Cytokine Mediated Regulation of Interferon-Gamma-Induced Ido Activation

MacKenzie, Colin R.; González, Raquel Guadarrama; Kniep, Eva; Roch, Simone; Däubener, Walter

doi:10.1007/978-1-4615-4709-9_66

Cited by 61 publications

(34 citation statements)

References 13 publications

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“…As expected from other studies on myeloid cells, IFN-γ induced the expression of IDO mRNA ( Figure 1A). In the presence of IFN-γ, TGF-β decreased and TNF-α increased IDO expression (data not shown), consistent with others' results (Kwidzinski et al 2005;MacKenzie et al 1999;Robinson et al 2003;Yuan et al 1998). However IL-4, which has been reported to inhibit IDO expression in a number of cell types, increased IFN-γ induced IDO expression ( Figure 1B).…”

Section: Il-4 Increases Ifn-γ Induced Ido Expression In Microgliasupporting

confidence: 91%

IFN‐γ‐induced IDO and WRS expression in microglia is differentially regulated by IL‐4

Yadav

Burudi

Alirezaei

et al. 2007

Glia

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Indoleamine 2,3-dioxygenase (IDO), a tryptophan catabolizing enzyme, has been implicated in the pathogenesis of various neurological disorders. IDO expression is induced by IFN-γ and leads to neurotoxicity by generating quinolinic acid. Additionally, it inhibits the immune response through both tryptophan depletion and generating other tryptophan catabolites. IL-4 and IL-13 have been shown to control IDO expression by antagonizing the effects of IFN-γ in different cell types. Here, we investigated the effects of these cytokines on IDO expression in microglia. Interestingly, we observed that both IL-4 and IL-13 greatly enhanced IFN-γ induced IDO expression. However, tryptophanyl-tRNA synthetase (WRS), which is coinduced with IDO by IFN-γ, is downregulated by IL-4 and IL-13. The effect of IL-4 and IL-13 was independent of STAT-6. Modulation of IDO but not WRS was eliminated by inhibition of protein phosphatase 2A (PP2A) activity. The phosphatidylinositol 3-kinase (PI3K) pathway further differentiated the regulation of these two enzymes, as inhibiting the PI3K pathway eliminated IFN-γ induction of IDO, whereas such inhibition greatly enhanced WRS expression. These findings show discordance between modulations of expression of two distinct enzymes utilizing tryptophan as a common substrate, and raise the possibility of their involvement in regulating immune responses in various neurological disorders.

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Section: Il-4 Increases Ifn-γ Induced Ido Expression In Microgliasupporting

confidence: 91%

IFN‐γ‐induced IDO and WRS expression in microglia is differentially regulated by IL‐4

Yadav

Burudi

Alirezaei

et al. 2007

Glia

View full text Add to dashboard Cite

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“…These could then migrate to the SLN, before any tumour spread takes place and prime the site for tumour growth, by producing IDO and TGFb1, and making the SLN an immunoprivileged site suitable for melanoma metastasis. In studies on mouse and human macrophages activated with IFNg to secret IDO, TGFb was shown to inhibit IDO secretion (Bogdan and Nathan, 1993;MacKenzie et al, 1999). However, it is conceivable that tolerogenic DCs may react differently to DCs primed to activate immune responses.…”

Section: Discussionmentioning

confidence: 99%

Mechanisms of local immunosuppression in cutaneous melanoma

et al. 2007

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Cutaneous melanoma is highly immunogenic, yet primary melanomas and metastases develop successfully in otherwise immunocompetent patients. To investigate the local immunosuppressive microenvironment, we examined the presence of suppressor T lymphocytes and tolerising dendritic cells (DCs), the expression of immunosuppressive cytokines (IL-10, TGFb1 and TGFb2) and the enzyme indoleamine 2,3-dioxygenase (IDO) using qRT -PCR and immunohistochemistry in primary skin melanomas, negative and positive sentinel lymph nodes (SLN), and lymph nodes with advanced metastases. Our results indicate that tolerogenic DCs and suppressor T lymphocytes are present in melanoma at all stages of disease progression. They express transforming growth factor b receptor 1 (TGFbR1), and are therefore susceptible to TGFb1 and TGFb2 specifically expressed by primary melanoma. We found that expression of IDO and interleukin 10 (IL-10) increased with melanoma progression, with the highest concentration in positive SLN. We suggest that negative SLN contain immunosuppressive cells and cytokines, due to preconditioning by tolerogenic DCs migrating from the primary melanoma site to the SLN. In primary melanoma, TGFb2 is likely to render peripheral DCs tolerogenic, while in lymph nodes IDO and TGFb1 may have a major effect. This mechanism of tumourassociated immunosuppression may inhibit the immune response to the tumour and may explain the discrepancy between the induction of systemic immunity by anti-melanoma vaccines and their poor performance in the clinic.

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“…The lower levels of expression of IDO found in the relatively stable phase of infection (chronic, group B) likely reflect the low level of virus in the brain and may also reflect a differential regulation of IL-4, IL-10, and transforming growth factor ␤, all possible inhibitors of IFN-␥ activity (23). Previous studies have shown that IL-4, generated mainly by Th2-like T cells, and TNF-␣ are elevated in predementia HIV patients, although, later during dementia, IL-4 is down-regulated (39).…”

Section: Discussionmentioning

confidence: 99%