A role for STAT3 and cathepsin S in IL-10 down-regulation of IFN-γ-induced MHC class II molecule on primary human blood macrophages

Chan, Loi Yuen; Cheung, Benny K. W.; Li, J.; Lau, Alan F.

doi:10.1189/jlb.1009659

Cited by 61 publications

(45 citation statements)

References 60 publications

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“…Binding of IFN γ to its receptor activates STAT-1, which in turn binds to transcription factors that will stimulate MHC-II, protein kinase (PKR), and ribonuclease L expression. Thus, blocking or failure of the IFN γ signaling pathway confers higher susceptibility to infections, suggesting that secretion of IFN γ may be an important effector function for the suppression of HIV-1 and other viral infections [31–33]. In this study, the IFN γ +874TT genotype, which is associated with high IFN γ production, was related to considerably higher levels of CD4+ T lymphocytes compared to the other two genotypes (AA and AT).…”

Section: Discussionmentioning

confidence: 56%

Polymorphisms in the IFNγ, IL-10, and TGFβGenes May Be Associated with HIV-1 Infection

et al. 2015

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Objective. This study investigated possible associations between the TNFα-308G/A, IFN+874A/T, IL-6-174C/G, IL-10-1082A/G, and TGFβ-509C/T polymorphisms with HIV-1 infection, in addition to correlation of the polymorphisms with clinical markers of AIDS progression, such as levels of CD4+/CD8+ T lymphocytes and plasma viral load. Methods. A total of 216 individuals who were infected with HIV-1 and on antiretroviral therapy (ART) and 294 individuals from the uninfected control group were analyzed. Results. All individuals evaluated were negative for total anti-HBc, anti-HCV, anti-T. pallidum, and anti-HTLV-1/2. The polymorphisms were identified by PCR-RFLP. Individuals presenting the IFN+874A allele as well as the AA genotype were more frequent in the HIV-1 infected group compared to the control group (P < 0.05), in addition to having lower levels of CD4+ T lymphocytes. The CD8+ T lymphocytes count was significantly lower in individuals with the IL-10-1082 GG genotype. The TGFβ-509TT genotype was associated with higher plasma viral load. Conclusions. The results suggest that the presence of the IFN+874A allele confers susceptibility to HIV-1 infection and a decrease in the number of CD4+ T lymphocytes. In addition, the genotype associated with high serum levels of TGFβ may be associated with an increase in plasma viral load.

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Section: Discussionmentioning

confidence: 56%

Polymorphisms in the IFNγ, IL-10, and TGFβGenes May Be Associated with HIV-1 Infection

et al. 2015

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“…This might occur through LIF-induced activation of STAT3 that could exert a negative control, directly or indirectly, by acting in proximal or distal transcriptional activators of the hCG genes. In accordance with this proposed mechanism, a recent study has demonstrated that the inhibitory effects of IL10 on the antigen-presenting capacity of interferon c (IFNG)-stimulated human macrophages may act, via STAT3, by a negative transcriptional regulation of cathepsin S and major histocompatibility complex (MHC) II genes [50]. Therefore, a detailed promoter analysis would be required to explore whether STAT3, and even STAT1 or STAT1-STAT3 heterodimers, plays a role in mediating the inhibitory action of LIF on the promoters of hCG gene and an opposed positive action of LIF on fusion-related gene promoters.…”

Section: Leduc Et Almentioning

confidence: 72%

Leukemia Inhibitory Factor Regulates Differentiation of Trophoblastlike BeWo Cells Through the Activation of JAK/STAT and MAPK3/1 MAP Kinase-Signaling Pathways1

Leduc

Bourassa

Asselin

et al. 2012

Biology of Reproduction

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It is well established that syncytium formation involves the fusion of mononucleated trophoblasts into a multinucleated structure and the secretion of hormonal factors, such as human chorionic gonadotropin (hCG). These morphological and biochemical changes are regulated by a plethora of ligands, which upon binding to specific receptors trigger the activation of many signaling pathways, such as janus kinase/signal transducer and activator of transcription (JAK/STAT) and the mitogen-activated protein (MAP) kinase extracellular signal-regulated kinases 1 and 2 (MAPK3/1). We used the forskolin-induced syncytialization of trophoblastlike BeWo cells to characterize at the cellular level the effect mediated by leukemia inhibitory factor (LIF) on trophoblast differentiation and to describe its action at the molecular level. Forskolin induces both hCG secretion and BeWo cell syncytial fusion. Although LIF had no effect on the undifferentiated state of the cells, the cytokine generated a strong reduction in forskolin-induced hCG release. In contrast to its effect on hCG secretion, LIF exerts a synergistic effect toward forskolin-induced fusion. LIF reduced hormonal production through a STAT1- and STAT3-dependent mechanism, whereas MAPK3/1 was not involved in this process. However, both types of signaling molecules were required to mediate the action of LIF in forskolin-induced cell fusion. These data provide novel insights into the regulation of trophoblast cell differentiation by LIF and describe for the first time the molecular mechanism underlying the effect of the cytokine.

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“…It is possible that STAT3 may play a major role in this effect since many cytokines produced by tumors one way or another may trigger STAT3 signaling in myeloid cells and up-regulation of STAT3 is a common finding in myeloid cells in TB hosts (34–36). On the other hand, it is known that up-regulation of STAT3 results in reduction of MHC class II expression in DCs (17, 37, 38). …”

Section: Discussionmentioning

confidence: 99%

Antigen-Specific CD4+ T Cells Regulate Function of Myeloid-Derived Suppressor Cells in Cancer via Retrograde MHC Class II Signaling

et al. 2012

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Myeloid-derived suppressor cells (MDSC) play a major role in cancer-related immune suppression, yet the nature of this suppression remains controversial. In this study, we evaluated the ability of MDSC to elicit CD4+ T cell tolerance in different mouse tumor models. In contrast to CD8+ T-cell tolerance, which could be induced by MDSC in all the tumor models tested, CD4+ T-cell tolerance could be elicited in only one of the models (MC38) where a substantial level of MHC class II was expressed on MDSC, compared to control myeloid cells. Mechanistic investigations revealed that MDSC deficient in MHC class II could induce tolerance to CD8+ T cells but not to CD4+ T cells. Unexpectedly, antigen-specific CD4+ T cells (but not CD8+ T cells) could dramatically enhance the immune suppressive activity of MDSC by converting them into powerful non-specific suppressor cells. This striking effect was mediated by direct cell-cell contact through cross-linking of MHC class II on MDSC. We also implicated an Ets-1 transcription factor-regulated increase in expression of Cox-2 and prostaglandin E2 in MDSCs in mediating this effect. Together, our findings suggest that activated CD4+ T cells that are antigen-specific may enhance the immune suppressive activity of MDSC, a mechanism that might serve normally as a negative feedback loop to control immune responses that becomes dysregulated in cancer.

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A role for STAT3 and cathepsin S in IL-10 down-regulation of IFN-γ-induced MHC class II molecule on primary human blood macrophages

Cited by 61 publications

References 60 publications

Polymorphisms in the IFNγ, IL-10, and TGFβGenes May Be Associated with HIV-1 Infection

Polymorphisms in the IFNγ, IL-10, and TGFβGenes May Be Associated with HIV-1 Infection

Leukemia Inhibitory Factor Regulates Differentiation of Trophoblastlike BeWo Cells Through the Activation of JAK/STAT and MAPK3/1 MAP Kinase-Signaling Pathways1

Antigen-Specific CD4+ T Cells Regulate Function of Myeloid-Derived Suppressor Cells in Cancer via Retrograde MHC Class II Signaling

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