Inflammatory signaling compromises cell responses to interferon alpha

HuangFu, Wei-Chun; Qian, Juan; Liu, Chengbao; Liu, Jianghuai; Lokshin, Anna; Baker, Darren P.; Rui, Hallgeir; Fuchs, Serge Y.

doi:10.1038/onc.2011.221

Cited by 64 publications

(70 citation statements)

References 53 publications

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“…5B, lane 4). This attenuation is consistent with negative feedback of IFNAR signalling, which is mediated by signalling inhibitors such as suppressor of cytokine signaling (SOCS) proteins or other mechanisms induced by inflammatory cytokines such as TNF or IL-1 (36, 43, 44). Thus in macrophages while TNF initially induces an autocrine IFN-β response it also overtime limits IFN signalling to induce a tempered response.…”

Section: Resultssupporting

confidence: 72%

Modulation of TNF-Induced Macrophage Polarization by Synovial Fibroblasts

Donlin

Jayatilleke

Γιαννοπούλου³

et al. 2014

The Journal of Immunology

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Mesenchymal stromal cells have emerged as powerful modulators of the immune system. Here we explored how the human macrophage response to tumor necrosis factor (TNF) is regulated by human synovial fibroblasts, the representative stromal cell type in the synovial lining of joints that become activated during inflammatory arthritis. We found that synovial fibroblasts strongly suppressed TNF-mediated induction of an interferon (IFN)-β autocrine loop and downstream expression of IFN-stimulated genes (ISGs), including chemokines CXCL9 and CXCL10 that are characteristic of classical macrophage activation. TNF induced the production of soluble synovial fibroblast factors that suppressed the macrophage production of IFN-β, and cooperated with TNF to limit the responsiveness of macrophages to IFN-β by suppressing activation of Jak-STAT signalling. Genome-wide transcriptome analysis showed that co-cultured synovial fibroblasts modulate the expression of approximately one third of TNF-regulated genes in macrophages, including genes in pathways important for macrophage survival and polarization towards an alternatively activated phenotype. Pathway analysis revealed that gene expression programs regulated by synovial fibroblasts in our co-culture system were also regulated in rheumatoid arthritis (RA) synovial macrophages, suggesting that these fibroblast-mediated changes may contribute to RA pathogenesis. This work furthers our understanding of the interplay between innate immune and stromal cells during an inflammatory response, one that is particularly relevant to inflammatory arthritis. Our findings also identify modulation of macrophage phenotype as a new function for synovial fibroblasts that may prove to be a contributing factor in arthritis pathogenesis.

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Section: Resultssupporting

confidence: 72%

Modulation of TNF-Induced Macrophage Polarization by Synovial Fibroblasts

Donlin

Jayatilleke

Γιαννοπούλου³

et al. 2014

The Journal of Immunology

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“…36,37 Notably, ligation of CD180 can trigger the activation of various kinases such as Lyn, PI3K, BTK, PKC b, and MAPKs. 23,24 To elucidate which kinases participate in the CD180 ligation-mediated inhibition of IFN-a signaling, murine B cells were pretreated with dasatinib (Lyn inhibitor), LY294002 (PI3K inhibitor), ibturinib (BTK inhibitor), enzastaurin (PKC b inhibitor), U0126 (ERK inhibitor), SP600126 (JNK inhibitor), or SB203580 (p38 inhibitor) for 1 h prior to stimulation with anti-CD180 or IFN-a for 4 h. As shown in Figure 5a and 5b, pretreatment of dasatinib, LY294002, and ebturinib, rather than enzastaurin, U0126, SP600126, SB203580, could totally reverse the inhibitory effect of anti-CD180 on the IFN-a-induced expression of IFIT1 and MX1.…”

Section: Ligation Of Cd180 Also Inhibits the Ifn-a-induced Tyrosine Pmentioning

confidence: 99%

Ligation of CD180 inhibits IFN-α signaling in a Lyn-PI3K-BTK-dependent manner in B cells

