The Effects of HIV on the Regulation of IL-12 Family Cytokines, IL-12, IL-23, and IL-27 Production in Human Monocyte-derived Macrophages PDF Download
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Author: Shifawn O'Hara Publisher: ISBN: Category : Cytokines Languages : en Pages : 0
Book Description
IL-12 family cytokines IL-23 and IL-27 play an important role linking innate and adaptive immunity, and regulating T-cell responses. The production of IL-12, a structurally similar cytokine, is decreased in chronic HIV infection; therefore IL-23 and IL-27 may also be influenced by HIV infection. I hypothesized that HIV inhibits LPS-induced IL-23 and IL-27 production in human MDMs by suppressing the activation of signalling pathways regulating their expression. In vitro HIV-infection of MDMs did not have any effect on basal secretion of IL-23 or IL-27; however, HIV inhibited LPS-induced production of IL-12/23 p40 and IL-23 p19, and IL-27 EBI3 and IL-27 p28 mRNA expression, and IL-23, IL-12/23 p40 and IL-27 secretion. In order to evaluate the molecular mechanisms by which HIV inhibits IL-23 and IL-27 in LPS-stimulated MDMs, the signalling pathways regulating their expression were evaluated. The PI3K, p38 MAPK, and JNK MAPK pathways were found to positively regulate LPS-induced IL-27 secretion. Interestingly, in vitro HIV infection inhibited LPS-induced p38 and JNK MAPK activation in MDMs. In summary, I have shown that HIV inhibits IL-23 and IL-27 production in LPS-stimulated MDMs and that HIV may inhibit LPS-induced IL-27 production through the inhibition of p38 and JNK MAPK activation. It is currently unknown whether PKCs regulate LPS-induced IL-23 or IL-27 in human monocytes/macrophages. I demonstrated that classical PKCs differentially regulate LPS-induced IL-23 and IL-27 secretion within THP-1 cells, primary monocytes, and MDMs. Classical PKCs were found to positively regulate LPS-induced IL-12/23 p40 and IL-27 p28 mRNA expression and IL-12/23 p40, IL-23, and IL-27 secretion in primary human monocytes. Similarly, the classical PKCs were found to positively regulate IL-27 p28 mRNA expression and IL-27 secretion in THP-1 cells. However, classical PKCs did not regulate LPS-induced IL-27 production in MDMs, or LPS-induced IL-23 production in THP-1 cells. Overall, this demonstrates that classical PKCs differentially regulate LPS-induced IL-23 and IL-27 production in different myeloid cells.
Author: Shifawn O'Hara Publisher: ISBN: Category : Cytokines Languages : en Pages : 0
Book Description
IL-12 family cytokines IL-23 and IL-27 play an important role linking innate and adaptive immunity, and regulating T-cell responses. The production of IL-12, a structurally similar cytokine, is decreased in chronic HIV infection; therefore IL-23 and IL-27 may also be influenced by HIV infection. I hypothesized that HIV inhibits LPS-induced IL-23 and IL-27 production in human MDMs by suppressing the activation of signalling pathways regulating their expression. In vitro HIV-infection of MDMs did not have any effect on basal secretion of IL-23 or IL-27; however, HIV inhibited LPS-induced production of IL-12/23 p40 and IL-23 p19, and IL-27 EBI3 and IL-27 p28 mRNA expression, and IL-23, IL-12/23 p40 and IL-27 secretion. In order to evaluate the molecular mechanisms by which HIV inhibits IL-23 and IL-27 in LPS-stimulated MDMs, the signalling pathways regulating their expression were evaluated. The PI3K, p38 MAPK, and JNK MAPK pathways were found to positively regulate LPS-induced IL-27 secretion. Interestingly, in vitro HIV infection inhibited LPS-induced p38 and JNK MAPK activation in MDMs. In summary, I have shown that HIV inhibits IL-23 and IL-27 production in LPS-stimulated MDMs and that HIV may inhibit LPS-induced IL-27 production through the inhibition of p38 and JNK MAPK activation. It is currently unknown whether PKCs regulate LPS-induced IL-23 or IL-27 in human monocytes/macrophages. I demonstrated that classical PKCs differentially regulate LPS-induced IL-23 and IL-27 secretion within THP-1 cells, primary monocytes, and MDMs. Classical PKCs were found to positively regulate LPS-induced IL-12/23 p40 and IL-27 p28 mRNA expression and IL-12/23 p40, IL-23, and IL-27 secretion in primary human monocytes. Similarly, the classical PKCs were found to positively regulate IL-27 p28 mRNA expression and IL-27 secretion in THP-1 cells. However, classical PKCs did not regulate LPS-induced IL-27 production in MDMs, or LPS-induced IL-23 production in THP-1 cells. Overall, this demonstrates that classical PKCs differentially regulate LPS-induced IL-23 and IL-27 production in different myeloid cells.
