Ectopic expression of CD74 in Ikkβ-deleted mouse hepatocytes.
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.
Koch
Katherine S
KS
Hepatocyte 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
Leffert
Hyam L
HL
D000818:Animals; D017951:Antigen Presentation / Q000235:genetics / Q000276:immunology; D000944:Antigens, Differentiation, B-Lymphocyte / Q000096:biosynthesis* / Q000276:immunology; D002454:Cell Differentiation / Q000235:genetics; D002471:Cell Transformation, Neoplastic / Q000235:genetics / Q000276:immunology; D002478:Cells, Cultured; D005786:Gene Expression Regulation; D055786:Gene Knockout Techniques; D022781:Hepatocytes / Q000276:immunology* / Q000378:metabolism* / Q000473:pathology; D000949:Histocompatibility Antigens Class II / Q000096:biosynthesis* / Q000276:immunology; D051550:I-kappa B Kinase / Q000037:antagonists & inhibitors / Q000235:genetics / Q000378:metabolism*; D020672:I-kappa B Proteins / Q000378:metabolism; D019746:Intramolecular Oxidoreductases / Q000276:immunology / Q000378:metabolism; D008263:Macrophage Migration-Inhibitory Factors / Q000276:immunology / Q000378:metabolism; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D015398:Signal Transduction
D000944:Antigens, Differentiation, B-Lymphocyte; D000949:Histocompatibility Antigens Class II; D020672:I-kappa B Proteins; D008263:Macrophage Migration-Inhibitory Factors; C045084:invariant chain; D051550:I-kappa B Kinase; C496562:Ikbkb protein, mouse; D019746:Intramolecular Oxidoreductases; C076231:Mif protein, mouse