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

Koch KS, Leffert HL - Hepat Med (2010)

Bottom Line: 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.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.

View Article: PubMed Central - PubMed

Affiliation: Hepatocyte Growth Control and Stem Cell Laboratory, Department of Pharmacology, School of Medicine, University of California, San Diego, CA, USA.

ABSTRACT
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.

No MeSH data available.


Related in: MedlinePlus

Hepatic immunologic ectopia: a constellation of constitutive immunophenotypes associated with IkkβΔhep hepatocytes. The diagram illustrates elements of the basic hypothesis, viz., that compared to IkkβF/F hepatocytes, IkkβΔhep hepatocytes ectopically express MIF receptors associated with MAPK signaling pathways, IFN-γ regulatory proteins which facilitate hepatocellular responses to IFN-γ (an activator of hepatic macrophages, as well as several immune system cells that may be situated in hepatotoxic livers), and antigen-presentation-competent MHC class II receptors (which respond to DEN-associated antigens and elicit specialized intrahepatic CD4+ and CD8+ T cell responses). CD74 serves a triple role: as a component of the MIF receptor along with CD44 (at plasma membrane sites); as a source of RIP-mediated fragments that migrate into the nucleus where they activate p65 (‘RelA’)/NF-κB-mediated transcription; and, as the intracytoplasmic MHC Class II chaperone in a complex with MHC Class II heterodimers that binds processed antigen (the antigen is then presented extracellularly). Depending upon the intrahepatic microenvironment, the separate or collective functions of these molecules are postulated to lead to cellular immune system-mediated anti-hepatocyte responses, hepatocyte proliferation and/or hepatocyte death. The annotations and symbols are defined in the figure (see text and references for further details).Abbreviations: MAPK, mitogen-activated protein kinase; MHC, major histocompatibility complex; MIF, macrophage migration inhibitory factor; RIP, regulated intramembrane proteolysis.
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f1-hmer-2-039: Hepatic immunologic ectopia: a constellation of constitutive immunophenotypes associated with IkkβΔhep hepatocytes. The diagram illustrates elements of the basic hypothesis, viz., that compared to IkkβF/F hepatocytes, IkkβΔhep hepatocytes ectopically express MIF receptors associated with MAPK signaling pathways, IFN-γ regulatory proteins which facilitate hepatocellular responses to IFN-γ (an activator of hepatic macrophages, as well as several immune system cells that may be situated in hepatotoxic livers), and antigen-presentation-competent MHC class II receptors (which respond to DEN-associated antigens and elicit specialized intrahepatic CD4+ and CD8+ T cell responses). CD74 serves a triple role: as a component of the MIF receptor along with CD44 (at plasma membrane sites); as a source of RIP-mediated fragments that migrate into the nucleus where they activate p65 (‘RelA’)/NF-κB-mediated transcription; and, as the intracytoplasmic MHC Class II chaperone in a complex with MHC Class II heterodimers that binds processed antigen (the antigen is then presented extracellularly). Depending upon the intrahepatic microenvironment, the separate or collective functions of these molecules are postulated to lead to cellular immune system-mediated anti-hepatocyte responses, hepatocyte proliferation and/or hepatocyte death. The annotations and symbols are defined in the figure (see text and references for further details).Abbreviations: MAPK, mitogen-activated protein kinase; MHC, major histocompatibility complex; MIF, macrophage migration inhibitory factor; RIP, regulated intramembrane proteolysis.

Mentions: Based upon these observations, we propose the hypothesis that augmented susceptibility of IkkβΔhep mice to HCC requires functional hepatocellular expression of CD74, MIF41,42 receptors, IFN-γ regulatory proteins, and antigen-presentation by MHC class II receptors. We refer to this apparently unique phenotypic cluster as “hepatic immunologic ectopia” (see Figure 1). One or more of these functions, if activated, might lead to hepatocellular antigen presentation, proliferation and/or death (via apoptosis or necrosis). Various MAPK and STAT pathways may be called into play as mediators of these responses.


