Detection of pathogen by pattern recognition receptors leads to activation of inflammasome which plays a crucial role in immune system. The inflammasome regulates the release of cytokines, such as interleukin (IL)-1beta, IL-18 and high-mobility group box 1 (HMGB1). Double-stranded RNA-dependent protein kinase (PKR) is a critical component of an inflammatory complex. Recently, the critical role of PKR was reported in regulation of multiple inflammasomes.
Cytokines ; eIF-2 Kinase ; Immune System ; Inflammasomes ; Interleukin-18 ; Interleukins ; Receptors, Pattern Recognition

Inflammation is an immune response mediated by innate immune cells of tissues, against invading microbes and cellular stress. The hallmark of inflammatory responses is the activation of inflammasomes — multiprotein oligomers comprising intracellular pattern recognition receptors and inflammatory effectors — such as ASC and pro-cysteine-aspartic protease (pro-caspase)-1. Inflammasomes can be classified as canonical or non-canonical, and their activation in response to various ligands commonly induces caspase-1 activation and gasdermin D (GSDMD) processing, leading to caspase-1-mediated maturation and secretion of the pro-inflammatory cytokines IL-1β and IL-18, and GSDMD-mediated pyroptosis through pore generation in cell membranes. Although inflammation protects the host from harmful stimuli, chronic inflammation is a critical risk factor for inflammatory diseases, and several studies have investigated the role of canonical inflammasomes in inflammatory responses and diseases, with emerging studies focusing on the role of non-canonical inflammasomes. This review discusses recent studies on the regulatory roles of the caspase-11 non-canonical inflammasome in the pathogenesis of inflammatory diseases. Additionally, it provides an insight into the development of novel therapeutics based on targeting caspase-11 non-canonical inflammasome and its downstream effectors to prevent and treat human inflammatory conditions.
Cell Membrane ; Cytokines ; Humans ; Inflammasomes* ; Inflammation ; Interleukin-18 ; Ligands ; Pyroptosis ; Receptors, Pattern Recognition ; Risk Factors

OBJECTIVE: To investigate the effect of interference of P2X4 receptor expression in tumor-associated macrophages (TAMs) on invasion and migration of glioma cells. METHODS: C57BL/6 mouse models bearing gliomas in the caudate nucleus were examined for glioma pathology with HE staining and expressions of Iba-1 and P2X4 receptor with immunofluorescence assay. RAW264.7 cells were induced into TAMs using conditioned medium from GL261 cells, and the changes in mRNA expressions of macrophage polarization-related markers and the mRNA and protein expressions of P2X4 receptor were detected with RT-qPCR and Western blotting. The effect of siRNA-mediated P2X4 interference on IL-1β and IL-18 mRNA and protein expressions in the TAMs was detected with RT-qPCR and Western blotting. GL261 cells were cultured in the conditioned medium from the transfected TAMs, and the invasion and migration abilities of the cells were assessed with Transwell invasion and migration experiment. RESULTS: The glioma tissues from the tumor-bearing mice showed a significantly greater number of Iba-1-positive cells, where an obviously increased P2X4 receptor expression was detected (P=0.001), than the brain tissues of the control mice (P < 0.001). The M2 macrophage markers (Arg-1 and IL-10) and M1 macrophage markers (iNOS and TNF-α) were both significantly up-regulated in the TAMs derived from RAW264.7 cells (all P < 0.01), but the up-regulation of the M2 macrophage markers was more prominent; the expression levels of P2X4 receptor protein and mRNA were both increased in the TAMs (P < 0.05). Interference of P2X4 receptor expression significantly lowered the mRNA(P < 0.01)and protein (P < 0.01, P < 0.05)expression levels of IL-1β and IL-18 in the TAMs and obviously inhibited the ability of the TAMs to promote invasion and migration of the glioma cells (P < 0.05). CONCLUSION Interference of P2X4 receptor in the TAMs suppresses the migration and invasion of glioma cells possibly by lowering the expressions of IL-1β and IL-18.
Animals ; Culture Media, Conditioned ; Glioma ; Interleukin-18 ; Mice ; Mice, Inbred C57BL ; RNA, Messenger ; Receptors, Purinergic P2X4/metabolism* ; Tumor-Associated Macrophages

OBJECTIVETo evaluate the role of interleukin (IL)-18 and IL-18 receptor (IL-18R) in the predominant Th1 type cytokine response in patients with immune thrombocytopenia (ITP).

