scholarly journals Molecular Inflammatory Responses Measured in Blood of Patients with Severe Community-Acquired Pneumonia

2003 ◽  
Vol 10 (5) ◽  
pp. 813-820 ◽  
Author(s):  
Silvia Fernández-Serrano ◽  
Jordi Dorca ◽  
Mercè Coromines ◽  
Jordi Carratalà ◽  
Francesc Gudiol ◽  
...  
Keyword(s):  
Inflammatory Response ◽  
Inflammatory Responses ◽  
Community Acquired Pneumonia ◽  
Causative Organism ◽  
Time Interval ◽  
Necrosis Factor Alpha ◽  
Arterial Blood ◽  
Tnf Α ◽  
Intensive Care Unit Admittance ◽  
Severe Community Acquired Pneumonia

ABSTRACT In order to analyze the characteristics of the inflammatory response occurring in blood during pneumonia, we studied 38 patients with severe community-acquired pneumonia. Venous and arterial blood samples were collected at study entry and on days 1, 2, 3, 5, and 7 after inclusion. The concentrations of proinflammatory (tumor necrosis factor alpha [TNF-α], interleukin 1β [IL-1β], IL-6, and IL-8) and anti-inflammatory (IL-10) cytokines were determined in order to detect differences related to the origin of the sample, the causative organism, the clinical variables, and the final outcome of the episode. Legionella pneumonia infections showed higher concentrations of TNF-α, IL-6, IL-8, and IL-10. After 24 h, plasma IL-6, IL-8, and IL-10 concentrations in pneumococcal episodes increased, whereas in the same time interval, cytokine concentrations in Legionella episodes markedly decreased. The characteristics of the inflammatory response in bacteremic pneumococcal episodes were different from those in nonbacteremic episodes, as indicated by the higher plasma cytokine concentrations in the former group. Finally, our analysis of cytokine concentrations with regard to the outcome—in terms of the need for intensive care unit admittance and/or mechanical ventilation as well as mortality—suggests that there is a direct relationship between the intensity of the inflammatory response measured in blood and the severity of the episode.

Comparing the effect of intestinal bacteria from rabbit, pig, and chicken on inflammatory response in cultured rabbit crypt and villus

2019 ◽  
Vol 65 (1) ◽  
pp. 59-67 ◽  
Author(s):  
Hong Xiao Cui ◽  
Xiu Rong Xu
Keyword(s):  
Inflammatory Response ◽  
Inflammatory Responses ◽  
Intestinal Bacteria ◽  
Inflammatory Factors ◽  
Rabbit Ileum ◽  
Necrosis Factor Alpha ◽  
Heat Treated ◽  
Tnf Α ◽  
Factor Alpha ◽  
Anti Inflammatory

Rabbit is susceptible to intestinal infection, which often results in severe inflammatory response. To investigate whether the special community structure of rabbit intestinal bacteria contributes to this susceptibility, we compared the inflammatory responses of isolated rabbit crypt and villus to heat-treated total bacteria in pig, chicken, and rabbit ileal contents. The dominant phylum in pig and chicken ileum was Firmicutes, while Bacteroidetes was dominant in rabbit ileum. The intestinal bacteria from rabbit induced higher expression of toll-like receptor 4 (TLR4) in rabbit crypt and villus (P < 0.05). TLR2 and TLR3 expression was obviously stimulated by chicken and pig intestinal bacteria (P < 0.05) but not by those of rabbit. The ileal bacteria from those three animals all increased the expression of tumor necrosis factor alpha (TNF-α) and interleukin 6 (IL-6) in crypts and villus (P < 0.05). Chicken and pig ileal bacteria also stimulated the expression of anti-inflammatory factors interferon beta (IFN-β) and IL-10 (P < 0.05), while those of rabbit did not (P > 0.05). In conclusion, a higher abundance of Gram-negative bacteria in rabbit ileum did not lead to more expressive pro-inflammatory cytokines in isolated rabbit crypt and villus, but a higher percentage of Lactobacillus in chicken ileum might result in more expressive anti-inflammatory factors.

