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

Yadav, Manisha; Burudi, E.M.E.; Alirezaei, Mehrdad; Flynn, Claudia C.; Watry, Debbie D.; Lanigan, Caroline; Fox, Howard S.

doi:10.1002/glia.20544

Cited by 55 publications

(53 citation statements)

References 65 publications

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“…IDO is the rate-limiting enzyme in the kynurenine pathway, which converts tryptophan into quinolinic acid and/or kynurenine. Because the kynurenine pathway and 5-HT production share the same precursor tryptophan, overexpression of IDO is associated with 5-HT depletion, which has both physiological and psychological consequences 35 . Interestingly, quinolinic acid produced in this pathway is an NMDA receptor agonist, while kynurenine is an NMDA receptor antagonist.…”

Section: Discussionmentioning

confidence: 99%

Exploratory Investigation of Early Biomarkers for Chronic Fatigue in Prostate Cancer Patients Following Radiation Therapy

et al. 2017

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Background Fatigue is one of the most debilitating side effects of cancer therapy. Identifying biomarkers early during cancer therapy may help us understand the biologic underpinnings of the persistence of fatigue following therapy. Objective We aimed to identify early biomarkers of fatigue by examining correlations of levels of cytokines during external beam radiation therapy (EBRT) with persistence of fatigue one year following treatment completion in men with non-metastatic prostate cancer (NM-PC). Methods A sample of 34 men with NM-PC scheduled to receive EBRT were followed at baseline (T1), midpoint of EBRT (T2), and one year following EBRT (T3). Demographic and clinical data were obtained by chart review. The Functional Assessment of Cancer Therapy-Fatigue (FACT-F) was administered to measure fatigue levels. Plasma cytokine levels were determined at T1 and T2 using the Bio-Rad Bio-Plex Cytokine Assay Kits. Results Significant correlations were observed between levels of IL-3, IL-8, IL-9, IL-10, IL-16, IP10, IFNα2, IFNγ, and SDF1α at T2 with worsening of fatigue from T1 to T3. Conclusions Immunological changes prior to chronic fatigue development may reflect the long term response to radiation therapy-induced damage. Implications for Practice Early biomarkers for chronic fatigue related to cancer therapy will help advance our understanding of the etiology of this distressing symptom and will help nurses identify patients at risk for developing chronic fatigue after cancer treatment. This information will also aide in patient education, as well as symptom management.

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Section: Discussionmentioning

confidence: 99%

Exploratory Investigation of Early Biomarkers for Chronic Fatigue in Prostate Cancer Patients Following Radiation Therapy

et al. 2017

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“…The effect of IFN-␥ on microglial numbers may be important for the progression of LCMV-mediated disease. Microglia have been shown to secrete anti-inflammatory molecules such as IL-10, transforming growth factor ␤, and indoleamine 2,3-dioxygenase (47,80) that could dampen the immune response and lead to the decreased anorexia and weight loss seen in MIIG mice compared to wild-type controls. Future experiments will examine the potential immunosuppressive role of MG1 microglia in this model.…”

Section: Discussionmentioning

confidence: 99%

Gamma Interferon Signaling in Macrophage Lineage Cells Regulates Central Nervous System Inflammation and Chemokine Production

