Disease relevance of Il18

• Thus, we tested the role of IL-18 in regulation of bronchial asthma [1].
• Interleukin 18 (IL-18) in synergy with IL-2 induces lethal lung injury in mice: a potential role for cytokines, chemokines, and natural killer cells in the pathogenesis of interstitial pneumonia [2].
• Acute graft-versus-host disease (aGVHD), the fatal side effects of bone marrow transplantation, was shown to be accompanied by elevation of serum levels of interleukin 18 (IL-18) [3].
• Interleukin 18 induces the sequential activation of natural killer cells and cytotoxic T lymphocytes to protect syngeneic mice from transplantation with Meth A sarcoma [4].
• Interleukin 18 causes hepatic ischemia/reperfusion injury by suppressing anti-inflammatory cytokine expression in mice [5].
• Neutralization of IL-13 or IFN-gamma during Ag plus IL-18 challenges inhibited the combination of eosinophilic infiltration, lung fibrosis, and periostin deposition or the combination of neutrophilic infiltration and AHR, respectively [6].
• In isolated adult mouse cardiomyocytes, simulated ischemia/reperfusion enhanced oxidative stress and biologically active IL-18 expression via IKK-dependent NF-kappaB activation [7].

High impact information on Il18

• IL-18 mRNA is expressed in a wide range of cells including Kupffer cells, macrophages, T cells, B cells, dendritic cells, osteoblasts, keratinocytes, astrocytes, and microglia [8].
• This results in the cleavage and activation of the proinflammatory cytokines IL-1beta and IL-18 [9].
• The molecular mechanisms responsible for the hepatic insulin resistance in the Il18-/- mice involved an enhanced expression of genes associated with gluconeogenesis in the liver of Il18-/- mice, resulting from defective phosphorylation of STAT3 [10].
• In addition, rIL-18 reversed hyperglycemia in Il18-/- mice through activation of STAT3 phosphorylation [10].
• Obesity of Il18-/- mice resulted from accumulation of fat tissue based on increased food intake [10].

Chemical compound and disease context of Il18

• Recombinant Mycobacterium bovis bacillus Calmette-Guérin (BCG) expressing mouse IL-18 augments Th1 immunity and macrophage cytotoxicity [11].
• Moreover, IL-18 induced macrophages to secrete both TNF and nitric oxide after a Listeria infection [12].
• EXPERIMENTAL DESIGN: Murine IL-18 gene was transduced into activated T lymphocytes by an adenovirus vector encoding IL-18 (AdIL-18) liposome complex method [13].
• To increase the antitumor effects of cytosine deaminase (AdCD) gene therapy and induce more potent antitumor immunity, Th1 cytokine interleukin-18 encoded adenovirus (AdIL18) was combined with adenovirus encoding CD (AdCD) for the therapy of established murine B16 melanoma [14].
• Spleen and peritoneal macrophages obtained from innately resistant A/J mice released low levels of interleukin 18 (IL-18) upon infection with Salmonella typhimurium C5 RP4 [15].

Biological context of Il18

• Gene expression, synthesis, and secretion of interleukin 18 and interleukin 1beta are differentially regulated in human blood mononuclear cells and mouse spleen cells [16].
• This was partially due to the absence of any up-regulation of the IL-18 receptor treated with IL-12, and it might suggest the presence of the cross-talk between Jak-Stat and mitogen-activated protein kinase pathways in cytokine signaling [17].
• Herein, we show both in vitro and in vivo that exposure to the pro-Th1 cytokines IL-12 and IL-18 promotes Fas-dependent apoptosis of these cells in the spleen [18].
• This is the first report demonstrating that IL-18 promotes a Th2 phenotype in vivo, and potently induces allergic sensitization [19].
• We then examined signal transduction pathways involved in IL-18-induced MCP-1 production [20].

Anatomical context of Il18

• Thus, Ag and IL-18 stimulate memory Th1 cells to induce severe airway inflammation and AHR in the naive host [1].
• Recombinant IL-18 was found to inhibit OCL formation in cocultures of osteoblasts and hemopoietic cells of spleen or bone marrow origin [21].
• Interleukin 18 acts on memory T helper cells type 1 to induce airway inflammation and hyperresponsiveness in a naive host mouse [1].
• Interleukin-18 (interferon-gamma-inducing factor) is produced by osteoblasts and acts via granulocyte/macrophage colony-stimulating factor and not via interferon-gamma to inhibit osteoclast formation [21].
• The stromal cell populations used for comparison differed in their ability to promote osteoclast-like multinucleated cell (OCL) formation. mRNA for IL-18 was found to be expressed in greater abundance in lines that were unable to support OCL formation than in supportive cells [21].