Author: Shifawn O'Hara Publisher: ISBN: Category : Cytokines Languages : en Pages :
Book Description
IL-12 family cytokines IL-23 and IL-27 play an important role linking innate and adaptive immunity, and regulating T-cell responses. The production of IL-12, a structurally similar cytokine, is decreased in chronic HIV infection; therefore IL-23 and IL-27 may also be influenced by HIV infection. I hypothesized that HIV inhibits LPS-induced IL-23 and IL-27 production in human MDMs by suppressing the activation of signalling pathways regulating their expression. In vitro HIV-infection of MDMs did not have any effect on basal secretion of IL-23 or IL-27; however, HIV inhibited LPS-induced production of IL-12/23 p40 and IL-23 p19, and IL-27 EBI3 and IL-27 p28 mRNA expression, and IL-23, IL-12/23 p40 and IL-27 secretion. In order to evaluate the molecular mechanisms by which HIV inhibits IL-23 and IL-27 in LPS-stimulated MDMs, the signalling pathways regulating their expression were evaluated. The PI3K, p38 MAPK, and JNK MAPK pathways were found to positively regulate LPS-induced IL-27 secretion. Interestingly, in vitro HIV infection inhibited LPS-induced p38 and JNK MAPK activation in MDMs. In summary, I have shown that HIV inhibits IL-23 and IL-27 production in LPS-stimulated MDMs and that HIV may inhibit LPS-induced IL-27 production through the inhibition of p38 and JNK MAPK activation. It is currently unknown whether PKCs regulate LPS-induced IL-23 or IL-27 in human monocytes/macrophages. I demonstrated that classical PKCs differentially regulate LPS-induced IL-23 and IL-27 secretion within THP-1 cells, primary monocytes, and MDMs. Classical PKCs were found to positively regulate LPS-induced IL-12/23 p40 and IL-27 p28 mRNA expression and IL-12/23 p40, IL-23, and IL-27 secretion in primary human monocytes. Similarly, the classical PKCs were found to positively regulate IL-27 p28 mRNA expression and IL-27 secretion in THP-1 cells. However, classical PKCs did not regulate LPS-induced IL-27 production in MDMs, or LPS-induced IL-23 production in THP-1 cells. Overall, this demonstrates that classical PKCs differentially regulate LPS-induced IL-23 and IL-27 production in different myeloid cells.
