scholarly journals Systemic Expression of Cytokine Production in Patients with Severe Pneumococcal Pneumonia: Effects of Treatment with a β-Lactam versus a Fluoroquinolone

2008 ◽  
Vol 52 (7) ◽  
pp. 2395-2402 ◽  
Author(s):  
Esther Calbo ◽  
Montserrat Alsina ◽  
Mónica Rodríguez-Carballeira ◽  
Josep Lite ◽  
Javier Garau
Keyword(s):  
Pneumococcal Pneumonia ◽  
Cytokine Production ◽  
Inflammatory Responses ◽  
Randomized Study ◽  
Venous Blood ◽  
Severe Pneumonia ◽  
Necrosis Factor Alpha ◽  
Tnf Α ◽  
Severity Scores ◽  
Over Time

ABSTRACT Bacterial alveolar invasion is followed by an inflammatory response. A systemic extension of the compartmentalized immune response has been described in patients with severe pneumonia. The data suggest that some antimicrobials may induce a differential release of cytokines. We conducted a prospective, randomized study in adult patients with severe pneumococcal pneumonia to measure the effects of ceftriaxone and levofloxacin in the systemic cytokine expression over time. Demographic, clinical characteristics, and severity scores were recorded. The serum concentrations of tumor necrosis factor alpha (TNF-α), interleukin-1β (IL-1β), IL-6, IL-8, IL-10, and IL-1 receptor agonist were measured at 0, 24, 72, and 120 h. A total of 32 patients were included in the study. Both groups were homogeneous in terms of age, comorbidities, severity of disease, and corticosteroid or statin use. With the single exception of IL-1β, all cytokines were detected in venous blood. All of the cytokines studied showed a similar pattern of progressive decrease over time. No significant differences in the concentrations of any of the cytokines studied were found, with the exception of TNF-α, for which lower concentrations were obtained at 120 h in the levofloxacin group (P = 0.014). Basal oxygen saturation (P = 0.034) and heart rate (P = 0.029) returned to normal values earlier in the levofloxacin arm. We demonstrated that in patients with severe pneumococcal pneumonia pro- and anti-inflammatory responses could be detected in venous blood, representing a systemic extension of the compartmentalized response. Treatment with a β-lactam agent or a fluoroquinolone has different effects on cytokine production and its systemic expression, impacting the clinical course of the disease.

scholarly journals Haemophilus influenzae Porin Induces Toll-Like Receptor 2-Mediated Cytokine Production in Human Monocytes and Mouse Macrophages

2004 ◽  
Vol 72 (2) ◽  
pp. 1204-1209 ◽  
Author(s):  
Marilena Galdiero ◽  
Massimiliano Galdiero ◽  
Emiliana Finamore ◽  
Fabio Rossano ◽  
Maria Gambuzza ◽  
...  
Keyword(s):  
Haemophilus Influenzae ◽  
Cytokine Production ◽  
Inflammatory Responses ◽  
Adaptor Protein ◽  
Monocytic Cell ◽  
Monocytic Cell Line ◽  
Necrosis Factor Alpha ◽  
Human Monocytic Cell Line ◽  
Tnf Α ◽  
Human Monocytic Cell

ABSTRACT The production of proinflammatory cytokines is likely to play a major pathophysiological role in meningitis and other infections caused by Haemophilus influenzae type b (Hib). Previous studies have shown that Hib porin contributes to signaling of the inflammatory cascade. We examined here the role of Toll-like receptors (TLRs) and the TLR-associated adaptor protein MyD88 in Hib porin-induced production of tumor necrosis factor alpha (TNF-α) and interleukin-6 (IL-6). Hib porin-induced TNF-α and IL-6 production was virtually eliminated in macrophages from TLR2- or MyD88-deficient mice. In contrast, macrophages from lipopolysaccharide (LPS)-hyporesponsive C3H/HeJ mice, which are defective in TLR4 function, responded normally to Hib porin. Moreover anti-TLR2 antibodies but not anti-TLR4 antibodies significantly reduced Hib porin-stimulated TNF-α and IL-6 release from the human monocytic cell line THP-1. These data indicate that the TLR2/MyD88 pathway plays an essential role in Hib porin-mediated cytokine production. These findings may be useful in the development of alternative therapies aimed at reducing excessive inflammatory responses during Hib infections.