METHODSFifteen patients with active phase ITP, eighteen in remission and thirteen healthy controls were enrolled in this study. T-bet and GATA-3 mRNA levels in peripheral blood mononucleated cells (PBMNC) were measured by reverse transcriptase polymerase chain reaction (RT-PCR); the plasma IL-18 level by enzyme linked immunosorbent assay (ELISA), the expression of IL-18R on CD3(+) lymphocytes and total lymphocytes by flow cytometry(FCM).

RESULTSThe T-bet mRNA levels in patients with active phase ITP was 3.572 fold as much as that in the controls (P < 0.05), while the GATA-3 mRNA levels were 0.378 fold of that in controls (P < 0.05). The levels of plasma IL-18 and IL-18R on CD3(+) lymphocytes were significantly increased in active phase ITP than in remission phase and controls. There was no difference in ratio of T-bet/GATA-3 between remitted ITP and controls and so was for T-bet mRNA, GATA-3 mRNA, plasma IL-18 and IL-18R on CD3(+) lymphocytes.

CONCLUSIONITP as a disease of Th1-dominant response there is an unbalance between T-bet and GATA-3 in its active phase; IL-18 and IL-18R being upregulated.

Adolescent ; Adult ; Aged ; Case-Control Studies ; Female ; GATA3 Transcription Factor ; metabolism ; Humans ; Interleukin-18 ; immunology ; metabolism ; Male ; Middle Aged ; Purpura, Thrombocytopenic, Idiopathic ; immunology ; metabolism ; Receptors, Interleukin-18 ; immunology ; metabolism ; T-Box Domain Proteins ; metabolism ; Th1 Cells ; immunology ; metabolism ; Young Adult

PURPOSE: Interleukin 18 (IL-18) is now recognized as an important regulator of innate and acquired immune response. IL-18 is a proinflammatory cytokine which induces IFN-gamma, TNF-alpha, Granulocyte-macrophage Colony-stimulating factor (GM-CSF), IL-1, IL-4 and IL-10, to activate killing by lymphocytes, and to up-regulate the expression of certain chemokine receptors. The authors hypothesized that elevated concentration of IL-18 was related to the pathophysiology of KS. The aims of the present study was to evaluate serial changes of serum IL-18 level in acute and subacute phase of KD, and Comparison of serum IL-18 levels, biochemical profiles and the duration of fever. METHODS: We determined simultaneously the serum concentrations of IL-18 and C-reactive protein (CRP) as well as the white blood cell (WBC) count in 23 patients with acute and subacute phase of KD, 23 with respiratory tract infection (febrile controls) and 10 healthy children (afebrile controls). RESULTS: Acute-phase KD patients showed a significantly higher mean IL-18 value (492.80+/-143.70 pg/mL) than that of subaute-phase KD patients(230.67+/-144.13 pg/mL) and afebrile control (223.97+/-164.12 pg/mL)(p<0.05). Subacute-phase KD patients showed a significantly lower level of IL-18 compared to febrile control(519.77+/-242.05 pg/mL)(P<0.05). The IL-18 values in the acute-phase patients showed a positive correlation with CRP (r=0.413, P=0.030), but there were no other correlations between serum IL-18 value and other profiles. CONCLUSION: The results showed increased IL-18 values in the acute phase and normal values in subacute phase of KD. but IL-18 values were not directly correlated with WBC count, CRP and the duration of fever except between IL-18 value and CRP in the acute phaseof KD. The results suggest that IL-18 pathways were activated in the acute phase of KD, and IL-18 production may not be associated with the severity of inflammation in KD.
C-Reactive Protein ; Child ; Fever* ; Granulocyte-Macrophage Colony-Stimulating Factor ; Homicide ; Humans ; Inflammation ; Interleukin-1 ; Interleukin-10 ; Interleukin-18* ; Interleukin-4 ; Leukocytes ; Lymphocytes ; Mucocutaneous Lymph Node Syndrome* ; Receptors, Chemokine ; Reference Values ; Respiratory Tract Infections ; Tumor Necrosis Factor-alpha

