Ataxin-10 Inhibits TNF-α-Induced Endothelial Inflammation via Suppressing Interferon Regulatory Factor-1.

Endothelial inflammation is a crucial event in the initiation of atherosclerosis. Here, we identify Ataxin-10 protein as a novel negative modulator of endothelial activation by suppressing IRF-1 transcription activity. The protein level of Ataxin-10 is relatively higher in human vascular endothelial cells, which can be significantly suppressed by TNF-α in both HUVECs and HLMECs. Overexpression of Ataxin-10 markedly inhibited the mRNA expressions of VCAM-1 and several cytokines including MCP-1, CXCL-1, CCL-5, and TNF-α; thus, it can also suppress monocyte adhesion to endothelial cells. Accordingly, Ataxin-10 silencing promoted endothelial inflammation. However, Ataxin-10 did not affect the MAPK/NF-κB signaling pathway stimulated by TNF-α in HUVECs. Using the yeast two-hybrid assay, we found that Ataxin-10 can directly bind to interferon regulatory factor-1 (IRF-1). Upon TNF-α stimulation, Ataxin-10 promoted the cytoplasmic localization of IRF-1, which inhibited the transcription of VCAM-1. Moreover, knockdown of IRF-1 can eliminate the effect of Ataxin-10 on the expression of VCAM-1 in HUVECs induced by TNF-α. Taken together, these results indicate that Ataxin-10 inhibits endothelial cell activation and may serve as a promising therapeutic target for some vascular inflammatory-related diseases such as atherosclerosis.

SARS-CoV-2 inhibits induction of the MHC class I pathway by targeting the STAT1-IRF1-NLRC5 axis.

The MHC class I-mediated antigen presentation pathway plays a critical role in antiviral immunity. Here we show that the MHC class I pathway is targeted by SARS-CoV-2. Analysis of the gene expression profile from COVID-19 patients as well as SARS-CoV-2 infected epithelial cell lines reveals that the induction of the MHC class I pathway is inhibited by SARS-CoV-2 infection. We show that NLRC5, an MHC class I transactivator, is suppressed both transcriptionally and functionally by the SARS-CoV-2 ORF6 protein, providing a mechanistic link. SARS-CoV-2 ORF6 hampers type II interferon-mediated STAT1 signaling, resulting in diminished upregulation of NLRC5 and IRF1 gene expression. Moreover, SARS-CoV-2 ORF6 inhibits NLRC5 function via blocking karyopherin complex-dependent nuclear import of NLRC5. Collectively, our study uncovers an immune evasion mechanism of SARS-CoV-2 that targets the function of key MHC class I transcriptional regulators, STAT1-IRF1-NLRC5.

KPNB1 Inhibitor Importazole Reduces Ionizing Radiation-Increased Cell Surface PD-L1 Expression by Modulating Expression and Nuclear Import of IRF1.

Programmed death-ligand 1 (PD-L1) is an immune checkpoint molecule that negatively regulates anti-tumor immunity. Recent reports indicate that anti-cancer treatments, such as radiation therapy, increase PD-L1 expression on the surface of tumor cells. We previously reported that the nuclear transport receptor karyopherin-ß1 (KPNB1) is involved in radiation-increased PD-L1 expression on head-and-neck squamous cell carcinoma cells. However, the mechanisms underlying KPNB1-mediated, radiation-increased PD-L1 expression remain unknown. Thus, the mechanisms of radiation-increased, KPNB1-mediated PD-L1 expression were investigated by focusing on the transcription factor interferon regulatory factor 1 (IRF1), which is reported to regulate PD-L1 expression. Western blot analysis showed that radiation increased IRF1 expression. In addition, flow cytometry showed that IRF1 knockdown decreased cell surface PD-L1 expression of irradiated cells but had a limited effect on non-irradiated cells. These findings suggest that the upregulation of IRF1 after irradiation is required for radiation-increased PD-L1 expression. Notably, immunofluorescence and western blot analyses revealed that KPNB1 inhibitor importazole not only diffused nuclear localization of IRF1 but also decreased IRF1 upregulation by irradiation, which attenuated radiation-increased PD-L1 expression. Taken together, these findings suggest that KPNB1 mediates radiation-increased cell surface PD-L1 expression through both upregulation and nuclear import of IRF1.

Rotavirus NSP1 Inhibits Type I and Type III Interferon Induction.

