IL-27 Activates Human Monocytes via STAT1 and Suppresses IL-10 Production but the Inflammatory Functions of IL-27 Are Abrogated by TLRs and p38

Kalliolias, George D.; Ivashkiv, Lionel B.

doi:10.4049/jimmunol.180.9.6325

Cited by 113 publications

(151 citation statements)

References 59 publications

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“…Expression of SOCS3 is slightly modulated by IL-27. Induction of SOCS expression in human T cells by IL-27 is a salient finding and is in concert with activation of STAT1 and SOCS1 in human macrophages (Kalliolias and Ivashkiv 2008). Whether the IL-27-mediated IL-17 inhibition is attributed to a SOCS1-mediated dampening of STAT1 or STAT3 and the role of SOCS3 remains to be determined.…”

Section: Discussionmentioning

confidence: 99%

Interleukin-27-Mediated Suppression of Human Th17 Cells Is Associated with Activation of STAT1 and Suppressor of Cytokine Signaling Protein 1

Liu

Rohowsky‐Kochan

2011

Journal of Interferon & Cytokine Research

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Accumulating evidence indicates that interleukin (IL)-27, a member of the IL-12 family of cytokines, antagonizes pathological Th17 effector cell responses. Relatively little is known about the cytokines that regulate human Th17 cells. In this study, we investigated the effect of IL-27 on the differentiation of human Th17 cells and on committed memory Th17 cells. We demonstrate that IL-27 suppresses the development of human Th17 cells by downregulating retinoid orphan nuclear receptor C expression and that this inhibition is associated with the induction of the intracellular signaling factors STAT1 and induction of the suppressor of cytokine signaling protein 1. The IL-27-mediated inhibition of IL-17 is independent of IL-10. We show that IL-27 inhibits differentiation of naïve T cells into IL-17 þ T cells under different Th17 polarizing conditions. IL-27 suppresses other Th17 subset cytokines such as IL-22 and IL-21 but not tumor necrosis factor-a. Moreover, we also show that IL-27 inhibits IL-17 production by committed Th17 memory cells, which is independent of IL-10. These studies show that IL-27 negatively regulates both the developing and committed human Th17 responses and therefore may be a promising therapeutic approach in the treatment of Th17-mediated diseases.

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Section: Discussionmentioning

confidence: 99%

Interleukin-27-Mediated Suppression of Human Th17 Cells Is Associated with Activation of STAT1 and Suppressor of Cytokine Signaling Protein 1

Liu

Rohowsky‐Kochan

2011

Journal of Interferon & Cytokine Research

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“…43,59 However, this effect might depend on the target cells and on the microenvironment. 66 IL-27 polymorphisms affecting IL-27 have been associated to an increased susceptibility to ovarian cancer. 67 As proposed by Kalliolas et al, 66 IL-27 may exhibit opposite effects on innate and adaptive immune cells.…”

Section: Discussionmentioning

confidence: 99%

“…66 IL-27 polymorphisms affecting IL-27 have been associated to an increased susceptibility to ovarian cancer. 67 As proposed by Kalliolas et al, 66 IL-27 may exhibit opposite effects on innate and adaptive immune cells. It is more likely that monocytes/ macrophages express IL-27 upon stimulation.…”

Section: Discussionmentioning

confidence: 99%

The ecto-ATPDase CD39 is involved in the acquisition of the immunoregulatory phenotype by M-CSF-macrophages and ovarian cancer tumor-associated macrophages: Regulatory role of IL-27

et al. 2016

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(2016) The ectoATPDase CD39 is involved in the acquisition of the immunoregulatory phenotype by M-CSFmacrophages and ovarian cancer tumor-associated macrophages: Regulatory role of IL-27, OncoImmunology, 5:7, e1178025, DOI: 10.1080/2162402X.2016 Targeting mediators that control the generation or the differentiation of immunoregulatory macrophages represents a therapeutic challenge to overcome tumor-associated immunosuppression. The ectonucleotidase CD39 hydrolyzes ATP into extracellular adenosine that exhibits potent immunosuppressive properties when signaling through the A2A adenosine receptor. We report here that CD14 C CD163 C TAM isolated from ovarian cancer patients and macrophages generated in vitro with M-CSF, express high levels of the membrane ectonucleotidase CD39 compared to classically activated macrophages. The CD39 inhibitor POM-1 and adenosine deaminase (ADA) diminished some of the immunosuppressive functions of CD14 high CD163 high CD39 high macrophages, such as IL-10 secretion. We identified the cytokine IL-27, secreted by tumor-infiltrating neutrophils, located close to infiltrating CD163 C macrophages, as a major rheostat of CD39 expression and consequently, on the acquisition of immunoregulatory properties by macrophages. Accordingly, the depletion of IL-27 downregulated CD39 and PD-L1 expression as well as IL-10 secretion by M-CSF-macrophages. Collectively, these data suggest that CD39, drived by IL-27 and CD115 ligands in ovarian cancer, maintains the immunosuppressive phenotype of TAM. This work brings new information on the acquisition of immunosuppressive properties by tumor-infiltrating macrophages.

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“…Although not responsible for the differentiation of alternatively activated macrophages, IL-27 may play an important role in the modulation of alternatively activated macrophage function (34). In contrast, IL-27 augments production of TNF-a, IL-12, IL-6, and IFN-g by human monocytes/macrophages (35,36).…”

mentioning

confidence: 99%

Essential Role for IL-27 Receptor Signaling in Prevention of Th1-Mediated Immunopathology during Malaria Infection

Findlay

Greig

Stumhofer

et al. 2010

The Journal of Immunology

110

123

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Successful resolution of malaria infection requires induction of proinflammatory immune responses that facilitate parasite clearance; however, failure to regulate this inflammation leads to immune-mediated pathology. The pathways that maintain this immunological balance during malaria infection remain poorly defined. In this study, we demonstrate that IL-27R–deficient (WSX-1−/−) mice are highly susceptible to Plasmodium berghei NK65 infection, developing exacerbated Th1-mediated immune responses, which, despite highly efficient parasite clearance, lead directly to severe liver pathology. Depletion of CD4+ T cells—but not CD8+ T cells—prevented liver pathology in infected WSX-1−/− mice. Although WSX-1 signaling was required for optimal IL-10 production by CD4+ T cells, administration of rIL-10 failed to ameliorate liver damage in WSX-1−/− mice, indicating that additional, IL-10–independent, protective pathways are modulated by IL-27R signaling during malaria infection. These data are the first to demonstrate the essential role of IL-27R signaling in regulating effector T cell function during malaria infection and reveal a novel pathway that might be amenable to manipulation by drugs or vaccines.

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IL-27 Activates Human Monocytes via STAT1 and Suppresses IL-10 Production but the Inflammatory Functions of IL-27 Are Abrogated by TLRs and p38

Cited by 113 publications

References 59 publications

Interleukin-27-Mediated Suppression of Human Th17 Cells Is Associated with Activation of STAT1 and Suppressor of Cytokine Signaling Protein 1

Interleukin-27-Mediated Suppression of Human Th17 Cells Is Associated with Activation of STAT1 and Suppressor of Cytokine Signaling Protein 1

The ecto-ATPDase CD39 is involved in the acquisition of the immunoregulatory phenotype by M-CSF-macrophages and ovarian cancer tumor-associated macrophages: Regulatory role of IL-27

Essential Role for IL-27 Receptor Signaling in Prevention of Th1-Mediated Immunopathology during Malaria Infection

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