Continuous Hemoadsorption with a Cytokine Adsorber during Sepsis – a Review of the Literature

2017 ◽  
Vol 40 (5) ◽  
pp. 205-211 ◽  
Author(s):  
Khosrow S. Houschyar ◽  
Malcolm N. Pyles ◽  
Susanne Rein ◽  
Ina Nietzschmann ◽  
Dominik Duscher ◽  
...  
Keyword(s):  
Critical Illness ◽  
Inflammatory Response ◽  
Organ Failure ◽  
Inflammatory Cytokines ◽  
Inflammatory Responses ◽  
Experimental Studies ◽  
Complement Factor ◽  
Necrosis Factor Alpha ◽  
Tissue Ischemia ◽  
Tnf Α

Sepsis is a well-recognized healthcare issue worldwide, ultimately resulting in significant mortality, morbidity and resource utilization during and after critical illness. In its most severe form, sepsis causes multi-organ dysfunction that produces a state of critical illness characterized by severe immune dysfunction and catabolism. Sepsis induces the activation of complement factor via 3 pathways and the release of inflammatory cytokines such as tumor necrosis factor alpha (TNF-α) and interleukin-1beta (IL-1β), resulting in a systemic inflammatory response. The inflammatory cytokines and nitric oxide release induced by sepsis decrease systemic vascular resistance, resulting in profound hypotension. The combination of hypotension and microvascular occlusion results in tissue ischemia and ultimately leads to multiple organ failure. Several clinical and experimental studies have reported that treatment using adsorption of cytokines is beneficial during endotoxemia and sepsis. This review article analyzes the efficacy of CytoSorb® adsorber in reducing the inflammatory response during sepsis. The CytoSorb® adsorber is known to have excellent adsorption rates for inflammatory cytokines such as IL-1β, IL-6, IL-8, IL-10, and TNF-α. Studies have demonstrated that treatment with cytokine adsorbing columns has beneficial effects on the survival rate and inflammatory responses in animal septic models. Additionally, several cases have been reported in which treatment with cytokine adsorbing columns is very effective in hemodynamic stabilization and in preventing organ failure in critically ill patients. Although further investigations and clinical trials are needed, treatment with cytokine adsorbing columns may play an important role in the treatment of sepsis in the near future.

scholarly journals The Inflammatory Response Induced by Aspartic Proteases of Candida albicans Is Independent of Proteolytic Activity

2010 ◽  
Vol 78 (11) ◽  
pp. 4754-4762 ◽  
Author(s):  
Donatella Pietrella ◽  
Anna Rachini ◽  
Neelam Pandey ◽  
Lydia Schild ◽  
Mihai Netea ◽  
...  
Keyword(s):  
Candida Albicans ◽  
Inflammatory Response ◽  
Proteolytic Activity ◽  
Necrosis Factor Alpha ◽  
Pathogenic Yeast ◽  
Aspartic Proteases ◽  
Akt Activation ◽  
Tnf Α ◽  
Factor Alpha ◽  
Pepstatin A

ABSTRACT The secretion of aspartic proteases (Saps) has long been recognized as a virulence-associated trait of the pathogenic yeast Candida albicans. In this study, we report that different recombinant Saps, including Sap1, Sap2, Sap3, and Sap6, have differing abilities to induce secretion of proinflammatory cytokines by human monocytes. In particular Sap1, Sap2, and Sap6 significantly induced interleukin-1β (IL-1β), tumor necrosis factor alpha (TNF-α), and IL-6 production. Sap3 was able to stimulate the secretion of IL-1β and TNF-α. All Saps tested were able to induce Ca2+ influx in monocytes. Treatment of these Saps with pepstatin A did not have any effect on cytokine secretion, indicating that their stimulatory potential was independent from their proteolytic activity. The capacity of Saps to induce inflammatory cytokine production was also independent from protease-activated receptor (PAR) activation and from the optimal pH for individual Sap activity. The interaction of Saps with monocytes induced Akt activation and phosphorylation of IκBα, which mediates translocation of NF-κB into the nucleus. Overall, these results suggest that individual Sap proteins can induce an inflammatory response and that this phenomenon is independent from the pH of a specific host niche and from Sap enzymatic activity. The inflammatory response is partially dependent on Sap denaturation and is triggered by the Akt/NF-κB activation pathway. Our data suggest a novel, activity-independent aspect of Saps during interactions of C. albicans with the host.

scholarly journals Oral Mucosal Endotoxin Tolerance Induction in Chronic Periodontitis

2005 ◽  
Vol 73 (2) ◽  
pp. 687-694 ◽  
Author(s):  
Manoj Muthukuru ◽  
Ravi Jotwani ◽  
Christopher W. Cutler
Keyword(s):  
Immune Response ◽  
Oral Mucosa ◽  
Chronic Periodontitis ◽  
Intracellular Signaling ◽  
Inflammatory Responses ◽  
Endotoxin Tolerance ◽  
Necrosis Factor Alpha ◽  
Initial Stimulus ◽  
Tlr4 Mrna ◽  
Tnf Α

ABSTRACT The oral mucosa is exposed to a high density and diversity of gram-positive and gram-negative bacteria, but very little is known about how immune homeostasis is maintained in this environment, particularly in the inflammatory disease chronic periodontitis (CP). The cells of the innate immune response recognize bacterial structures via the Toll-like receptors (TLR). This activates intracellular signaling and transcription of proteins essential for the induction of an adaptive immune response; however, if unregulated, it can lead to destructive inflammatory responses. Using single-immunoenzyme labeling, we show that the human oral mucosa (gingiva) is infiltrated by large numbers of TLR2+ and TLR4+ cells and that their numbers increase significantly in CP, relative to health (P < 0.05, Student's t test). We also show that the numbers of TLR2+ but not TLR4+ cells increase linearly with inflammation (r 2 = 0.33, P < 0.05). Double-immunofluorescence analysis confirms that TLR2 is coexpressed by monocytes (MC)/macrophages (mφ) in situ. Further analysis of gingival tissues by quantitative real-time PCR, however, indicates that despite a threefold increase in the expression of interleukin-1β (IL-1β) mRNA during CP, there is significant (30-fold) downregulation of TLR2 mRNA (P < 0.05, Student's t test). Also showing similar trends are the levels of TLR4 (ninefold reduction), TLR5 (twofold reduction), and MD-2 (sevenfold reduction) mRNA in CP patients compared to healthy persons, while the level of CD14 was unchanged. In vitro studies with human MC indicate that MC respond to an initial stimulus of lipopolysaccharide (LPS) from Porphyromonas gingivalis (PgLPS) or Escherichia coli (EcLPS) by upregulation of TLR2 and TLR4 mRNA and protein; moreover, IL-1β mRNA is induced and tumor necrosis factor alpha (TNF-α), IL-10, IL-6, and IL-8 proteins are secreted. However, restimulation of MC with either PgLPS or EcLPS downregulates TLR2 and TLR4 mRNA and protein and IL-1β mRNA and induces a ca. 10-fold reduction in TNF-α secretion, suggesting the induction of endotoxin tolerance by either LPS. Less susceptible to tolerance than TNF-α were IL-6, IL-10, and IL-8. These studies suggest that certain components of the innate oral mucosal immune response, most notably TLRs and inflammatory cytokines, may become tolerized during sustained exposure to bacterial structures such as LPS and that this may be one mechanism used in the oral mucosa to attempt to regulate local immune responses.

scholarly journals Proinflammatory responses in SARS-CoV-2 infected and soluble spike glycoprotein S1 subunit activated human macrophages

2021 ◽  
Author(s):  
Kim Chiok ◽  
Kevin Hutchison ◽  
Lindsay Grace Miller ◽  
Santanu Bose ◽  
Tanya A Miura
Keyword(s):  
Virus Infection ◽  
Inflammatory Response ◽  
Virus Replication ◽  
Inflammatory Mediators ◽  
Inflammatory Responses ◽  
Activated Macrophages ◽  
Human Macrophages ◽  
Tnf Α ◽  
Proinflammatory Responses

Critically ill COVID-19 patients infected with SARS-CoV-2 display signs of generalized hyperinflammation. Macrophages trigger inflammation to eliminate pathogens and repair tissue, but this process can also lead to hyperinflammation and resulting exaggerated disease. The role of macrophages in dysregulated inflammation during SARS-CoV-2 infection is poorly understood. We used SARS-CoV-2 infected and glycosylated soluble SARS-CoV-2 Spike S1 subunit (S1) treated THP-1 human-derived macrophage-like cell line to clarify the role of macrophages in pro-inflammatory responses. Soluble S1 upregulated TNF-α and CXCL10 mRNAs, and induced secretion of TNF-α from THP-1 macrophages. While THP-1 macrophages did not support productive SARS-CoV-2 replication, virus infection resulted in upregulation of both TNF-α and CXCL10 genes. Our study shows that S1 is a key viral component inducing inflammatory response in macrophages, independently of virus replication. Thus, virus-infected or soluble S1-activated macrophages may become sources of pro-inflammatory mediators contributing to hyperinflammation in COVID-19 patients.

scholarly journals Enterococcus faecalisDemonstrates Pathogenicity through Increased Attachment in anEx VivoPolymicrobial Pulpal Infection

2018 ◽  
Vol 86 (5) ◽  
Author(s):  
Wayne Nishio Ayre ◽  
Genevieve Melling ◽  
Camille Cuveillier ◽  
Madhan Natarajan ◽  
Jessica L. Roberts ◽  
...  
Keyword(s):  
Inflammatory Response ◽  
Host Response ◽  
Ex Vivo ◽  
Necrosis Factor Alpha ◽  
Content Type ◽  
Streptococcus Anginosus ◽  
Cell Counts ◽  
Tnf Α ◽  
Factor Alpha ◽  
Infection Types

ABSTRACTThis study investigated the host response to a polymicrobial pulpal infection consisting ofStreptococcus anginosusandEnterococcus faecalis, bacteria commonly implicated in dental abscesses and endodontic failure, using a validatedex vivorat tooth model. Tooth slices were inoculated with planktonic cultures ofS. anginosusorE. faecalisalone or in coculture atS. anginosus/E. faecalisratios of 50:50 and 90:10. Attachment was semiquantified by measuring the area covered by fluorescently labeled bacteria. Host response was established by viable histological cell counts, and inflammatory response was measured using reverse transcription-quantitative PCR (RT-qPCR) and immunohistochemistry. A significant reduction in cell viability was observed for single and polymicrobial infections, with no significant differences between infection types (∼2,000 cells/mm2for infected pulps compared to ∼4,000 cells/mm2for uninfected pulps).E. faecalisdemonstrated significantly higher levels of attachment (6.5%) thanS. anginosusalone (2.3%) and mixed-species infections (3.4% for 50:50 and 2.3% for 90:10), with a remarkable affinity for the pulpal vasculature. Infections withE. faecalisdemonstrated the greatest increase in tumor necrosis factor alpha (TNF-α) (47.1-fold forE. faecalis, 14.6-fold forS. anginosus, 60.1-fold for 50:50, and 25.0-fold for 90:10) and interleukin 1β (IL-1β) expression (54.8-fold forE. faecalis, 8.8-fold forS. anginosus, 54.5-fold for 50:50, and 39.9-fold for 90:10) compared to uninfected samples. Immunohistochemistry confirmed this, with the majority of inflammation localized to the pulpal vasculature and odontoblast regions. Interestingly,E. faecalissupernatant and heat-killedE. faecalistreatments were unable to induce the same inflammatory response, suggestingE. faecalispathogenicity in pulpitis is linked to its greater ability to attach to the pulpal vasculature.

scholarly journals Inhibition of NF-κB by Pyrrolidine Dithiocarbamate Prevents the Inflammatory Response in a Ligature-Induced Peri-Implantitis Model: A Canine Study

2018 ◽  
Vol 49 (2) ◽  
pp. 610-625 ◽  
Author(s):  
Chun-Yan He ◽  
Li-Peng Jiang ◽  
Cheng-Yue Wang ◽  
Yue Zhang
Keyword(s):  
Inflammatory Response ◽  
Protein Expression ◽  
Quantitative Polymerase Chain Reaction ◽  
Pyrrolidine Dithiocarbamate ◽  
Mrna Levels ◽  
Periodontal Ligament Fibroblasts ◽  
Necrosis Factor Alpha ◽  
Periodontal Tissues ◽  
Periodontal Inflammation ◽  
Tnf Α

Background/Aims: The roles of toll-like receptor 4 (TLR4) and nuclear factor-kappa B (NF-κB) in peri-implantitis are unclear. Here, we used a canine model of peri-implantitis to explore the effects of inhibiting NF-κB with pyrrolidine dithiocarbamate (PDTC) on the inflammatory response in ligature-induced peri-implantitis. Methods: After successfully establishing the peri-implantitis model, beagles were randomly assigned to normal, model or PDTC groups. ELISA tests were used to determine the levels of interleukin (IL)-1, IL-6, IL-8 and tumor necrosis factor alpha (TNF-α). Immunohistochemistry was employed to assess the expression of NF-κB p65. Reverse transcription-quantitative polymerase chain reaction (RT-qPCR) was performed to determine the mRNA levels of TLR4 and NF-κB p65, and western blot analysis was used to measure the protein levels of TLR4 in periodontal tissues from each group. Periodontal ligament fibroblasts (PDLFs) were cultured and subsequently classified into PDLF normal, PDLF model, PDLF LPS, PDLF PDTC, and PDLF LPS + PDTC groups. An immunofluorescence assay was used to measure the expression level of NF-κB p65. The CCK-8 assay and flow cytometry were performed to evaluate cell proliferation and apoptosis. Results: The in vitro results indicated that NF-κB p65 and TLR4 were upregulated in canine periodontal tissues, and PDTC could suppress the expression levels of NF-κB p65 and TLR4. Inflammation could increase TLR4 protein expression in canine periodontal tissue, and PDTC could inhibit the inflammation-induced increase in TLR4 protein expression. These results revealed that PDTC could reverse the LPS-induced increases in the levels of IL-1, IL-6, IL-8 and TNF-α. In vivo, the results demonstrated that PDTC inhibited the LPS-induced NF-κB p65 upregulation, and PDTC could reverse the inhibitory effect of the PDLF model + LPS on the proliferation of periodontal fibroblasts. The results also showed that in the PDLF model, LPS promoted PDLF apoptosis by inducing implant periodontitis in canines, but PDTC inhibited the PDLF apoptosis and relieved implant periodontitis in canines. Conclusion: Based on our results, we concluded that PDTC can inhibit the expression of NF-κB and alleviate the inflammatory response induced by LPS, thereby preventing periodontal inflammation and reducing the development of peri-implantitis.

scholarly journals Mycoplasma pneumoniae-Derived Lipopeptides Induce Acute Inflammatory Responses in the Lungs of Mice

2007 ◽  
Vol 76 (1) ◽  
pp. 270-277 ◽  
Author(s):  
Takashi Shimizu ◽  
Yutaka Kida ◽  
Koichi Kuwano
Keyword(s):  
Mycoplasma Pneumoniae ◽  
Inflammatory Responses ◽  
Lavage Fluid ◽  
Peritoneal Macrophages ◽  
Necrosis Factor Alpha ◽  
Chemokine Production ◽  
Cytokines And Chemokines ◽  
Tnf Α ◽  
Mouse Peritoneal Macrophages

ABSTRACT The pathogenesis of Mycoplasma pneumoniae infection is considered to be in part attributable to excessive immune responses. In this study, we investigated whether synthetic lipopeptides of subunit b of F0F1-type ATPase (F0F1-ATPase), NF-κB-activating lipoprotein 1 (N-ALP1), and N-ALP2 (named FAM20, sN-ALP1, and sN-ALP2, respectively) derived from M. pneumoniae induce cytokine and chemokine production and leukocyte infiltration in vivo. Intranasal administration of FAM20 and sN-ALP2 induced infiltration of leukocyte cells and production of chemokines and cytokines in bronchoalveolar lavage fluid, but sN-ALP1 failed to do so. The activity of FAM20 was notably higher than that of sN-ALP2. FAM20 and sN-ALP2 induced tumor necrosis factor alpha (TNF-α) through Toll-like receptor 2 in mouse peritoneal macrophages. Moreover, in the range of low concentrations of lipopeptides, FAM20 showed relatively high activity of inducing TNF-α in mouse peritoneal macrophages compared to synthetic lipopeptides such as MALP-2 and FSL-1, derived from Mycoplasma fermentans and Mycoplasma salivarium, respectively. These findings indicate that the F0F1-ATPase might be a key molecule in inducing cytokines and chemokines contributing to inflammatory responses during M. pneumoniae infection in vivo.

scholarly journals Phenotypic Switching in Cryptococcus neoformans Contributes to Virulence by Changing the Immunological Host Response

2008 ◽  
Vol 76 (9) ◽  
pp. 4322-4331 ◽  
Author(s):  
Abraham Guerrero ◽  
Bettina C. Fries
Keyword(s):  
Inflammatory Response ◽  
Cryptococcus Neoformans ◽  
Transforming Growth Factor Beta ◽  
Transforming Growth Factor ◽  
Inflammatory Responses ◽  
Interleukin 10 ◽  
Host Responses ◽  
Phenotypic Switching ◽  
Wild Type ◽  
Necrosis Factor Alpha

