TNF-α Suppresses IFN-γ-Induced MHC Class II Expression in HT1080 Cells by Destabilizing Class II<i>trans</i>-Activator mRNA

Han, Yi; Zhou, Z-H. Lucy; Ransohoff, Richard M.

doi:10.4049/jimmunol.163.3.1435

Cited by 26 publications

References 51 publications

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Regulation of myeloid cell function and major histocompatibility complex class II expression by tumor necrosis factor

Mueller¹,

Skapenko²,

Grünke³

et al. 2005

Arthritis & Rheumatism

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Objective. Tumor necrosis factor (TNF)-neutralizing agents are the most successful means of ameliorating systemic autoimmune inflammation. Neutralization of TNF, however, is often associated with the development of autoantibodies, particularly to nuclear antigens, and the mechanisms of this are unknown. We undertook this study to analyze the effect of TNF and its neutralization on the expression of major histocompatibility complex class II molecules and on the function of antigen-presenting myeloid cells in rheumatoid arthritis (RA).Methods. Monocytes were isolated from the peripheral blood of RA patients before and after anti-TNF monoclonal antibody (mAb) treatment and from the peripheral blood of controls by negative selection, differentiated in vitro to macrophages, and analyzed by flow cytometry for HLA-DR expression. T cell responses to activation by myeloid cells were assessed in proliferation assays, and messenger RNA (mRNA) levels of the class II transactivator (CIITA) were determined by semiquantitative reverse transcriptase-polymerase chain reaction.Results. HLA-DR expression was significantly reduced on myeloid cells from RA patients with active disease, but was increased to normal levels after anti-TNF mAb treatment. Concordantly, in vitro application of TNF to monocytes from healthy individuals reduced their ability to up-regulate HLA-DR during differentiation to macrophages and, importantly, inhibited their ability to stimulate T cells in mixed lymphocyte reactions. Molecular analysis revealed that the effect of TNF on HLA-DR expression was mediated via suppression of the transcription factor CIITA. Conclusion. The data indicate that TNF decreases

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Regulation of myeloid cell function and major histocompatibility complex class II expression by tumor necrosis factor

Mueller¹,

Skapenko²,

Grünke³

et al. 2005

Arthritis & Rheumatism

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The MHC class II transactivator (CIITA) mRNA stability is critical for the HLA class II gene expression in myelomonocytic cells

et al. 2005

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The human promyelocytic U937 cells express detectable levels of MHC class II (MHC-II) molecules. Treatment with 12-o--tetradecanoyl phorbol 13-acetate (TPA), inducing macrophage-like differentiation, produces a dramatic decrease of MHC-II expression as result of down-modulation of the activation of immune response gene 1 (AIR-1)-encoded MHC-II transactivator (CIITA). This event is specific, as MHC class I remains unaffected. Similar results are observed with U937 cells expressing an exogenous fulllength CIITA. Molecular studies demonstrate that TPA treatment affects the stability of CIITA mRNA rather than CIITA transcription. Importantly, cis-acting elements within the distal 650 bp of the 1035-bp 3 0 untranslated region (3 0 UTR, nucleotides 3509-4543) are associated to transcript instability. Transcription inhibitors actinomycin D and 5,6-dichlororibofuranosyl benzimidazole, and the translation inhibitor cycloheximide significantly rescue the accumulation of CIITA mRNA in TPA-treated cells. A similar effect is also observed after treatment with staurosporine and the PKC-specific inhibitor GF109203X. The instability of CIITA mRNA produced by TPA in U937 cells is not seen in B cells. These results demonstrate the presence of an additional level of control of MHC-II expression in the macrophage cell lineage depending upon the control of CIITA mRNA stability, most likely mediated by differentiation-induced, 3 0 UTR-interacting factors which require kinase activity for their destabilizing function.

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Immune function of astrocytes

Dong

Benveniste

2001

Glia

1,164

877

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Astrocytes are the major glial cell within the central nervous system (CNS) and have a number of important physiological properties related to CNS homeostasis. The aspect of astrocyte biology addressed in this review article is the astrocyte as an immunocompetent cell within the brain. The capacity of astrocytes to express class II major histocompatibility complex (MHC) antigens and costimulatory molecules (B7 and CD40) that are critical for antigen presentation and T-cell activation are discussed. The functional role of astrocytes as immune effector cells and how this may influence aspects of inflammation and immune reactivity within the brain follows, emphasizing the involvement of astrocytes in promoting Th2 responses. The ability of astrocytes to produce a wide array of chemokines and cytokines is discussed, with an emphasis on the immunological properties of these mediators. The significance of astrocytic antigen presentation and chemokine/cytokine production to neurological diseases with an immunological component is described.

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TNF-α Suppresses IFN-γ-Induced MHC Class II Expression in HT1080 Cells by Destabilizing Class IItrans-Activator mRNA

Cited by 26 publications

References 51 publications

Regulation of myeloid cell function and major histocompatibility complex class II expression by tumor necrosis factor

Regulation of myeloid cell function and major histocompatibility complex class II expression by tumor necrosis factor

The MHC class II transactivator (CIITA) mRNA stability is critical for the HLA class II gene expression in myelomonocytic cells

Immune function of astrocytes

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