Lin¹,

Tripathi²,

Sholl³

et al. 2009

J Virol

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Intracranial (i.c.) infection of mice with lymphocytic choriomeningitis virus (LCMV) results in anorexic weight loss, mediated by T cells and gamma interferon (IFN-␥). Here, we assessed the role of CD4؉ T cells and IFN-␥ on immune cell recruitment and proinflammatory cytokine/chemokine production in the central nervous system (CNS) after i.c. LCMV infection. We found that T-cell-depleted mice had decreased recruitment of hematopoietic cells to the CNS and diminished levels of IFN-␥, CCL2 (MCP-1), CCL3 (MIP-1␣), and CCL5 (RANTES) in the cerebrospinal fluid (CSF). Mice deficient in IFN-␥ had decreased CSF levels of CCL3, CCL5, and CXCL10 (IP-10), and decreased activation of both resident CNS and infiltrating antigen-presenting cells (APCs). The effects of IFN-␥ signaling on macrophage lineage cells was assessed using transgenic mice, called "macrophages insensitive to interferon gamma" (MIIG) mice, that express a dominant-negative IFN-␥ receptor under the control of the CD68 promoter. MIIG mice had decreased levels of CCL2, CCL3, CCL5, and CXCL10 compared to controls despite having normal numbers of LCMV-specific CD4 ؉ T cells in the CNS. MIIG mice also had decreased recruitment of infiltrating macrophages and decreased activation of both resident CNS and infiltrating APCs. Finally, MIIG mice were significantly protected from LCMV-induced anorexia and weight loss. Thus, these data suggest that CD4 ؉ T-cell production of IFN-␥ promotes signaling in macrophage lineage cells, which control (i) the production of proinflammatory cytokines and chemokines, (ii) the recruitment of macrophages to the CNS, (iii) the activation of resident CNS and infiltrating APC populations, and (iv) anorexic weight loss.Immune cell recruitment to and infiltration of the central nervous system (CNS) is central to the pathology of a variety of inflammatory neurological diseases, including infectious meningoencephalitis, multiple sclerosis, and cerebral ischemia (59, 60). Chemokines have been shown to be highly upregulated in both human diseases and animal models of neuroinflammation and are thought to be important mediators of immune cell entry into the CNS (59, 60). (27) and serve to amplify the ongoing inflammatory response (25, 28). However, in some EAE studies, neither CCL3 nor CXCL10 were required for disease (72,73). During CNS viral infection, CXCL10 and CCL5 are highly produced in several models (2,41,48,82). In addition, mice deficient in CCR5, which binds (among others) CCL3 and CCL5, do not display impaired CNS inflammation after certain viral infections (13). Thus, the role of chemokines in CNS inflammation is likely complex and dissimilar between autoimmune and viral infection models.IFN-␥ is present in the CNS during autoimmunity and infection (7,54,69). Several studies suggest that IFN-␥ can be a potent inducer of CNS chemokine expression. Adenoviral expression of IFN-␥ in the CNS strongly induced CCL5 and CXCL10 mRNA and protein, and this induction was dependent on the presence of the IFN-␥ receptor (50). In EAE and Toxopla...

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“…In some normal cell types, IDO expression, which is known to be induced by both type I (␣) and type II (␥) IFNs, can also be modulated by the Th1/Th2 cytokine profile. Anti-inflammatory cytokines, such as TGF-␤, IL-4, and IL-13 have been shown to control IDO expression by antagonizing the IFN-␥ effect in human fibroblasts and monocytes (29 -31), whereas the opposite has been reported in eosinophils (32) and microglia (33). Th1 and Th2 cytokines were reported in human breast tumors, but the impacts of this cytokine mixture on IDO expression in tumor cells are currently unknown.…”

mentioning

confidence: 99%

Human Activated T Lymphocytes Modulate IDO Expression in Tumors through Th1/Th2 Balance

Godin-Ethier

Pelletier

Hanafi

et al. 2009

The Journal of Immunology

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Previous cancer vaccination approaches have shown some efficiency in generating measurable immune responses, but they have rarely led to tumor regression. It is therefore possible that tumors emerge with the capacity to down-regulate immune counterparts, through the local production of immunosuppressive molecules, such as IDO. Although it is known that IDO exerts suppressive effects on T cell functions, the mechanisms of IDO regulation in tumor cells remain to be characterized. Here, we demonstrate that activated T cells can induce functional IDO expression in breast and kidney tumor cell lines, and that this is partly attributable to IFN-γ. Moreover, we found that IL-13, a Th2 cytokine, has a negative modulatory effect on IDO expression. Furthermore, we report IDO expression in the majority of breast and kidney carcinoma samples, with infiltration of activated Th1-polarized T cells in human tumors. These findings demonstrate complex control of immune activity within tumors. Future immune therapeutic interventions should thus include strategies to counteract these negative mechanisms.

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

Cited by 55 publications

References 65 publications

Exploratory Investigation of Early Biomarkers for Chronic Fatigue in Prostate Cancer Patients Following Radiation Therapy

Exploratory Investigation of Early Biomarkers for Chronic Fatigue in Prostate Cancer Patients Following Radiation Therapy

Gamma Interferon Signaling in Macrophage Lineage Cells Regulates Central Nervous System Inflammation and Chemokine Production

Human Activated T Lymphocytes Modulate IDO Expression in Tumors through Th1/Th2 Balance

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