Hypothesis: Targeted Ikkβ deletion upregulates MIF signaling responsiveness and MHC class II expression in mouse hepatocytes.

Macrophage migration inhibitory factor (MIF) is causally related to the pathogenesis of chronic liver disease but its hepatocellular mechanisms of action are largely unknown. Scattered reports in the literature hint at functional connections between the expression of MIF and major histocompatibility complex (MHC) Class II molecules. Not surprisingly, these relationships have not yet been explored in hepatocytes because MIF and MHC Class II cell surface receptors are commonly expressed by other cell types including various antigen presenting cells of the immune system. On the other hand, mounting evidence suggests that heteromeric MIF receptors share a common molecule with intracellular MHC Class II complexes, viz., CD74, which also serves as the MHC Class II chaperone; and, while it is unclear what cancer-related role(s) MHC Class II receptors might play, increasing evidence suggests that MIF and CD74 are also implicated in the biology of hepatocellular carcinoma. These reports are provocative for two reasons: firstly, Ikkβ (Δ) (hep) mice carrying hepatocyte-targeted deletions of Ikkβ, an IκB kinase complex subunit required for the activation of the transcription factor NF-κB (nuclear factor-κB), have been shown to display heightened susceptibilities to hepatotoxins and chemical hepatocarcinogens; secondly, microarray profiling observations indicate that Ikkβ(Δhep) hepatocytes constitutively and "ectopically" overexpress genes, particularly CD74, CD44 (a MIF-receptor subunit) and MHC Class II I-A/E β and I-A α chains, and gene families that regulate host immune process and immune defense responses. These findings together suggest that Ikkβ(Δhep) mice might express functional MIF and MHC Class II receptors, leading to increased hepatocellular sensitivity to MIF signaling as well as to the unusual property of antigen presentation; both functions might contribute to the heightened liver disease phenotypes of Ikkβ(Δhep) mice. The findings raise questions about the potential existence of cohorts of human patients with genetic abnormalities of Ikkβ that might confer heightened susceptibility to liver disease including hepatocellular carcinoma.