Associations of Il18 with chemical compounds

• LPS induces IL-18 secretion from Kupffer cells in a caspase-1-dependent manner [22].
• These results demonstrate that early neutrophil influx following allergen challenge is mediated by IL-1, IL-18, and p38 MAPK [23].
• CONCLUSION: These data show reduced atherosclerosis and Th1 activity in spite of increased serum cholesterol in IL-18 deficient apoE(-/-) mice [24].
• Repetitive topical application (weekly for six consecutive weeks) of trinitrochlorobenzene to their ears also elicited a stronger cutaneous inflammation in keratin 5/interleukin 18 transgenic mice than seen in immunoglobulin/interleukin 18 transgenic or wild-type mice [25].
• WP-treated KCASP1Tg mice had significant elevation in the serum levels of histamine, IgE and IL-18 as compared with IPD-treated KCASP1Tg mice. mRNA expression of IL-4 and IL-5 in the skin lesions from WP-treated KCASP1Tg mice was significantly higher than in those from IPD-treated mice [26].

Physical interactions of Il18

• IL-18 binding and inhibition of interferon gamma induction by human poxvirus-encoded proteins [27].
• IFN-gamma up-regulates IL-18 gene expression via IFN consensus sequence-binding protein and activator protein-1 elements in macrophages [28].

Enzymatic interactions of Il18

• Specifically, IL-18 induced phosphorylation of phosphorylates p56(lck) (LCK) and mitogen-activated protein kinase (MAPK) [29].

Regulatory relationships of Il18

• Furthermore, mice having received IFN-gamma-expressing Th1 cells sorted from polarized Th1 cells developed severe airway inflammation and AHR after intranasal administration of Ag and IL-18 [1].
• This conclusion was supported by the following findings: 1) A 24-h treatment with IL-12 plus IL-18 enhanced Fas expression and annexin staining among basophil precursor-enriched lin(-)c-kit(-) splenocytes [18].
• IFN-gamma-inducing factor up-regulates Fas ligand-mediated cytotoxic activity of murine natural killer cell clones [30].
• Our results indicate that while endogenous IL-18 facilitates alum-induced IL-4 production, OVA-specific immunoglobulin G1 (IgG1) and IgE production remain unaffected [31].
• IL-18 induced up-regulation of the TNFRI on the surface of LEC [32].

Other interactions of Il18

• These results suggest FasL-mediated caspase-1-dependent IL-18 secretion in aGVHD in mice [3].
• The lethal effect by IL-18/IL-2 was completely eliminated in severe combined immunodeficient mice pretreated with antiasialo-GM1 antibody and normal mice pretreated with anti-NK1.1 but not with anti-CD4 or anti-CD8, monoclonal antibody [2].
• CD4(+) T cells strongly responded to IL-18 to secrete IL-5 and GM-CSF [33].
• Partial impairment of interleukin-12 (IL-12) and IL-18 signaling in Tyk2-deficient mice [17].
• Furthermore, under blockade of IL-18, anti-inflammatory cytokines such as IL-4 and IL-10 were greatly up-regulated [5].
• Inhibition of ERK1/2 or NFATc4 knockdown reverses IL-18-mediated adiponectin suppression [34].

Analytical, diagnostic and therapeutic context of Il18

• The inhibitory effect of IL-18 was limited to the early phase of the cocultures, which coincides with proliferation of hemopoietic precursors [21].
• Lethally irradiated recipients having transplantation with H-2 disparate donor splenocytes demonstrated aGVHD and contained markedly elevated serum levels of IL-18 [3].
• Hepatic IL-18 expression was up-regulated from 1 to 8 hours after reperfusion [5].
• Signal transducer and activator of transcription 6 (STAT6) was significantly activated under blockade of IL-18 [5].
• Administration of anti-IL-18 Abs caused a 100- to 1000-fold increase in bacterial counts in the spleen of infected mice but did not change IFN-gamma production levels [35].

References