Therapy for inflammatory bowel disease (IBD) has changed, with several new agents being evaluated. The era of anti-tumor necrosis factor (anti-TNF) antibody therapy saw remarkable progress in IBD therapy. Some patients, however, do not respond to anti-TNF treatment, or their response decreases over time. This phenomenon highlights the need to identify new molecular targets for therapy in IBD. The targets of new therapeutic molecules in IBD must aim to restore immune dysregulation by the inhibition of proinflammatory cytokines (TNF-α, interleukin [IL]-6, IL-13, IL-17, IL-18, and IL-21) and augmentation of the effect of anti-inflammatory cytokines (IL-10, IL-11, and transforming growth factor β) and to pursue new anti-inflammatory targets, such as regulatory T-cell therapy, Smad7 antisense, Janus-activated kinase inhibition, Toll-like receptor stimulation, leukocyte adhesion, and blockade of T-cell homing via integrins and mucosal addressin cellular adhesion molecule-1. In addition, potential molecular targets could restore mucosal barrier function and stimulate mucosal healing. Despite these potential targets, the value and clinical significance of most new molecules remain unclear, and clinical efficacy and safety must be better defined before their implementation in clinical practice. This article aims to review the promising and emerging molecular targets that could be clinically meaningful for novel therapeutic approaches.
Biological Products* ; Colitis, Ulcerative ; Crohn Disease ; Cytokines ; Humans ; Inflammatory Bowel Diseases* ; Integrins ; Interleukin-11 ; Interleukin-13 ; Interleukin-17 ; Interleukin-18 ; Interleukins ; Leukocytes ; Necrosis ; Phosphotransferases ; T-Lymphocytes ; Toll-Like Receptors ; Transforming Growth Factors ; Treatment Outcome

IL-18 is a crucial pro-inflammatory cytokine that mediates chronic intestinal inflammation. Metformin, an anti-diabetic drug, was reported to have ameliorative effects on inflammatory bowel disease. Recently, the mechanism of action of metformin was explained as a modulation of gut microbiota. In this study, fecal microbiota transplantation (FMT) using fecal material from metformin-treated mice was found to upregulate the expression of GLP-1 and pattern-recognition receptors TLR1 and TLR4 for the improvement in hyperglycemia caused by a high-fat diet. Further, FMT downregulated the expression of the inflammatory cytokine IL-18. Within the genera Akkermansia, Bacteroides, and Butyricimonas, which were promoted by metformin therapy, Butyricimonas was found to be consistently abundant following FMT. Our findings suggest that modulation of gut microbiota is a key factor for the anti-inflammatory effects of metformin which is used for the treatment of hyperglycemia.
Animals ; Bacteroides ; Diet, High-Fat ; Down-Regulation ; Fecal Microbiota Transplantation ; Gastrointestinal Microbiome ; Glucagon-Like Peptide 1 ; Hyperglycemia ; Inflammation ; Inflammatory Bowel Diseases ; Interleukin-18 ; Metformin ; Mice ; Toll-Like Receptors

Killer cell Ig-like receptor (KIR) binds to HLA class I molecules on the surface of target cells, and it confers inhibitory signals to NK cells. Although NK cytotoxicity can be affected by the change of the surface expression of KIR on NK cells, the effect of cytokines on the regulation of KIR expression has not been thoroughly investigated. Here in our study, we investigated the effect of several cytokines, including IL-2, TGF-beta, IFN-gamma, IL-12 and IL-18, on the surface expression of CD158 KIR, which binds to HLA-C, by the use of FACS analysis. In the isolated NK cells, IL-2 obviously increased the surface expression of CD158 KIR after 72 hr in vitro culture, and this was evidenced by the increased percentage of CD158+ NK cells and the increased mean fluorescence intensity of CD158 in CD158+ NK cells. In contrast, TGF-beta decreased the surface expression of CD158 KIR after 72 hr culture. However, IFN-gamma, IL-12 and IL-18 did not change the expression of CD158 KIR. The modulated expression of KIR by IL-2 and TGF-beta can be associated with the changed NK-cytotoxic target-discriminating ability of NK cells upon their exposure to IL-2 and TGF-beta.
Antineoplastic Agents/*pharmacology ; Cells, Cultured ; Human ; Interferon Type II/pharmacology ; Interleukin-12/pharmacology ; Interleukin-18/pharmacology ; Interleukin-2/*pharmacology ; Killer Cells/cytology/*drug effects/*metabolism ; Receptors, Immunologic/*metabolism ; Support, Non-U.S. Gov't ; Transforming Growth Factor beta/*pharmacology

PURPOSE: Interleukin 18(IL-18) is a potent proinflammatory cytokine which induces IFN-gamma, GM-CSF, TNF-alpha and IL-1, to activate killing by lymphocytes, and to up-regulate the expression of certain chemokine receptors. Kawasaki disease (KD) is an inflammatory disease which increases serum levels of inflammatory cytokines, such as TNF-alpha and IL-6. This study was performed to examine the serum levels of proinflammatory cytokine IL-18 in KD. METHODS: Twenty patients with KD and 10 healthy children were enrolled in this study. Serum levels of IL-18 and TNF-alpha from the patients with acute and subacute stage of KD and normal controls were measured by using ELISA. Acute phase reactants such as ESR and C-reactive protein were measured during the acute stage of the disease. RESULTS: There was a significant increase in serum levels of IL-18 measured at the acute stage of KD(818.0+/-253.4 pg/mL) compared with those of subacute stage (367.7+/-140.1 pg/mL) (P<0.01) and normal controls(348.6+/-122.9 pg/mL)(P<0.01). However, the increase of IL-18 was not correlated with the increase of TNF-alpha(R=-0.156, P=0.488) or other acute phase reactants. CONCLUSION: The results showed that IL-18 was increased during the acute stage of KD, but the increase of IL-18 was not directly correlated with TNF-alpha. This results suggest that Il-18 is not a useful marker to estimate the severity of inflammation in KD.
Acute-Phase Proteins ; C-Reactive Protein ; Child ; Cytokines ; Enzyme-Linked Immunosorbent Assay ; Granulocyte-Macrophage Colony-Stimulating Factor ; Homicide ; Humans ; Inflammation ; Interleukin-1 ; Interleukin-18* ; Interleukin-6 ; Interleukins ; Lymphocytes ; Mucocutaneous Lymph Node Syndrome* ; Receptors, Chemokine ; Tumor Necrosis Factor-alpha

OBJECTIVETo discuss the roles of serum interleukin-18 (IL-18), interleukin-10 (IL-10) and soluble interleukin-2R (sIL-2R) in the pathogenesis of chronic hepatitis C and to observe the effects of interferon (IFN) on the above- mentioned serum cytokines.

METHODSThe levels of above- mentioned cytokines were detected in 10 healthy individuals, 24 asymptomatic hepatitis virus C (HCV) carriers and 27 patients with chronic hepatitis C (before and after IFN treatment) using enzyme linked immunosorbent assay (ELISA).

RESULTSThe levels of the cytokines in patients with chronic hepatitis C are higher than in healthy people (P < 0.05) and in asymptomatic HCV carriers (P < 0.05). The values of the cytokines show a significant positive correlation to ALT (P < 0.05). Levels of tested cytokines decreased observably after IFN treatment (P < 0.05). The grades of the serum levels for sIL-2R and IL-10 before IFN treatment (from high to low) were categorized accordingly: non-response group > partial- response group > complete- response group (P < 0.05).

CONCLUSIONSThe tested cytokines co-participate in the pathogenesis of chronic hepatitis C, and can be used to evaluate the effect of IFN on the immune state of organisms. Furthermore, sIL-2R and IL-10 are important for predicting the anti-viral efficacy of IFN.

Adolescent ; Adult ; Antiviral Agents ; therapeutic use ; Female ; Hepatitis C, Chronic ; blood ; drug therapy ; Humans ; Interferon-alpha ; therapeutic use ; Interleukin-10 ; blood ; Interleukin-18 ; blood ; Male ; Middle Aged ; Receptors, Interleukin-2 ; blood ; Recombinant Proteins