scholarly journals Campylobacter jejuni Induces Maturation and Cytokine Production in Human Dendritic Cells

2006 ◽  
Vol 74 (5) ◽  
pp. 2697-2705 ◽  
Author(s):  
Lan Hu ◽  
Mechelle D. Bray ◽  
Manuel Osorio ◽  
Dennis J. Kopecko
Keyword(s):  
Dendritic Cells ◽  
Campylobacter Jejuni ◽  
Cytokine Production ◽  
Diarrheal Disease ◽  
Inflammatory Responses ◽  
Bacterial Invasion ◽  
Microbial Infection ◽  
Necrosis Factor Alpha ◽  
Adaptive Immune ◽  
Tnf Α

ABSTRACT Campylobacter jejuni is a leading bacterial cause of human diarrheal disease in both developed and developing nations. Colonic mucosal invasion and the resulting host inflammatory responses are thought to be the key contributing factors to the dysenteric form of this disease. Dendritic cells (DCs) play an important role in both the innate and adaptive immune responses to microbial infection. In this study, the interaction between human monocyte-derived dendritic cells and C. jejuni was studied. We found that C. jejuni was readily internalized by DCs over a 2-h period. However, after a prolonged infection period (24 or 48 h) with C. jejuni, only a few viable bacteria remained intracellularly. Minimal cytotoxicity of C. jejuni to dendritic cells was observed. C. jejuni induced the maturation of dendritic cells over 24 h, as indicated by up-regulation of cell surface marker proteins CD40, CD80, and CD86. In addition, Campylobacter-infected DCs triggered activation of NF-κB and significantly stimulated production of interleukin-1β (IL-1β), IL-6, IL-8, IL-10, IL-12, gamma interferon, and tumor necrosis factor alpha (TNF-α) compared to uninfected DCs. Active bacterial invasion of DCs was not necessary for the induction of these cytokines, as heat-killed C. jejuni stimulated similar levels of cytokine production as live bacteria. Purified lipooligosaccharide of C. jejuni appears to be the major stimulant for the increased production of cytokines by DCs. Taken together, these data indicate that during infection, Campylobacter triggers an innate inflammatory response through increased production of IL-1β, IL-6, IL-8, and TNF-α and initiates a Th1-polarized adaptive immune response as predicted from the high level of production of IL-12.

scholarly journals Acute and Recovery Changes of TNF-α and IL-1β in Response to Aerobic Exercise in Smokers and Non-smokers

2018 ◽  
Vol 3 (3) ◽  
pp. 109-113
Author(s):  
MohammadAli Seyed Hoseini ◽  
Mojtaba Eizadi ◽  
Ashraf Amini ◽  
Zahra Mirakhori
Keyword(s):  
Aerobic Exercise ◽  
Exercise Test ◽  
Repeated Measures ◽  
Acute Exercise ◽  
Inflammatory Responses ◽  
Interleukin 1 ◽  
Venous Blood ◽  
Maximal Heart Rate ◽  
Necrosis Factor Alpha ◽  
Tnf Α

Introduction: Recent evidence has shown that acute exercise modulates the immune response in healthy individuals, although the effect on smokers has not drawn much attention. This study examined acute and post exercise inflammatory responses in smokers and nonsmokers to moderate aerobic exercise. Methods: For this purpose, Fifteen recreationally sedentary male smokers and 15 nonsmokers matched for age (35.5 ± 5.8 years) and BMI(31.30 ± 4.5 kg/m2) were familiarized and underwent aerobic exercise testing involved 40 min running on flat surface with no slope at 70(%) of maximal heart rate. Venous blood was obtained pre-exercise (baseline), 0, 60 min and 24 hours for analysis of tumor necrosis factor-alpha (TNF-α), and interleukin-1 beta (IL-1β) of 2 groups. Experimental data were analyzed by one-way analysis of variance with repeated measures in each group. Results: No differences existed between groups for baseline IL-1B between 2 groups but serum TNF-α was higher in smokers. Aerobic exercise test results a significant decrease in serum TNF-α at 0, 60 min and 24 hours compared baseline in smokers but not in non-smokers. Serum IL-1βremained unchanged at all blood samples after exercise test in both groups. Conclusion: All together, based on acute and recovery response of TNF-α to exercise, it seems that a moderate aerobic exercise has beneficial effects on inflammatory profile in smokers.

scholarly journals POS0204 AUTOANTIBODIES AND SYSTEMIC LUPUS ERYTHEMATOSUS INDUCED BY ANTI-TUMOUR NECROSIS FACTOR ALPHA THERAPY IN RHEUMATOID ARTHRITIS

2021 ◽  
Vol 80 (Suppl 1) ◽  
pp. 318.1-318
Author(s):  
D. Santos Oliveira ◽  
A. Martins ◽  
F. R. Martins ◽  
F. Oliveira Pinheiro ◽  
M. Rato ◽  
...  
Keyword(s):  
Lupus Erythematosus ◽  
Disease Duration ◽  
Seroconversion Rate ◽  
Necrosis Factor Alpha ◽  
Malar Rash ◽  
Tnf Α ◽  
Factor Alpha ◽  
Necrosis Factor ◽  
Over Time

Background:Anti-tumour necrosis factor alpha (anti-TNF-α) therapy is commonly used to treat inflammatory conditions such as rheumatoid arthritis (RA). Autoantibodies namely antinuclear antibodies (ANA) induced by these treatments are well established. However, anti-TNF-α-induced systemic lupus erythematosus (SLE) is rarely described and its incidence is yet unknown.Objectives:This study aimed to determine the prevalence of ANA seroconversion and to characterize the development of SLE induced by anti-TNF-α therapy in patients with RA over time.Methods:An observational retrospective cohort study was conducted with at least one year of follow-up. Patients with diagnosis of RA, according to American College of Rheumatology criteria (ACR), and registered on Rheumatic Diseases Portuguese Register (Reuma.pt) who started their first anti-TNFα between 2003 and 2019 were included. Patients with positive ANA (titer ≥100) and/or positive double-strand DNA (dsDNA) antibodies and/or with a diagnosis of SLE at their first visit were excluded. Demographic, clinical and laboratory data were obtained by consulting Reuma.pt. As there are no recognized criteria for drug-induced SLE, the diagnosis of SLE induced by anti-TNF-α was considered if there is a temporal relationship between clinical manifestations and anti-TNF-α-therapy, the presence of at least 1 serologic ACR criteria (ANA or anti-dsDNA) and at least 1 nonserologic ACR criteria (arthritis, serositis, hematologic disorder or malar rash) [1]. Continuous variables are presented with mean, standard deviation, median, quartile 1 and quartile 3. Categorical variables are presented with absolute and relative frequencies.Results:A total of 211 patients (mean age of 49.9±10.9 years old; 84.4% female) were included with a median follow-up time of 6 [3-14] years. We found a seroconversion rate for ANA of 75.4% (n=159) with median treatment duration of 31 [8.5-70.5] months. The most common titre was 1/100 with diffuse and speckled patterns. ANA seroconversion was higher for etanercept (47.8%, n=76) than with adalimumab (23.9%, n=38), infliximab (13.8%, n=22), golimumab (12.6%, n=20) or certolizumab (1.9%, n=3). SLE induced by anti-TNF-α occurred in two patients (0.9%) with erosive and seropositive (rheumatoid factor and anti-citrullinated protein antibodies) RA previously treated with two conventional synthetic disease-modifying antirheumatic drugs, including methotrexate. The first patient, a female with 66 years old and 17 years of disease duration, developed SLE after 16 months of infliximab, with constitutional symptoms, abrupt worsening of polyarthritis, ANA titer of 1/320 diffuse pattern and positive dsDNA (248 UI/mL) antibodies. The second patient, a woman with 43 years old and 11 years of disease duration, developed SLE after 41 months of adalimumab with malar rash and ANA titer of 1/320 diffuse pattern, positive dsDNA (285 UI/mL), positive anti-histone antibodies and hypocomplementemia. In these two cases, anti-TNF-α therapy was stopped and recovery was spontaneous without treatment. The first patient switched to adalimumab and the second switched to golimumab without recurrence of SLE for more than ten years.Conclusion:We found a high rate of ANA seroconversion induced by anti-TNFα therapy in patients with RA. However, similar to previous literature, only 0.9% of patients developed SLE with mild manifestations without major organ involvement. Although the drug with the highest ANA seroconversion rate was etanercept, those responsible for induced SLE were infliximab and adalimumab. Patients improved after discontinuation of therapy and tolerated an alternative anti-TNF-α drug without recurrence of induced SLE over time. Therefore, ANA and SLE induced by anti-TNF-α should be considered and reported in the follow-up of RA patients. Further research is needed to explore the impact of this adverse event on the outcomes of treatment over time.References:[1]Hochberg MC. Arthritis Rheum. 1997;40(9):1725.Disclosure of Interests:None declared

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 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.