Type I interferons (IFNs) are produced by most cells in response to virus infection and stimulate a program of anti-viral gene expression in neighboring cells to suppress virus replication. Type III IFNs have similar properties, however their effects are limited to epithelial cells at mucosal surfaces due to restricted expression of the type III IFN receptor. Rotavirus (RV) replicates in intestinal epithelial cells that respond predominantly to type III IFNs, and it has been shown that type III rather than type I IFNs are important for controlling RV infections in vivo. The RV NSP1 protein antagonizes the host type I IFN response by targeting IRF-3, IRF-5, IRF-7, or ß-TrCP for proteasome-mediated degradation in a strain-specific manner. Here we provide the first demonstration that NSP1 proteins from several human and animal RV strains antagonize type III as well as type I IFN induction. We also show that NSP1 is a potent inhibitor of IRF-1, a previously undescribed property of NSP1 which is conserved among human and animal RVs. Interestingly, all NSP1 proteins were substantially more effective inhibitors of IRF-1 than either IRF-3 or IRF-7 which has significance for evasion of basal anti-viral immunity and type III IFN induction in the intestinal epithelium.

Porcine deltacoronavirus (PDCoV) infection antagonizes interferon-λ1 production.

Porcine deltacoronavirus (PDCoV) is a novel swine enteropathogenic coronavirus that causes watery diarrhea, vomiting and mortality in nursing piglets. Type III interferons (IFN-λs) are the major antiviral cytokines in intestinal epithelial cells, the target cells in vivo for PDCoV. In this study, we found that PDCoV infection remarkably inhibited Sendai virus-induced IFN-λ1 production by suppressing transcription factors IRF and NF-κB in IPI-2I cells, a line of porcine intestinal mucosal epithelial cells. We also confirmed that PDCoV infection impeded the activation of IFN-λ1 promoter stimulated by RIG-I, MDA5 and MAVS, but not by TBK1 and IRF1. Although the expression levels of IRF1 and MAVS were not changed, PDCoV infection resulted in reduction of the number of peroxisomes, the platform for MAVS to activate IRF1, and subsequent type III IFN production. Taken together, our study demonstrates that PDCoV suppresses type III IFN responses to circumvent the host's antiviral immunity.

Analysis of the relationship between microRNA-31 and interferon regulatory factor-1 in hepatocellular carcinoma cells.

OBJECTIVE: MicroRNAs (miRNAs) play a role in the pathogenesis of hepatocellular carcinoma (HCC). This study was designed to elucidate the role of microRNA-31 (miR-31) in HCC. MATERIALS AND METHODS: HuH7 cell lines were transfected with miR-31 mimic or miR-31 inhibitor to investigate the role of miR-31 in regulating interferon regulatory factor-1 (IRF-1). The mRNA and protein expression levels of IRF-1 were quantitatively detected by quantitative Real Time-Polymerase Chain Reaction (qRT-PCR) and Western blot, respectively. Subsequently, Dual-Luciferase reporter assay was also performed. RESULTS: The expression level of miR-31 was significantly up-regulated in HuH7 cells when compared with that in primary human hepatocytes (hHC). Dual-Luciferase reporter assay indicated that IRF-1 was the direct target of miR-31. The expression levels of IRF-1 were decreased in HuH7 and HepG2 cell lines. IRF-1 was negatively correlated with miR-31 in HCC tissues and paired adjacent tissues. The expression level of miR-31 was inversely correlated with IRF-1. MiR-31 inhibitor up-regulated the expression levels of IRF-1 in HuH7 cells, whereas miR-31 mimic down-regulated the expression levels of IRF-1. Furthermore, the miR-31 mimic repressed IRF-1-3'UTR reporter activity, whereas the miR-31 inhibitor enhanced IRF-1-3'UTR reporter activity depending on the concentration of miR-31 mimic and miR-31 inhibitor. CONCLUSIONS: These results indicated that miR-31 can regulate the expression level of IRF-1 in HCC, which probably provided novel theoretical evidence for the application of target miR-31 treatment of HCC.

Overexpression of PSAT1 promotes metastasis of lung adenocarcinoma by suppressing the IRF1-IFNγ axis.