You

Dong

et al. 2015

Cell Mol Immunol

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A hallmark of systemic lupus erythematosus (SLE) is the consistent production of various auto-antibodies by auto-reactive B cells. Interferon-a (IFN-a) signaling is highly activated in SLE B cells and plays a vital role in the antibody response by B cells. Previous studies have shown that CD180-negative B cells, which are dramatically increased in SLE patients, are responsible for the production of auto-antibodies. However, the association between CD180 and IFN-a signaling remains unknown. In the present study, we explored the effect of CD180 on regulating the activation of IFN-a signaling in B cells. We found that the number of CD180-negative B cells was increased in MRL/Mp-Fas(lpr/lpr) lupus-prone mice compared with wild-type mice. Phenotypic analysis showed that CD180-negative B cells comprised CD138 1 plasmablast/plasma cells and GL-7 1 germinal center (GC) B cells. Notably, ligation of CD180 significantly inhibited the IFN-a-induced phosphorylation of signal transducer and activator of transcription 2 (STAT-2) and expression of IFN-stimulated genes (ISGs) in a Lyn-PI3K-BTK-dependent manner in vitro. Moreover, ligation of CD180 could also inhibit IFN-a-induced ISG expression in B cells in vivo. Furthermore, the Toll-like receptor 7 and Toll-like receptor 9 signaling pathways could significantly downregulate CD180 expression and modulate the inhibitory effect of CD180 signaling on the activation of IFN-a signaling. Collectively, our results highlight the close association between the increased proportion of CD180-negative B cells and the activation of IFN-a signaling in SLE. Our data provide molecular insight into the mechanism of IFN-a signaling activation in SLE B cells and a potential therapeutic approach for SLE treatment. Cellular & Molecular Immunology

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“…This phosphorylation can be induced by ligands (Zheng et al, 2011b) and additional stimuli including inflammation (Bhattacharya et al, 2014). Importantly, melanoma cells are known to upregulate the levels of βTrcp2/HOS (Kumar et al, 2007b) and produce inflammatory cytokines that stimulate IFNAR1 ubiquitination and suppress IFN signaling (Huangfu et al, 2012). …”

Section: Introductionmentioning

confidence: 99%

Suppression of Type I Interferon Signaling Overcomes Oncogene-Induced Senescence and Mediates Melanoma Development and Progression

Katlinskaya

Katlinski

et al. 2016

Cell Reports

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Oncogene activation induces DNA damage responses and cell senescence. We report a key role of type I interferons (IFN) in oncogene-induced senescence. IFN signaling-deficient melanocytes expressing activated Braf do not exhibit senescence and develop aggressive melanomas. Restoration of IFN signaling in IFN-deficient melanoma cells induces senescence and suppresses melanoma progression. Additional data from human melanoma patients and mouse transplanted tumor models suggest the importance of non-cell-autonomous IFN signaling. Inactivation of IFN pathway is mediated by the IFN receptor IFNAR1 downregulation that invariably occurs during melanoma development. Mice harboring an IFNAR1 mutant, which is partially resistant to downregulation, delay melanoma development, suppress metastatic disease, and better respond to BRAF or PD1 inhibitors. These results suggest that IFN signaling is an important tumor suppressive pathway that inhibits melanoma development and progression and argue for targeting IFNAR1 downregulation to prevent metastatic disease and improve the efficacy of molecularly-targeted and immune-targeted melanoma therapies.

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Inflammatory signaling compromises cell responses to interferon alpha

Cited by 64 publications

References 53 publications

Modulation of TNF-Induced Macrophage Polarization by Synovial Fibroblasts

Modulation of TNF-Induced Macrophage Polarization by Synovial Fibroblasts

Ligation of CD180 inhibits IFN-α signaling in a Lyn-PI3K-BTK-dependent manner in B cells

Suppression of Type I Interferon Signaling Overcomes Oncogene-Induced Senescence and Mediates Melanoma Development and Progression

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