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.

scholarly journals Point mutation bias in SARS-CoV-2 variants results in increased ability to stimulate inflammatory responses

2020 ◽  
Vol 10 (1) ◽  
Author(s):  
Masato Kosuge ◽  
Emi Furusawa-Nishii ◽  
Koyu Ito ◽  
Yoshiro Saito ◽  
Kouetsu Ogasawara
Keyword(s):  
Severe Acute Respiratory Syndrome ◽  
Rna Editing ◽  
Inflammatory Responses ◽  
Rna Viruses ◽  
Point Mutations ◽  
Gene Mutations ◽  
Severe Pneumonia ◽  
Mutation Bias ◽  
Enhanced Production ◽  
Tnf Α

Abstract Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infection induces severe pneumonia and is the cause of a worldwide pandemic. Coronaviruses, including SARS-CoV-2, have RNA proofreading enzymes in their genomes, resulting in fewer gene mutations than other RNA viruses. Nevertheless, variants of SARS-CoV-2 exist and may induce different symptoms; however, the factors and the impacts of these mutations are not well understood. We found that there is a bias to the mutations occurring in SARS-CoV-2 variants, with disproportionate mutation to uracil (U). These point mutations to U are mainly derived from cytosine (C), which is consistent with the substrate specificity of host RNA editing enzymes, APOBECs. We also found the point mutations which are consistent with other RNA editing enzymes, ADARs. For the C-to-U mutations, the context of the upstream uracil and downstream guanine from mutated position was found to be most prevalent. Further, the degree of increase of U in SARS-CoV-2 variants correlates with enhanced production of cytokines, such as TNF-α and IL-6, in cell lines when compared with stimulation by the ssRNA sequence of the isolated virus in Wuhan. Therefore, RNA editing is a factor for mutation bias in SARS-CoV-2 variants, which affects host inflammatory cytokines production.

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.

scholarly journals Toll-Like Receptor 2 Recognition of the Microsporidia Encephalitozoon spp. Induces Nuclear Translocation of NF-κB and Subsequent Inflammatory Responses

2008 ◽  
Vol 76 (10) ◽  
pp. 4737-4744 ◽  
Author(s):  
Jeffrey Fischer ◽  
Colby Suire ◽  
Hollie Hale-Donze
Keyword(s):  
Nuclear Translocation ◽  
Inflammatory Responses ◽  
Host Recognition ◽  
Direct Role ◽  
Necrosis Factor Alpha ◽  
Human Macrophages ◽  
Encephalitozoon Intestinalis ◽  
Intracellular Parasites ◽  
Tnf Α ◽  
Interfering Rna

ABSTRACT Microsporidia are obligate intracellular parasites that are ubiquitous in nature and have been recognized as causing an important emerging disease among immunocompromised individuals. Limited knowledge exists about the immune response against these organisms, and virtually nothing is known about the receptors involved in host recognition. Toll-like receptors (TLR) are pattern recognition receptors that bind to specific molecules found on pathogens and signal a variety of inflammatory responses. In this study, we show that both Encephalitozoon cuniculi and Encephalitozoon intestinalis are preferentially recognized by TLR2 and not by TLR4 in primary human macrophages. This is the first demonstration of host receptor recognition of any microsporidian species. TLR2 ligation is known to activate NF-κB, resulting in inflammatory cytokines, such as tumor necrosis factor alpha (TNF-α) and interleukin-8 (IL-8). We found that the infection of primary human macrophages leads to the nuclear translocation of NF-κB in as early as 1 h and the subsequent production of TNF-α and IL-8. To verify the direct role of TLR2 parasite recognition in the production of these cytokines, the receptor was knocked down in primary human macrophages using small interfering RNA. This knockdown resulted in decreases in both the nuclear translocation of NF-κB and the levels of TNF-α and IL-8 after challenge with spores. Taken together, these experiments directly link the initial inflammatory response induced by Encephalitozoon spp. to TLR2 stimulation in human macrophages.

Sign in / Sign up

Export Citation Format

Share Document