ABSTRACT Cryptococcus neoformans is an encapsulated opportunistic organism that can undergo phenotypic switching. In this process, the parent smooth colony (SM) switches to a more virulent mucoid colony (MC) variant. The host responses mounted against the SM and MC variants differ, and lower tissue interleukin 10 (IL-10) levels are consistently observed in lungs of MC-infected C57BL/6 and BALB/c mice. This suggested different roles of this cytokine in SM and MC infections. The objective of this study was to compare survival rates and characterize the host responses of SM- and MC-infected IL-10-depleted (IL-10−/−) mice, which exhibit a Th1-polarized immune response and are considered resistant hosts. As expected, SM-infected IL-10−/− mice survived longer than wild-type mice, whereas MC-infected IL-10−/− mice did not exhibit a survival benefit. Consistent with this observation, we demonstrated marked differences in the inflammatory responses of SM- and MC-infected IL-10−/− and wild-type mice. This included a more Th1-polarized inflammatory response with enhanced recruitment of macrophages and natural killer and CD8 cells in MC- than in SM-infected IL-10−/− and wild-type mice. In contrast, both SM-infected IL-10−/− and wild-type mice exhibited higher recruitment of CD4 cells, consistent with enhanced survival and differences in recruitment and Th1/Th2 polarization. Lung tissue levels of IL-21, IL-6, IL-4, transforming growth factor beta, IL-12, and gamma interferon were higher in MC-infected IL-10−/− and wild-type mice than in SM-infected mice, whereas tumor necrosis factor alpha levels were higher in SM-infected IL-10−/− mice. In conclusion, the MC variant elicits an excessive inflammatory response in a Th1-polarized host environment, and therefore, the outcome is negatively affected by the absence of IL-10.

scholarly journals Lipopolysaccharide and Tumor Necrosis Factor Alpha Inhibit Interferon Signaling in Hepatocytes by Increasing Ubiquitin-Like Protease 18 (USP18) Expression

2016 ◽  
Vol 90 (12) ◽  
pp. 5549-5560 ◽  
Author(s):  
Sonya A. MacParland ◽  
Xue-Zhong Ma ◽  
Limin Chen ◽  
Ramzi Khattar ◽  
Vera Cherepanov ◽  
...  
Keyword(s):  
Viral Infections ◽  
Inflammatory Responses ◽  
Ischemia Reperfusion Injury ◽  
Ischemia Reperfusion ◽  
Innate Immune ◽  
New Paradigm ◽  
Hepatic Ischemia ◽  
Necrosis Factor Alpha ◽  
Tnf Α ◽  
Inflammatory Stimuli

ABSTRACTInflammation may be maladaptive to the control of viral infection when it impairs interferon (IFN) responses, enhancing viral replication and spread. Dysregulated immunity as a result of inappropriate innate inflammatory responses is a hallmark of chronic viral infections such as, hepatitis B virus and hepatitis C virus (HCV). Previous studies from our laboratory have shown that expression of an IFN-stimulated gene (ISG), ubiquitin-like protease (USP)18 is upregulated in chronic HCV infection, leading to impaired hepatocyte responses to IFN-α. We examined the ability of inflammatory stimuli, including tumor necrosis factor alpha (TNF-α), lipopolysaccharide (LPS), interleukin-6 (IL-6) and IL-10 to upregulate hepatocyte USP18 expression and blunt the IFN-α response. Human hepatoma cells and primary murine hepatocytes were treated with TNF-α/LPS/IL-6/IL-10 and USP18, phosphorylated (p)-STAT1 and myxovirus (influenza virus) resistance 1 (Mx1) expression was determined. Treatment of Huh7.5 cells and primary murine hepatocytes with LPS and TNF-α, but not IL-6 or IL-10, led to upregulated USP18 expression and induced an IFN-α refractory state, which was reversed by USP18 knockdown. Liver inflammation was induced in vivo using a murine model of hepatic ischemia/reperfusion injury. Hepatic ischemia/reperfusion injury led to an induction of USP18 expression in liver tissue and promotion of lymphocytic choriomeningitis replication. These data demonstrate that certain inflammatory stimuli (TNF-α and LPS) but not others (IL-6 and IL-10) target USP18 expression and thus inhibit IFN signaling. These findings represent a new paradigm for how inflammation alters hepatic innate immune responses, with USP18 representing a potential target for intervention in various inflammatory states.IMPORTANCEInflammation may prevent the control of viral infection when it impairs the innate immune response, enhancing viral replication and spread. Blunted immunity as a result of inappropriate innate inflammatory responses is a common characteristic of chronic viral infections. Previous studies have shown that expression of certain interferon-stimulated genes is upregulated in chronic HCV infection, leading to impaired hepatocyte responses. In this study, we show that multiple inflammatory stimuli can modulate interferon stimulated gene expression and thus inhibit hepatocyte interferon signaling via USP18 induction. These findings represent a new paradigm for how inflammation alters hepatic innate immune responses, with the induction of USP18 representing a potential target for intervention in various inflammatory states.

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