Mechanisms for HIV Tat upregulation of IL‐10 and other cytokine expression: Kinase signaling and PKR‐mediated immune response

Li, J.; Lee, Davy C. W.; Cheung, Benny K. W.; Lau, Alan F.

doi:10.1016/j.febslet.2005.04.060

Cited by 58 publications

(61 citation statements)

References 30 publications

(38 reference statements)

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“…The PKR inhibitor 2-AP almost totally abolished IL-10 mRNA induction in murine macrophages (Fig. 4), consistent with the reported role for PKR in IL-10 induction in human PBMC by HIV-Tat stimulation (54). Consequently, S100A8 mRNA and protein levels were also reduced (Fig.…”

Section: Discussionsupporting

confidence: 77%

IL-10-Dependent S100A8 Gene Induction in Monocytes/Macrophages by Double-Stranded RNA

Endoh¹,

Chung²,

Clark

et al. 2009

The Journal of Immunology

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The S100 calcium-binding proteins S100A8 and S100A9 are elevated systemically in patients with viral infections. The S100A8-S100A9 complex facilitated viral replication in human CD4+ T lymphocytes latently infected with HIV-1- and S100A8-induced HIV-1 transcriptional activity. Mechanisms inducing the S100 genes and the potential source of these proteins following viral activation are unknown. In this study, we show that S100A8 was induced in murine macrophages, and S100A8 and S100A9 in human monocytes and macrophages, by polyinosinic:polycytidylic acid, a dsRNA mimetic. Induction was at the transcriptional level and was IL-10 dependent. Similar to LPS-induced S100A8, induction by dsRNA was dependent on p38 and ERK MAPK. Protein kinase R (PKR) mediates antiviral defense and participates in MyD88-dependent/independent signaling triggered by TLR4 or TLR3. Like IL-10, S100 induction by polyinosinic:polycytidylic acid and by LPS was inhibited by the specific PKR inhibitor 2-aminopurine, indicating a novel IL-10, PKR-dependent pathway. Other mediators such as IFN-β, which synergized with dsRNA, may also be involved. C/EBPβ bound the defined promoter region in response to dsRNA. S100A8 was expressed in lungs of mice infected with influenza virus and was maximal at day 8 with strong immunoreactivity in epithelial cells lining the airways and in mononuclear cells and declined early in the recovery phase, implying down-regulation by mediator(s) up-regulated during resolution of the infection. IL-10 is implicated in viral persistence. Since S100A8/S100A9 levels are likely to be maintained in conditions where IL-10 is raised, these proteins may contribute to viral persistence in patients infected by some RNA viruses.

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Section: Discussionsupporting

confidence: 77%

IL-10-Dependent S100A8 Gene Induction in Monocytes/Macrophages by Double-Stranded RNA

Endoh¹,

Chung²,

Clark

et al. 2009

The Journal of Immunology

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“…HIV-1 requires the cellular receptor CXCR4 (X4-tropic virus) or CCR5 (R5-tropic virus) for entrance into host epithelial cells (31). Using immunofluorescence microscopy, we were unable to detect either CXCR4 or CCR5 in our cultured human cholangiocytes, while control HT29 cells, which are susceptible to HIV-1 in- (Fig.…”

Section: H69 Cells Do Not Express Hiv-1 Coreceptorsmentioning

confidence: 70%

“…Tat is essential for replication of the viral genome, and it has been proposed that Tat is an important factor in HIV-induced pathogenesis of AIDS (2). Exogenous Tat has a variety of effects on cellular processes in uninfected cells, including increased binding of nuclear factor kappa B (NF-B) to DNA, increased production of cytokines, increased expression of cytokine receptors, and modulation of cell survival and proliferation (2,19,31,34,42). Furthermore, studies have demonstrated that Tat increases apoptosis in a variety of cell types, including cell types not directly infected by HIV-1 (4,42).…”

mentioning

confidence: 99%

The Human Immunodeficiency Virus Type 1 Tat Protein EnhancesCryptosporidium parvum-Induced Apoptosis in Cholangiocytes via a Fas Ligand-Dependent Mechanism

et al. 2007

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While Cryptosporidium parvum infection of the intestine has been reported in both immunocompetent and immunocompromised individuals, biliary infection is seen primarily in adult AIDS patients and is associated with development of AIDS cholangiopathy. However, the mechanisms of pathogen-induced AIDS cholangiopathy remain unclear. Since we previously demonstrated that the Fas/Fas ligand (FasL) system is involved in paracrine-mediated C. parvum cytopathicity in cholangiocytes, we also tested the potential synergistic effects of human immunodeficiency virus type 1 (HIV-1) transactivator of transcription (Tat)-mediated FasL regulation on C. parvum-induced apoptosis in cholangiocytes by semiquantitative reverse transcription-PCR, immunoblotting, immunofluorescence analysis, and immunogold electron microscopy. H69 cells do not express CXCR4 and CCR5, which are receptors required for direct HIV-1 viral infection. However, recombinant biologically active HIV-1-associated Tat protein increased FasL expression in the cytoplasm of cholangiocytes without a significant increase in apoptosis. We found that C. parvum-induced apoptosis was associated with translocation of intracellular FasL to the cell membrane surface and release of full-length FasL from infected H69 cells. Tat significantly (P < 0.05) increased C. parvum-induced apoptosis in bystander cells in a dose-dependent manner. Moreover, Tat enhanced both C. parvum-induced FasL membrane translocation and release of full-length FasL. In addition, the FasL neutralizing antibody NOK-1 and the caspase-8 inhibitor Z-IETD-fmk both blocked C. parvum-induced apoptosis in cholangiocytes. The data demonstrated that HIV-1 Tat enhances C. parvum-induced cholangiocyte apoptosis via a paracrine-mediated, FasL-dependent mechanism. Our results suggest that concurrent active HIV replication, with associated production of Tat protein, and C. parvum infection synergistically increase cholangiocyte apoptosis and thus jointly contribute to AIDS-related cholangiopathies.

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“…Although results from several studies strongly indicate Tat as a potential vaccine candidate, some studies show an immunosuppressive role of Tat, particularly against the coimmunogens, in the host (18,19). In addition, studies from patients have indicated an increase in IL-10 production from infected cells (20) and Tat has been implicated in such IL-10 induction (21,22). IL-10 is known to inhibit a broad spectrum of cellular immune responses.…”

Section: Hiv-1 Tat Suppresses Gp120-specific T Cell Response In Il-10mentioning

confidence: 99%

HIV-1 Tat Suppresses gp120-Specific T Cell Response in IL-10-Dependent Manner

Gupta

Boppana

Mishra

et al. 2008

The Journal of Immunology

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A large number of multicomponent vaccine candidates are currently in clinical evaluation, many of which also include the HIV-1 Tat protein, an important regulatory protein of the virus. However, whether Tat, a known immune effector molecule with a well-conserved sequence among different HIV subtypes, affects the immune response to a coimmunogen is not well understood. In this study, using a bicistronic vector expressing both gp120 and Tat, we have analyzed the role of Tat in elicitation of the gp120-specific immune response. The T cell responses to gp120 were greatly diminished in mice coimmunized with Tat as compared with mice immunized with gp120 alone. This immunosuppressive activity of Tat was not confined to viral Ag only because it also suppressed the immune response of unrelated Ag. Analysis of the cytokine profile suggests that Tat induces IL-10 and since IL-10 has been demonstrated to have appreciable T cell inhibitory activity, it is plausible that IL-10 could be responsible for Tat-mediated immunosuppression. Finally, the immunosuppressive effect of Tat was not observed in IL-10-deficient mice, confirming the role of IL-10 in Tat-mediated immunosuppression. Thus, our results demonstrate for the first time that the immunosuppressive effect of Tat is mediated through IL-10 and suggests that Tat-induced IL-10-mediated immune suppression seems to cripple immune surveillance during HIV-1 infection.

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Mechanisms for HIV Tat upregulation of IL‐10 and other cytokine expression: Kinase signaling and PKR‐mediated immune response

Cited by 58 publications

References 30 publications

IL-10-Dependent S100A8 Gene Induction in Monocytes/Macrophages by Double-Stranded RNA

IL-10-Dependent S100A8 Gene Induction in Monocytes/Macrophages by Double-Stranded RNA

The Human Immunodeficiency Virus Type 1 Tat Protein EnhancesCryptosporidium parvum-Induced Apoptosis in Cholangiocytes via a Fas Ligand-Dependent Mechanism

HIV-1 Tat Suppresses gp120-Specific T Cell Response in IL-10-Dependent Manner

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