Author: Kelley A. Chambers Publisher: ISBN: Category : Languages : en Pages : 0
Book Description
Progressive immunodeficiency in HIV infection is paralleled by a decrease in IL-12 production, a cytokine crucial for cellular immune function. This thesis reports an examination of the requirement for productive viral infection, the role of other cytokines, and the intracellular molecular targets of HIV-mediated suppression of IL-12 p40 expression, with particular emphasis on regulation of the IL-12 p40 promoter, and LPS-induced activation of MAP kinases. The reduction in LPS-induced IL-12 p40 protein and mRNA following acute in vitro HIV infection of THP-1 cells and monocyte-derived macrophages (MDM) was not attributed to IL-10 or TGF-beta activity, and was not restored by priming with IL-4, IL-13, or IFN-gamma. Suppression of IL-12 was dependent upon productive viral infection, and was due, at least in part, to impaired transcription of IL-12 p40. HIV infection of THP-1 cells reduced nuclear factor binding to the NF-kappaB, AP-1, and Sp1 sites of the IL-12 p40 promoter. Nuclear factor binding to these sites, in addition to the Ets-2 element, was also altered by HIV infection of MDM. By site-directed mutagenesis, each of these transcription factor binding sites were determined to be necessary for IL-12 p40 promoter activation. Binding of NF-kappaB p50, p65, c-Rel, c-Fos, c-Jun, Sp1 and Sp3 proteins to the IL-12 p40 promoter was reduced by HIV infection of THP-1 cells, while p50, c-Rel, c-Fos, c-Jun, IRF-1, ICSBP, and Ets-2 binding was altered by HIV in MDM. HIV infection did not affect cellular levels of the nuclear factors, with exception of NF-kappaB p65 in THP-1 cells, and c-Fos in MDM. HIV infection of myeloid cells decreased levels of phosphorylated JNK MAPK, impaired phosphorylation of p38 MAPK, and suppressed phosphorylation and degradation of IkappaBalpha while ERK 1/2 MAPK was unaffected. Taken together, these results suggest that impaired IL-12 production in HIV-infected myeloid cells occurs, in part, via disruption of IL-12 p40 transcription, and is dependent on productive infection, and independent of the activity of other cytokines. Inhibition of IL-12 p40 transcription is associated with disruption of nuclear factor binding to the NF-kappaB, AP-1, Sp1, and Ets-2 elements of the human IL-12 p40 promoter, which may be a consequence of altered MAPK activation.
Author: Jayasree P. Sundaram Publisher: ISBN: Category : Languages : en Pages : 24
Book Description
Objectives: The role of inflammatory cytokine levels in the pathogenesis of HIV associated neurocognitive (HAND) has been debated. Studies showed that the levels of inflammatory cytokines are linked to the development of HAND, regarless of highly active antiretroviral therapy (HAART) treatment status. However, these studies have not adequately demonstrated how HAART impacts inflammatory cytokine expression in the context of HIV infection. This compares cytokine expression in HIV-infected monoctye-derived macrophages treated with the integrase inhibitor, raltegravir (RAL) alone to those treated with the triple therapy of RAL, emtricitabine (FTC) and tenofovir difumarate (TDF). Methods: Pro-inflammatory cytokines, IFN-[gamma], IL-10, IL-12-p70, IL-1, IL-8, TNF-[alpha], and IL-6 were measured simultaneously in tissue culture supernatants from monocyte derived macrophages infected with HIV-1. We tested the effects of RAL alone compared to RAL/FTC/TDF triple therapy on the levels of these pro-inflammatory cytokines. Results: RAL alone achieves significantly higher suppression of inflammatory cytokines than does RAL+FTC/TDF in the context of HIV-infection over the course of 7 days. Specifically, RAL alone suppresses IL-6, IL-1[beta], and TNF-[alpha] significantly more than RAL+TFD/FTC after 1 day of infection. After 4 and 7 days, anti-inflammatory cytokine IL-10 was lower in the RAL-alone treated MDMs, and IL-8 was significantly higher than those treated with RAL+TDF/FTC. Conclusion: We conclude that RAL alone is superior to RAL/FTC/TDF combination therapy in terms of reducing the levels of pro-inflammatory cytokines in the context of HIV infection. Exploring these ex vivo results further with in vivo studies may further illuminate mechanisms of long-term inflammation during HIV infection.
Author: Shifawn O'Hara
Author: Shifawn O'Hara
Author: Shifawn O'Hara
Author: Ali Akbar Rahim Rahimi
Author: Niranjala Gajanayaka
Author: Wei Ma
Author: Kelley A. Chambers
Author: Mohammad Pirouz Daftarian
Author: Andréane Chénier
Author: Jayasree P. Sundaram
Author: