IL-18 Levels and the Outcome of Innate Immune Response to Lipopolysaccharide: Importance of a Positive Feedback Loop with Caspase-1 in IL-18 Expression

A/J mice were found to have amino acid differences in Naip5, one of the NOD-like receptors (NLRs) involved in the cytosolic recognition of pathogen-associated molecular patterns and one of the adaptor proteins for caspase-1 activation. This defect was associated with a susceptibility toLegionellainfection, suggesting an important role for Naip5 in the immune response also to other intracellular pathogens, such asMycobacterium leprae. In this study, the immune responses of macrophages from A/J mice againstM. lepraewere compared to those of macrophages from C57BL/6 mice. Infection withM. lepraeinduced high levels of TNF-αproduction and NF-κB activation in A/J and C57BL/6 macrophages. Caspase-1 activation and IL-1βsecretion were also induced in both macrophages. However, macrophages from A/J mice exhibited reduced caspase-1 activation and IL-1βsecretion compared to C57BL/6 macrophages. These results suggest that NLR family proteins may have a role in the innate immune response toM. leprae.

Download Full-text

Innate immune response toFrancisella tularensisis mediated by TLR2 and caspase-1 activation

Journal of Leukocyte Biology ◽

10.1189/jlb.0406294 ◽

2006 ◽

Vol 80 (4) ◽

pp. 766-773 ◽

Cited By ~ 63

Author(s):

Hanfen Li ◽

Suba Nookala ◽

Xiaowen R. Bina ◽

James E. Bina ◽

Fabio Re

Keyword(s):

Immune Response ◽

Innate Immune Response ◽

Innate Immune ◽

Caspase 1

Download Full-text

c-Jun N-Terminal Kinase 1 Is Required for Toll-Like Receptor 1 Gene Expression in Macrophages

Infection and Immunity ◽

10.1128/iai.00492-07 ◽

2007 ◽

Vol 75 (10) ◽

pp. 5027-5034 ◽

Cited By ~ 14

Author(s):

Hooman Izadi ◽

Amirreza T. Motameni ◽

Tonya C. Bates ◽

Elias R. Olivera ◽

Vega Villar-Suarez ◽

...

Keyword(s):

Immune Response ◽

Innate Immune Response ◽

Feedback Loop ◽

Innate Immune ◽

Proximal Promoter ◽

Innate Immune Responses ◽

Necrosis Factor Alpha ◽

Factor Alpha ◽

Molecular Patterns ◽

Necrosis Factor

ABSTRACT The regulation of innate immune responses to pathogens occurs through the interaction of Toll-like receptors (TLRs) with pathogen-associated molecular patterns and the activation of several signaling pathways whose contribution to the overall innate immune response to pathogens is poorly understood. We demonstrate a mechanism of control of murine macrophage responses mediated by TLR1/2 heterodimers through c-Jun N-terminal kinase 1 (JNK1) activity. JNK controls tumor necrosis factor alpha production and TLR-mediated macrophage responses to Borrelia burgdorferi, the causative agent of Lyme disease, and the TLR1/TLR2-specific agonist PAM3CSK4. JNK1, but not JNK2, activity regulates the expression of the tlr1 gene in the macrophage cell line RAW264.7, as well as in primary CD11b+ cells. We also show that the proximal promoter region of the human tlr1 gene contains an AP-1 binding site that is subjected to regulation by the kinase and binds two complexes that involve the JNK substrates c-Jun, JunD, and ATF-2. These results demonstrate that JNK1 regulates the response to TLR1/2 ligands and suggest a positive feedback loop that may serve to increase the innate immune response to the spirochete.

Download Full-text

Role of Caspase 1 in Murine Antibacterial Host Defenses and Lethal Endotoxemia

Infection and Immunity ◽

10.1128/iai.70.12.6896-6903.2002 ◽

2002 ◽

Vol 70 (12) ◽

pp. 6896-6903 ◽

Cited By ~ 46

Author(s):

Vishwas D. Joshi ◽

Dhananjaya V. Kalvakolanu ◽

John R. Hebel ◽

Jeffrey D. Hasday ◽

Alan S. Cross

Keyword(s):

Immune Response ◽

Innate Immune Response ◽

Endotoxic Shock ◽

Innate Immune ◽

Mrna Levels ◽

Host Defenses ◽

E Coli ◽

Caspase 1 ◽

Reverse Transcription Pcr

ABSTRACT Sepsis is thought to result from an exaggerated innate immune response to microbial components such as lipopolysaccharide (LPS), but the involvement of a specific mechanism(s) has not been identified. We studied the role of caspase 1 (Cas-1) in the murine innate immune response to infection with gram-negative bacteria and to nonlethal and lethal doses of LPS. cas-1 −/− and Cas-1 inhibitor (Ac-YVAD-CHO)-treated cas-1 +/+ mice were two- to threefold more susceptible to lethal Escherichia coli infection than cas-1 +/+ mice. Administration of Cas-1 products, interleukin-18 (IL-18) or IL-1β, protected three of three and six of seven mice, respectively, from lethal infection with E. coli compared to none of six of untreated mice (P = 0.0082). Therefore, cas-1 is essential for antibacterial host defense. Nonlethal (75 μg) and lethal (500 μg) doses of LPS induce different patterns of gamma interferon, IL-1β, and IL-18 expression. Consequently, the role of Cas-1, which cleaves pro-IL-18 and pro-IL-1β to their active forms, was investigated in these disparate conditions by using enzymatic assay and reverse transcription-PCR. At 75 μg, LPS induced a transient increase in IL-1β and IL-18 levels in serum, whereas at 500 μg it induced a 1.5-fold-higher IL-18 level in serum, which increased till death. At 75 μg of LPS, splenic cas-1 mRNA expression remained unchanged at all time points, but activity increased transiently at 3 h. In lethally treated mice, Cas-1 activity remained elevated until death; however, cas-1 mRNA levels increased at 3 h and decreased to basal levels by 8 h. Treatment with Cas-1 inhibitor protected mice from lethal endotoxemia. Thus, Cas-1 is essential for innate antibacterial host defenses and may represent a mechanism of innate immunity that upon excessive stimulation by microbial components may lead to endotoxic shock.

Download Full-text

Bacillus anthracis Capsule Activates Caspase-1 and Induces Interleukin-1β Release from Differentiated THP-1 and Human Monocyte-Derived Dendritic Cells

Infection and Immunity ◽

10.1128/iai.00956-09 ◽

2009 ◽

Vol 78 (1) ◽

pp. 387-392 ◽

Cited By ~ 12

Author(s):

Min-Hee Cho ◽

Hae-Jeong Ahn ◽

Hyun-Joon Ha ◽

Jungchan Park ◽

Jeong-Hoon Chun ◽

...

Keyword(s):

Immune Response ◽

Dendritic Cells ◽

Bacillus Anthracis ◽

Innate Immune Response ◽

Human Monocyte ◽

Innate Immune ◽

Interleukin 1Β ◽

Dependent Manner ◽

Caspase 1 ◽

Extracellular Release

ABSTRACT The poly-γ-d-glutamic acid (PGA) capsule is one of the major virulence factors of Bacillus anthracis, which causes a highly lethal infection. The antiphagocytic PGA capsule disguises the bacilli from immune surveillance and allows unimpeded growth of bacilli in the host. Recently, efforts have been made to include PGA as a component of anthrax vaccine; however, the innate immune response of PGA itself has been poorly investigated. In this study, we characterized the innate immune response elicited by PGA in the human monocytic cell line THP-1, which was differentiated into macrophages with phorbol 12-myristate 13-acetate (PMA) and human monocyte-derived dendritic cells (hMoDCs). PGA capsules were isolated from the culture supernatant of either the pXO1-cured strain of B. anthracis H9401 or B. licheniformis ATCC 9945a. PGA treatment of differentiated THP-1 cells and hMoDCs led to the specific extracellular release of interleukin-1β (IL-1β) in a dose-dependent manner. Evaluation of IL-1β processing by Western blotting revealed that cleaved IL-1β increased in THP-1 cells and hMoDCs after PGA treatment. Enhanced processing of IL-1β directly correlated with increased activation of its upstream regulator, caspase-1, also known as IL-1β-converting enzyme (ICE). The extracellular release of IL-1β in response to PGA was ICE dependent, since the administration of an ICE inhibitor prior to PGA treatment blocked induction of IL-1β. These results demonstrate that B. anthracis PGA elicits IL-1β production through activation of ICE in PMA-differentiated THP-1 cells and hMoDCs, suggesting the potential for PGA as a therapeutic target for anthrax.

Download Full-text

Effects of Therapeutic Hypothermia on Inflammasome Signaling after Traumatic Brain Injury

Journal of Cerebral Blood Flow & Metabolism ◽

10.1038/jcbfm.2012.99 ◽

2012 ◽

Vol 32 (10) ◽

pp. 1939-1947 ◽

Cited By ~ 57

Author(s):

Satoshi Tomura ◽

Juan Pablo de Rivero Vaccari ◽

Robert W Keane ◽

Helen M Bramlett ◽

W Dalton Dietrich

Keyword(s):

Traumatic Brain Injury ◽

Immune Response ◽

Brain Injury ◽

Therapeutic Hypothermia ◽

Innate Immune Response ◽

Cortical Neurons ◽

Purinergic Receptor ◽

Innate Immune ◽

Inflammasome Activation ◽

Caspase 1

Traumatic brain injury (TBI) activates the NALP1/NLRP1 inflammasome, which is an important component of the early innate inflammatory response to injury. We investigated the influence of therapeutic hypothermia on inflammasome activation after TBI. Adult male Sprague–Dawley rats were subjected to moderate fluid percussion brain injury. Temperature manipulation (33°C or 37°C) was initiated 30 minutes after TBI and maintained for 4 hours. At 4 or 24 hours after TBI, traumatized cortex and hippocampus were prepared for immunoblot or immunohistochemical analysis. In the normothermic groups, caspase-1, caspase-11 and expression of the purinergic receptor P2X7 increased at 24 hours after TBI. Posttraumatic hypothermia lead to decreased expression of these proteins at 24 hours compared with normothermic levels. Immunocytochemical studies showed that posttraumatic hypothermia also decreased caspase-1 staining in cerebral cortical neurons compared with normothermic TBI. Cultured cortical neurons subjected to stretch injury demonstrated significant secretion of caspase-1 into the culture medium and caspase-3 activation, both results reduced by hypothermic treatment. Posttraumatic hypothermia decreases inflammasome signaling in neurons and reduces the innate immune response to TBI at 24 hours after injury. Therapeutic hypothermia may protect the injured central nervous system by targeting the detrimental consequences of the innate immune response to injury.

Download Full-text

Downregulated NDR1 protein kinase inhibits innate immune response by initiating an miR146a-STAT1 feedback loop

Nature Communications ◽

10.1038/s41467-018-05176-7 ◽

2018 ◽

Vol 9 (1) ◽

Cited By ~ 6

Author(s):

Zhiyong Liu ◽

Qiang Qin ◽

Cheng Wu ◽

Hui Li ◽

Jia’nan Shou ◽

...

Keyword(s):

Immune Response ◽

Protein Kinase ◽

Innate Immune Response ◽

Feedback Loop ◽

Innate Immune

Download Full-text

Roles of IL-1 in Cancer: From Tumor Progression to Resistance to Targeted Therapies

International Journal of Molecular Sciences ◽

10.3390/ijms21176009 ◽

2020 ◽

Vol 21 (17) ◽

pp. 6009

Author(s):

Valerio Gelfo ◽

Donatella Romaniello ◽

Martina Mazzeschi ◽

Michela Sgarzi ◽

Giada Grilli ◽

...

Keyword(s):

Immune Response ◽

Tumor Cells ◽

Immune Cells ◽

Feedback Loop ◽

Innate Immune ◽

Critical Function ◽

Positive Feedback Loop ◽

Pathological Conditions ◽

Cancer Initiation

IL-1 belongs to a family of 11 members and is one of the seven receptor-agonists with pro-inflammatory activity. Beyond its biological role as a regulator of the innate immune response, IL-1 is involved in stress and chronic inflammation, therefore it is responsible for several pathological conditions. In particular, IL-1 is known to exert a critical function in malignancies, influencing the tumor microenvironment and promoting cancer initiation and progression. Thus, it orchestrates immunosuppression recruiting pro-tumor immune cells of myeloid origin. Furthermore, new recent findings showed that this cytokine can be directly produced by tumor cells in a positive feedback loop and contributes to the failure of targeted therapy. Activation of anti-apoptotic signaling pathways and senescence are some of the mechanisms recently proposed, but the role of IL-1 in tumor cells refractory to standard therapies needs to be further investigated.

