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Ectopic expression of CD74 in Ikkβ-deleted mouse hepatocytes
Katherine S Koch1, Hyam L Leffert
1Hepatocyte Growth Control and Stem Cell Laboratory, Department of Pharmacology, School of Medicine, University of California at San Diego, 9500 Gilman Drive MC 0636, La Jolla, CA 92093-0636, USA. kskoch@ucsd.edu
Insights
Deletion of Ikkβ in hepatocytes leads to abundant CD74 expression, suggesting a role for intrahepatocellular IKKβ in suppressing immune system molecules. This finding highlights potential new functions for IKKβ in liver immunity.
Area of Science:
- Immunology
- Hepatology
- Molecular Biology
Background:
- CD74 is a glycoprotein and MHC class II chaperone crucial for antigen processing, typically found on immune cells.
- CD74 heterodimerizes with CD44, forming receptors for macrophage migration inhibitory factor (MIF), a pro-inflammatory cytokine.
Purpose of the Study:
- To investigate the expression and function of CD74 in hepatocytes following the deletion of Ikkβ (inhibitor of κB kinase subunit β).
- To explore the implications of altered CD74 expression in hepatocytes for immune responses and liver function.
Main Methods:
- Utilized Alb-Cre-mediated deletion of Ikkβ in Ikkβ(F/F):Alb-Cre mice to create a model of hepatocyte-specific Ikkβ deficiency.
- Analyzed CD74 expression in hepatocytes using immunohistochemistry and microarray profiling.
- Examined the expression of associated genes, including CD44, MHC class II components, CIITA, and CD86.
Main Results:
- Constitutive and abundant CD74 expression was observed in adult hepatocytes of Ikkβ(Δhep) mice, particularly in midzonal-to-centrilobular regions.
- CD74 expression was absent in Ikkβ(F/F) hepatocytes and not augmented in Ikkβ(+/+):Alb-Cre mice.
- Microarray analysis revealed significantly augmented expression of CD44 and genes involved in antigen processing and host defense (MHC class II, CIITA, CD86) in Ikkβ(Δhep) hepatocytes.
Conclusions:
- Hepatocyte-specific deletion of Ikkβ induces CD74 expression, suggesting intrahepatocellular IKKβ normally suppresses immune-related molecules.
- Ikkβ(Δhep) hepatocytes may possess functional capabilities for class II-restricted antigen presentation and enhanced responsiveness to MIF signaling.
- These findings indicate novel roles for intrahepatocellular IKKβ in regulating immune system components within the liver.
Abstract:
CD74, a Type II membrane glycoprotein and MHC class II chaperone involved in antigen processing, is normally expressed by cells associated with the immune system. CD74 also forms heterodimers with CD44 to generate receptors to macrophage migration inhibitory factor (MIF), a proinflammatory cytokine. Following targeted Alb-Cre-mediated deletion of Ikkβ in Ikkβ(Δhep) mice (Ikkβ(F/F):Alb-Cre, a strain highly susceptible to chemically induced hepatotoxicity and hepatocarcinogenesis), CD74 is expressed abundantly by adult hepatocytes throughout liver acini, albeit more intensely in midzonal-to-centrilobular regions. By comparison, CD74 expression is not observed in Ikkβ(F/F) hepatocytes, nor is it augmented in the livers of Ikkβ(+/+):Alb-Cre mice; CD74 is barely detectable in cultured embryonic fibroblasts from Ikkβ(-/-) mice. Microarray profiling shows that constitutive CD74 expression in Ikkβ(Δhep) hepatocytes is accompanied by significantly augmented expression of CD44 and key genes associated with antigen processing and host defense, including MHC class II I-Aα, I-Aβ, and I-Eβ chains, CIITA and CD86. Taken together, these observations suggest that Ikkβ(Δhep) hepatocytes might express functional capacities for class II-restricted antigen presentation and heightened responsiveness to MIF-signaling, and also suggest further roles for intrahepatocellular IKKβ in the suppression or inactivation of molecules normally associated with the formation and differentiation of cells of the immune system.
