also promote hepatic lipogenesis and hence be expected to worsen hepatic steatosis. Studies on other tissues, including synovium from patients with rheumatoid arthritis [34], human and rodent colitis Cilengitide [35], aortic smooth muscle cells [36], and granulosa cells in the inflammatory response to ovulation [37], all show a consistent picture of induction of cell specific 11��-HSD1 gene expression in response to pro inflammatory cytokines, TNF�� and IL-1�� being the most commonly implicated [38]. The molecular mechanism by which 11��-HSD1 is induced in response to cytokines is not entirely clear, but key transcription factors of the C/EBP family play a crucial role [39], [40]. Simple hepatic steatosis is a relatively benign entity in the NAFLD disease spectrum with only a 2% risk of developing progressive disease in a twenty year period.