An increasing number of enzymes involved in serine biosynthesis have been identified and correlated with malignant evolution in various types of cancer. Here we showed that the overexpression of phosphoserine aminotransferase 1 (PSAT1) is widely found in lung cancer tissues compared with nontumor tissues and predicts a poorer prognosis in patients with lung adenocarcinoma. PSAT1 expression was examined in a tissue microarray by immunohistochemistry. The data show that the knockdown of PSAT1 dramatically inhibits the in vitro and in vivo metastatic potential of highly metastatic lung cancer cells; conversely, the enforced expression of exogenous PSAT1 predominantly enhances the metastatic potential of lung cancer cells. Importantly, manipulating PSAT1 expression regulates the in vivo tumor metastatic abilities in lung cancer cells. Adjusting the glucose and glutamine concentrations did not alter the PSAT1-driven cell invasion properties, indicating that this process might not rely on the activation of its enzymatic function. RNA microarray analysis of transcriptional profiling from PSAT1 alternation in CL1-5 and CL1-0 cells demonstrated that interferon regulatory factor 1 (IRF1) acts as a crucial regulator of PSAT1-induced gene expression upon metastatic progression. Decreasing the IRF1-IFIH1 axis compromised the PSAT1-prompted transcriptional reprogramming in cancer cells. Our results identify PSAT1 as a key regulator by a novel PSAT1/IRF1 axis in lung cancer progression, which may serve as a potential biomarker and therapeutic target for the treatment of lung cancer patients.

Interfering histone deacetylase 4 inhibits the proliferation of vascular smooth muscle cells via regulating MEG3/miR-125a-5p/IRF1.

In this study, we investigated the role ofhistone deacetylase 4 (HDAC4) and MEG3/miR-125a-5p/interferonregulatoryfactor 1 (IRF1) on vascular smooth muscle cell (VSMCs)proliferation. Platelet derived growth factor (PDGF)-BB was used toinduce the proliferation and migration of VSMCs. The expressionsof MEG3, miR-125a-5p, HDAC4 and IRF1in VSMCs were detectedby qRT-PCR and western blot, respectively. ChIP assay was usedto determine the relationship between MEG3 and HDAC4. Doubleluciferase reporter assay was used to test the regulation betweenmiR-125-5p and IRF1. Results showed that PDGF-BB decreasedthe expression of MEG3 and IRF1, while increased the expressionof miR-125a-5p and HDAC4. In addition, HDAC4 knockdowninhibited the proliferation and migration of VSMCs via upregulatingMEG3 and downregulating miR-125a-5p. MiR-125a-5p inhibitorcould repress the proliferation and migration of VSMCs andalleviate intimal hyperplasia (IH) by directly upregulating IRF1expression. These results suggested that HDAC4 interferenceinhibited PDGF-BB-induced VSMCs proliferation via regulatingMEG3/miR-125a-5p/IRF1 axis, and then alleviated IH.

Interferon Regulatory Factor 1 Activates Autophagy to Aggravate Hepatic Ischemia-Reperfusion Injury by Increasing High Mobility Group Box 1 Release.

BACKGROUND/AIMS: Interferon regulatory factor 1(IRF-1) and high mobility group box 1(HMGB1) have been independently identified as being key players in hepatic ischemia-reperfusion injury (IRI). We attempted to determine whether IRF-1 activates autophagy to aggravate hepatic IRI by increasing HMGB1 release. METHODS: The hepatic IRI model was generated in C57BL/6 mice, euthanized at 2, 6, 12 or 24 h after reperfusion. To examine the effects of HMGB1 release inhibition, Glycyrrhiza acid (GA) was administered to the mice and at six hours after injectiont. AML12 cells were immersed in mineral oil for 90 min and then cultured in complete Dulbecco's Modified Eagle's Medium (DMEM)/F12 to simulate IRI. AML12 cells were treated with IRF-1 siRNA, Ad-IRF-1 or GA. The serum levels of aspartate aminotransferase (AST) and alanine aminotransferase (ALT), as well as histological changes were examined. Next, autophagic vacuoles were detected by transmission electron microscopy (TEM) or LC3 dots. The expression of IRF-1 and HMGB1 mRNA were measured by real-time polymerase chain reaction. The expression of IRF-1, microtubule-associated protein 1 light chain 3 (LC3), Bcl-2, Beclin 1, HMGB1 were detected by western blotting or immunohistochemistry. RESULTS: The levels of hepatic IRF-1, mRNA and protein were significantly increased in livers after exposure to IRI, together with, IRI-induced increase of HMGB1 mRNA and release of HMGB1 in liver tissue. Knockout of IRF-1 decreased expression and release of HMGB1 in liver, and inhibiting the release of HMGB1 could alleviate hepatic IRI. In addition, knockout of IRF-1 downregulated LC3II and Beclin1, while number of autophagosomes or LC3 dots were increased. Up-regulating IRF-1 expression could increase the levels of LC3Ⅱ expression in AML12 cells after exposure to IRI. The levels of HMGB1 in Ad-IRF-1 transfected AML12 cell supernatants increased, together with number of LC3 dots increasing. However, GA could inhibit both Ad-IRF-1 induced HMGB1 release and the increase in the number of LC3 dots. CONCLUSIONS: IRF-1 activates autophagy to aggravate hepatic IRI by increasing HMGB1 release.

XAF1 forms a positive feedback loop with IRF-1 to drive apoptotic stress response and suppress tumorigenesis.

X-linked inhibitor of apoptosis (XIAP)-associated factor 1 (XAF1) is a proapoptotic tumor suppressor that is frequently inactivated in multiple human cancers. However, the molecular basis for the XAF1-mediated growth inhibition remains largely undefined. Here, we report that XAF1 forms a positive feedback loop with interferon regulatory factor-1 (IRF-1) and functions as a transcriptional coactivator of IRF-1 to suppress tumorigenesis. Under various stressful conditions, XAF1 transcription is activated by IRF-1, and elevated XAF1 stabilizes and activates IRF-1. Mechanistically, XAF1 binds to the multifunctional domain 2 of IRF-1 via the zinc finger domain 6, thereby hindering C-terminus of Hsc70-interacting protein (CHIP) interaction with and ubiquitination of IRF-1. Activation of the IRF-1-XAF1 loop greatly increases stress-induced apoptosis and decreases the invasive capability of tumor cells. Oncogenic Ras and growth factors interfere with the IRF-1-XAF1 interplay via Erk-mediated repression of XAF1 transcription. Furthermore, XAF1 enhances IRF-1-mediated transcription of proapoptotic genes via the XAF1-IRF-1 complex formation on these target promoters. Meanwhile, XAF1 inhibits NF-κB-mediated tumor cell malignancy by reinforcing IRF-1 binding to a subset of coregulated promoters. Expression levels of IRF-1 and XAF1 correlate tightly in both cancer cell lines and primary tumors, and XAF1-induced tumor regression is markedly attenuated in IRF-1-depleted tumors. Collectively, this study identifies a novel mechanism of XAF1-mediated tumor suppression, uncovering XAF1 as a feedback coactivator of IRF-1 under stressful conditions.

Interferon regulatory factor 1 inactivation in human cancer.

Interferon regulatory factors (IRFs) are a group of closely related proteins collectively referred to as the IRF family. Members of this family were originally recognized for their roles in inflammatory responses; however, recent research has suggested that they are also involved in tumor biology. This review focusses on current knowledge of the roles of IRF-1 and IRF-2 in human cancer, with particular attention paid to the impact of IRF-1 inactivation. The different mechanisms underlying IRF-1 inactivation and their implications for human cancers and the potential importance of IRF-1 in immunotherapy are also summarized.

The MEK Inhibitors Trametinib and Cobimetinib Induce a Type I Interferon Response in Human Keratinocytes.

Mitogen-activated protein kinase kinases (MEK) 1 and 2 have crucial roles in tumorigenesis, cell proliferation, and protection from apoptosis, and their inhibition is therefore an attractive therapeutic strategy in cancer. Orally available and highly selective MEK inhibitors have been developed and assessed in numerous clinical trials, either alone or in combination with cytotoxic chemotherapy and/or other targeted agents. Of note, a complex picture of class-specific adverse effects associates with these drugs, frequently including inflammatory skin rash. Here, we investigated the response of normal human keratinocytes to the MEK inhibitors trametinib and cobimetinib, alone and in combination with the v-Raf murine sarcoma viral oncogene homolog B (BRAF) inhibitors dabrafenib and vemurafenib, in terms of signal transduction and de novo gene expression. MEK inhibitors triggered enhanced expression of interferon regulatory factor 1 (IRF1) and phosphorylation of signal transducer and activator of transcription 1 (STAT1), and up-regulated the keratinocyte-specific type I interferon κ (IFN-κ), the anti-viral effectors interferon-induced tetratricopeptide repeats (IFIT) 1 and 2, and the pro-inflammatory chemokine (C-C motif) ligand 2 (CCL2) and the C-X-C motif chemokine 10 (CXCL10), both at the mRNA and protein level. Impairment of IRF1 expression, or abrogation of STAT1 phosphorylation due to IFN-κ gene silencing, suppressed anti-viral and pro-inflammatory gene expression. These data suggest that, similar to what we observed for epidermal growth factor receptor (EGFR) blockade, MEK inhibition activates a type I interferon response, which is now recognized as an effective anti-cancer response, in human epidermal keratinocytes.

PRDM16 represses the type I interferon response in adipocytes to promote mitochondrial and thermogenic programing.

Brown adipose has the potential to counteract obesity, and thus, identifying signaling pathways that regulate the activity of this tissue is of great clinical interest. PRDM16 is a transcription factor that activates brown fat-specific genes while repressing white fat and muscle-specific genes in adipocytes. Whether PRDM16 also controls other gene programs to regulate adipocyte function was unclear. Here, we identify a novel role for PRDM16 in suppressing type I interferon (IFN)-stimulated genes (ISGs), including Stat1, in adipocytes in vitro and in vivo Ectopic activation of type I IFN signaling in brown adipocytes induces mitochondrial dysfunction and reduces uncoupling protein 1 (UCP1) expression. Prdm16-deficient adipose displays an exaggerated response to type I IFN, including higher STAT1 levels and reduced mitochondrial gene expression. Mechanistically, PRDM16 represses ISGs through binding to promoter regions of these genes and blocking the activating function of IFN regulatory factor 1 (IRF1). Together, these data indicate that PRDM16 diminishes responsiveness to type I IFN in adipose cells to promote thermogenic and mitochondrial function.

miR-345 inhibits tumor metastasis and EMT by targeting IRF1-mediated mTOR/STAT3/AKT pathway in hepatocellular carcinoma.

MicroRNAs (miRNAs) have been reported to play critical roles in tumor progression including hepatocellular carcinoma (HCC). Thus, the underlying mechanisms need further investigation. Previous study reported that loss of miR-345 expression indicated a poor prognosis of HCC patients. This study evaluated whether loss of miR-345 could promote the tumor metastasis and epithelial-mesenchymal-transition (EMT) of HCC by targeting interferon regulatory factor 1 (IRF1)-mediated mTOR/STAT3/AKT signaling. Underexpression of miR-345 was identified in 65 cases of human HCC compared to matched tumor-adjacent tissues by qRT-PCR. Moreover, we found that reduced expression of mi-345 was observed in HCC cell lines. The restoration of miR-345 inhibited cell migration and invasion in HCCLM3 cells, while its loss facilitated the cell mobility of HepG2 cells. Furthermore, miR-345 over-expression reduced lung metastases of HCC cells in nude mice. Notably, miR-345 overexpression prohibited, while its knockdown enhanced the EMT process of HCC cell lines in vitro. Bioinformatics software predicted that IRF1 was a direct target of miR-345. We then observed the negative regulation of miR-345 on IRF1 protein expression and the direct binding between them was further verified by dual-luciferase assays in HCC cells. In addition, over-expression of IRF1 mRNA was inversely correlated with the level of miR-345 in HCC specimens. Restoration of IRF1 resulted in promoted EMT and cell mobility in miR-345 overexpressing HCCLM3 cells. It was found that mTOR/STAT3/AKT pathway and its downstream targets including Slug, Snail and Twist may be involved in IRF1 mediated EMT process. In conclusion, miR-345 acts as an inhibitor of EMT process in HCC cells by targeting IRF1 and this study highlights the potential effects of miR-345 on prognosis and treatment of HCC.

Effect of the plant derivative Compound A on the production of corticosteroid-resistant chemokines in airway smooth muscle cells.

Preclinical models of human conditions including asthma showed the therapeutic potential of Compound A (CpdA), a dissociated glucocorticoid (GC) receptor (GRα) ligand. Whether CpdA inhibits GC resistance, a central feature of severe asthma, has not been addressed. We investigated whether CpdA modulates cytokine-induced GC resistance in human airway smooth muscle (ASM) cells. Healthy and asthmatic ASM cells were treated with TNF-α/IFN-γ for 24 hours in the presence or absence of CpdA. ELISA and quantitative PCR assays were used to assess the effect of CpdA on chemokine expression. Activation of GRα by CpdA was assessed by quantitative PCR, immunostaining, and receptor antagonism using RU486. An effect of CpdA on the transcription factor interferon regulatory factor 1 (IRF-1) was investigated using immunoblot, immunostaining, and small interfering RNA (siRNA) knockdown. CpdA inhibited production of fluticasone-resistant chemokines CCL5, CX3CL1, and CXCL10 at protein and mRNA levels in both asthmatic and healthy cells. CpdA failed to induce expression of GC-induced Leucine Zipper while transiently inducing mitogen-activated protein kinase phosphatase 1 (MKP-1) at both mRNA and protein levels. CpdA inhibitory action was not associated with GRα nuclear translocation, nor was it prevented by RU486 antagonism. Activation of IRF-1 by TNF-α/IFN-γ was inhibited by CpdA. IRF-1 siRNA knockdown reduced cytokine-induced CCL5 and CX3CL1 production. siRNA MKP-1 prevented the inhibitory effect of CpdA on cytokine-induced CXCL10 production. For the first time, we show that CpdA inhibits the production of GC-resistant chemokines via GRα-independent mechanisms involving the inhibition of IRF-1 and up-regulation of MKP-1. Thus, targeting CpdA-sensitive pathways in ASM cells represents an alternative therapeutic approach to treat GC resistance in asthma.

The protective effects of Donepezil (DP) against cartilage matrix destruction induced by TNF-α.

The extracellular matrix apparatuses containing collagen and proteoglycan (aggrecan) are important factors for maintaining the integrity of cartilage. Collagen type II, the main component of total cartilage, is mainly degraded by matrix metalloproteinase13 (MMP-13), which is an important molecule responsible for joint damage in Osteoarthritis (OA). Donepezil (DP), a potent and selective acetylcholinesterase inhibitor, is a medication approved by the US Food and Drug Administration and used in the alleviation of dementia in Alzheimer's disease (AD). In this study, we found that DP treatment prevented the degradation of collagen type II induced by TNF-α. Mechanistically, DP treatment leads to the inhibition of the transcriptional activity of interferon response factor-1 (IRF-1), thereby prevents the induction of MMP-13. These findings suggest the potential therapeutic effects of DP in OA.

Attenuation of IFN-γ-induced B7-H1 expression by 15-deoxy-delta(12,14)-prostaglandin J2 via downregulation of the Jak/STAT/IRF-1 signaling pathway.

AIM: B7-H1, which belongs to the B7 family of costimulatory molecules, is implicated in the ability of tumors to evade the host immune response. The development of evasion mechanisms within the tumor microenvironment may be responsible for poor therapeutic responses. In this manuscript, we report that the 15-deoxy-δ(12,14)-prostaglandin J2 (15d-PGJ2), peroxisome proliferator-activated receptor gamma (PPARγ) activator leads to the downregulation of the cancer-associated expression of B7-H1 in response to interferon-gamma (IFN-γ) and the associated signaling cascades. MAIN METHODS: The expression of B7-H1 from IFN-γ-induced B16F10 melanoma cells was measured with flow cytometric analysis. The regulatory mechanisms of 15d-PGJ2 on cellular signaling pathways were examined using Western blot and electrophoretic mobility shift assays. KEY FINDINGS: The flow cytometric analysis revealed that the B7-H1 costimulatory molecule is significantly upregulated in B16F10 melanoma cells by stimulation with IFN-γ. However, 15d-PGJ2 strongly downregulates B7-H1 expression in IFN-γ-stimulated B16F10 melanoma cells. Furthermore, the significant damping effect of 15d-PGJ2 on B7-H1 expression involves the inhibition of the tyrosine phosphorylation of Janus kinase (Jak) and signal transducer(s) and activator(s) of transcription (STAT) and, thereby, the interferon regulatory factor-1 (IRF-1) trans-activation of STAT. These effects of 15d-PGJ2 were not abrogated by the PPARγ antagonist GW9662, indicating that they occur through a PPARγ-independent mechanism. SIGNIFICANCE: In this study, we demonstrate that 15d-PGJ2 suppresses the IFN-γ-elicited expression of B7-H1 by the inhibition of IRF-1 transcription via the Jak/STAT signaling pathway through a PPARγ-independent mechanism in mouse melanoma cells.

Glatiramer acetate inhibits degradation of collagen II by suppressing the activity of interferon regulatory factor-1.

Pro-inflammatory cytokines such as tumor necrosis factor-alpha (TNF-α) is considered to be the major one contributing to the process of development of osteoarthritis (OA).Interferon regulatory factor 1 (IRF-1) is an important transcriptional factor accounting for inflammation response induced by TNF-α. The physiological function of IRF-1 in OA is still unknown. In this study, we reported that the expression levels of IRF-1 in OA chondrocytes were significantly higher compared to those in normal chondrocytes, which was reversed by treatment with Glatiramer acetate (GA), a licensed clinical drug for treating patients suffering from multiple sclerosis (MS). We also found that GA is able to attenuate the upregulation of IRF-1 induced by TNF-α. Matrix metalloproteinase13 (MMP-13) is one of the downstream target genes of IRF-1, which can induce the degradation of collagen II. Importantly, our results indicated that GA suppressed the expression of MMP-13 as well as the degradation of collagen II. In addition, GA also suppressed TNF-α-induced production of NO and expression of iNOS. Finally, we found that the inhibition of STAT1 activation played a critical role in the inhibitory effects of GA on the induction of IRF-1 and MMP-13. These data suggest that GA might have a potential effect in therapeutic OA.

Human papillomavirus 16-encoded E7 protein inhibits IFN-γ-mediated MHC class I antigen presentation and CTL-induced lysis by blocking IRF-1 expression in mouse keratinocytes.

Human papillomavirus 16 (HPV16) infection causes 50 % or more of cervical cancers in women. The HPV16 E7 oncogene is continuously expressed in infected epithelium with its oncogenicity linked to cervical cancer. The E7 protein is an ideal target in control of HPV infection through T-cell-mediated immunity. Using HPV16 E7-transgenic mouse keratinocytes (KCs-E7) to investigate T-cell-mediated immune responses, we have shown previously that HPV16-encoded E7 protein inhibits IFN-γ-mediated enhancement of MHC class I antigen processing and T-cell-induced target cell lysis. In this study, we found that HPV16 E7 suppresses IFN-γ-induced phosphorylation of STAT1((Tyr701)), leading to the blockade of interferon regulatory factor-1 (IRF-1) and transporter associated antigen processing subunit 1 (TAP-1) expression in KCs-E7. The results of a (51)Cr release assay demonstrated that IFN-γ-treated KCs-E7 escaped from CTL recognition because HPV16 E7 downregulated MHC class I antigen presentation on KCs. Restoration of IRF-1 expression in KCs-E7 overcame the inhibitory effect of E7 protein on IFN-γ-mediated CTL lysis and MHC class I antigen presentation on KCs. Our results suggest that HPV16 E7 interferes with the IFN-γ-mediated JAK1/JAK2/STAT1/IRF-1 signal transduction pathway and reduces the efficiency of peptide loading and MHC class I antigen presentation on KCs-E7. These results may reveal a new mechanism whereby HPV16 escapes from immune surveillance in vivo.

HIV and interferon regulatory factor 1: a story of manipulation and control.

Members of the interferon regulatory factor (IRF) family control the expression of numerous proteins, many of which are central to regulating host immune responses. IRF1 is one of the central mediators of the innate and adaptive immune responses required for antigen processing and presentation, Th1/Th2 differentiation, and natural killer (NK) cell and macrophage function. Many viruses have evolved mechanisms to target the IRF1 pathway in order to promote viral pathogenesis. During early HIV infection, IRF1 acts as a double-edged sword, critical for driving viral replication as well as eliciting antiviral responses. In this review, we describe the strategies that HIV-1 has evolved to modulate IRF1 in order to enhance viral replication and to disarm the host immune system. IRF1 has been shown to be an important factor in natural protection against HIV in highly exposed seronegative (HESN) individuals and is crucial in regulating the initial stages of HIV replication and HIV disease progression, as well as the establishment of latency. An understanding of how the protective effects of IRF1 responses are controlled in HESN individuals, naturally resistant to HIV infection, may provide important clues on how to regain control of HIV and tip the balance of immunity in favor of the host, or provide new opportunities to eliminate HIV in its host altogether.