Download Full-text

Positive Feedback Loop of Long Noncoding RNA OASL-IT1 and Innate Immune Response Restricts the Replication of Zika Virus in Epithelial A549 Cells

Journal of Innate Immunity ◽

10.1159/000513606 ◽

2021 ◽

pp. 177-191

Author(s):

Yi Wang ◽

Zhiting Huo ◽

Quanshi Lin ◽

Yuxia Lin ◽

Cancan Chen ◽

...

Keyword(s):

Viral Infection ◽

Positive Feedback ◽

Zika Virus ◽

Noncoding Rna ◽

Feedback Loop ◽

Noncoding Rnas ◽

A549 Cells ◽

Innate Immune ◽

Poly I:C ◽

Positive Feedback Loop

Expression of host noncoding RNAs and coding mRNAs is significantly altered by viral infection. In the current study, we screened the transcriptional profile of human lung epithelial A549 cells infected with Zika virus (ZIKV) by microarray assay. Seventy-nine long noncoding RNAs (lncRNAs) and 140 mRNAs were differentially expressed (DE). The bioinformatics analysis revealed that the mRNAs adjacent to the DE lncRNAs were closely related to the host responses to viral infection. We selected 7 lncRNAs from the top 50 hits for validation. The quantitative real-time PCR data confirmed that expression of selected lncRNAs was induced by ZIKV infection. Moreover, the expression of 7 lncRNAs was induced by infection of dengue virus, Japanese encephalitis virus, or vesicular stomatitis virus, or by treatment of poly(I:C) and IFN-β. Furthermore, loss of innate immune adaptor IPS-1 or receptor IFNAR1 resulted in lower induction levels of several lncRNAs by ZIKV. Overexpression of 3 lncRNAs (RPL27-OT1, OASL-IT1, and REC8-OT3) reduced the virus yields of ZIKV. Knockout of OASL-IT1 significantly enhanced ZIKV replication. In OASL-IT1 knockout cells, the levels of interferons (IFNs) and the activation of 3 innate immune signaling pathways triggered by ZIKV were dramatically reduced. Collectively, our work found a positive feedback loop in the IFN system, in which IFNs and OASL-IT1 regulate each other, thereby promoting establishment of antiviral defense.

Download Full-text

Oral Immune Activation by Disgust and Disease-Related Pictures

Journal of Psychophysiology ◽

10.1027/0269-8803/a000143 ◽

2015 ◽

Vol 29 (3) ◽

pp. 119-129 ◽

Cited By ~ 4

Author(s):

Richard J. Stevenson ◽

Deborah Hodgson ◽

Megan J. Oaten ◽

Luba Sominsky ◽

Mehmet Mahmut ◽

...

Keyword(s):

Immune Response ◽

Immune Responses ◽

Innate Immune Response ◽

Negative Control ◽

Innate Immune ◽

Innate Immune Responses ◽

Immune Markers ◽

Before And After ◽

Secondary Analyses ◽

Image Set

Abstract. Both disgust and disease-related images appear able to induce an innate immune response but it is unclear whether these effects are independent or rely upon a common shared factor (e.g., disgust or disease-related cognitions). In this study we directly compared these two inductions using specifically generated sets of images. One set was disease-related but evoked little disgust, while the other set was disgust evoking but with less disease-relatedness. These two image sets were then compared to a third set, a negative control condition. Using a wholly within-subject design, participants viewed one image set per week, and provided saliva samples, before and after each viewing occasion, which were later analyzed for innate immune markers. We found that both the disease related and disgust images, relative to the negative control images, were not able to generate an innate immune response. However, secondary analyses revealed innate immune responses in participants with greater propensity to feel disgust following exposure to disease-related and disgusting images. These findings suggest that disgust images relatively free of disease-related themes, and disease-related images relatively free of disgust may be suboptimal cues for generating an innate immune response. Not only may this explain why disgust propensity mediates these effects, it may also imply a common pathway.

Download Full-text