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

Koch KS, Leffert HL - Hepat Med (2010)

Hepatic immunologic ectopia: a constellation of constitutive immunophenotypes associated with IkkβΔhep hepatocytes. The diagram illustrates elements of the basic hypothesis, viz., that compared to IkkβF/F hepatocytes, IkkβΔhep hepatocytes ectopically express MIF receptors associated with MAPK signaling pathways, IFN-γ regulatory proteins which facilitate hepatocellular responses to IFN-γ (an activator of hepatic macrophages, as well as several immune system cells that may be situated in hepatotoxic livers), and antigen-presentation-competent MHC class II receptors (which respond to DEN-associated antigens and elicit specialized intrahepatic CD4+ and CD8+ T cell responses). CD74 serves a triple role: as a component of the MIF receptor along with CD44 (at plasma membrane sites); as a source of RIP-mediated fragments that migrate into the nucleus where they activate p65 (‘RelA’)/NF-κB-mediated transcription; and, as the intracytoplasmic MHC Class II chaperone in a complex with MHC Class II heterodimers that binds processed antigen (the antigen is then presented extracellularly). Depending upon the intrahepatic microenvironment, the separate or collective functions of these molecules are postulated to lead to cellular immune system-mediated anti-hepatocyte responses, hepatocyte proliferation and/or hepatocyte death. The annotations and symbols are defined in the figure (see text and references for further details).Abbreviations: MAPK, mitogen-activated protein kinase; MHC, major histocompatibility complex; MIF, macrophage migration inhibitory factor; RIP, regulated intramembrane proteolysis.
© Copyright Policy
Related In: Results  -  Collection

Show All Figures
getmorefigures.php?uid=PMC3756905&req=5

f1-hmer-2-039: Hepatic immunologic ectopia: a constellation of constitutive immunophenotypes associated with IkkβΔhep hepatocytes. The diagram illustrates elements of the basic hypothesis, viz., that compared to IkkβF/F hepatocytes, IkkβΔhep hepatocytes ectopically express MIF receptors associated with MAPK signaling pathways, IFN-γ regulatory proteins which facilitate hepatocellular responses to IFN-γ (an activator of hepatic macrophages, as well as several immune system cells that may be situated in hepatotoxic livers), and antigen-presentation-competent MHC class II receptors (which respond to DEN-associated antigens and elicit specialized intrahepatic CD4+ and CD8+ T cell responses). CD74 serves a triple role: as a component of the MIF receptor along with CD44 (at plasma membrane sites); as a source of RIP-mediated fragments that migrate into the nucleus where they activate p65 (‘RelA’)/NF-κB-mediated transcription; and, as the intracytoplasmic MHC Class II chaperone in a complex with MHC Class II heterodimers that binds processed antigen (the antigen is then presented extracellularly). Depending upon the intrahepatic microenvironment, the separate or collective functions of these molecules are postulated to lead to cellular immune system-mediated anti-hepatocyte responses, hepatocyte proliferation and/or hepatocyte death. The annotations and symbols are defined in the figure (see text and references for further details).Abbreviations: MAPK, mitogen-activated protein kinase; MHC, major histocompatibility complex; MIF, macrophage migration inhibitory factor; RIP, regulated intramembrane proteolysis.
Mentions: Based upon these observations, we propose the hypothesis that augmented susceptibility of IkkβΔhep mice to HCC requires functional hepatocellular expression of CD74, MIF41,42 receptors, IFN-γ regulatory proteins, and antigen-presentation by MHC class II receptors. We refer to this apparently unique phenotypic cluster as “hepatic immunologic ectopia” (see Figure 1). One or more of these functions, if activated, might lead to hepatocellular antigen presentation, proliferation and/or death (via apoptosis or necrosis). Various MAPK and STAT pathways may be called into play as mediators of these responses.

Bottom Line: 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.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.

View Article: PubMed Central - PubMed

Affiliation: Hepatocyte Growth Control and Stem Cell Laboratory, Department of Pharmacology, School of Medicine, University of California, San Diego, CA, USA.

ABSTRACT
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.

No MeSH data available.


Related in: MedlinePlus