Upregulation Of Interleukin-18 Research Articles

The NLRP3 inflammasome is essential for IL-18 production in a murine model of macrophage activation syndrome.

Hyperinflammatory disease is associated with an aberrant immune response resulting in cytokine storm. One such instance of hyperinflammatory disease is known as macrophage activation syndrome (MAS). The pathology of MAS can be characterised by significantly elevated serum levels of interleukin-18 (IL-18) and interferon gamma (IFNγ). Given the role for IL-18 in MAS, we sought to establish the role of inflammasomes in the disease process. Using a murine model of CpG-oligonucleotide-induced MAS, we discovered that the expression of the NLRP3 inflammasome was increased and correlated with IL-18 production. Inhibition of the NLRP3 inflammasome or the downstream caspase-1 prevented MAS-mediated upregulation of IL-18 in the plasma but, interestingly, did not alleviate key features of hyperinflammatory disease including hyperferritinaemia and splenomegaly. Furthermore blockade of IL-1 receptor with its antagonist IL-1Ra did not prevent the development of CpG-induced MAS, despite being clinically effective in the treatment of MAS. These data demonstrate that, during the development of MAS, the NLRP3 inflammasome was essential for the elevation in plasma IL-18 - a key cytokine in clinical cases of MAS - but was not a driving factor in the pathogenesis of CpG-induced MAS.

Effects of two different exercise paradigms on cardiac function, BDNF-TrkB expression, and myocardial protection in the presence and absence of Western diet.

Brain-derived neurotrophic factor (BDNF) -tropomyosin-related kinase receptor B (TrkB) signaling is a vital regulator of myocardial performance. Here, we tested the impact of high-intensity interval training (HIIT) and moderate-intensity continuous training (MICT) on heart function, metabolic parameters, and serum/cardiac BDNF (with its TrkB receptor) in animals fed a Western (WD) or regular diet (ND). Further, myocardial expression of pro-inflammatory cytokine interleukin-18 (IL-18) and cardioprotective molecule heme oxygens-1 (HO-1) were monitored. Wistar rats were divided into HIIT, MICT, and sedentary (SED), all fed a WD or ND, for 12weeks. Heart function, protein expression, and serum factors were assessed via echocardiography, western blotting, and ELISA, respectively. WD plus SED caused insulin resistance, dyslipidemia, visceral fat deposition, serum BDNF depletion as well as cardiac upregulation of IL-18 and downregulation of HO-1, without affecting, heart function and BDNF-TrkB expression. The cardiometabolic risk factors, serum BDNF losses, and IL-18 overexpression were similarly obviated by HIIT and MICT, although HO-1 expression was boosted by HIIT exclusively (even in ND). HIIT enhanced heart function, regardless of the diet. HIIT augmented cardiac BDNF expression, with a significant difference between ND and WD. Likewise, HIIT instigated TrkB expression only in ND. HIIT and MICT can cope with myocardial inflammation and cardiometabolic risk factors in WD consumers and, exclusively, HIIT may grant further protection by increasing heart function, BDNF-TrkB expression, and HO-1 expression. Thus, the HIIT paradigm should be considered as a preference for subjects who require heart function to be preserved or enhanced.

The role of Interleukin-18 in recurrent early pregnancy loss

BackgroundA successful pregnancy is a unique and complex immunological state. Cytokines seem to be crucial for the implementation of a tolerogenic environment at the feto-maternal interphase towards the semi-allogenic fetus. Importantly, the switch from a Th1- to a Th2 cytokine profile might play a key role. Interestingly, Interleukin-18 (IL-18) can induce either Th1 or Th2 immune response depending on the local cytokine environment. Therefore, this study investigates the expression of IL-18 in early pregnancy loss. Patients and MethodsThe TaqMan® Human Cytokine Network Array was carried out with placental tissue of patients with healthy pregnancies (n = 15) and recurrent miscarriage (n = 15) in order to investigate differences in IL-18 mRNA expression. Immunohistochemical staining was applied to examine the IL-18 protein expression in the syncytiotrophoblast and decidua of healthy pregnancies (n = 15), spontaneous (n = 12) and recurrent miscarriage (n = 9). The characterization of IL-18 expressing cells in the decidua was evaluated by double-immunofluorescence. Correlation analysis between IL-18 protein expression and clinical data of the study population was performed via spearman correlation coefficient. ResultsGene expression analysis revealed a 4,9-times higher expression of IL-18 in recurrent miscarriage patients. IL-18 protein expression was significantly upregulated only in the decidua in the recurrent miscarriage group (p = 0.031). We did not observe significant changes of IL-18 protein expression in spontaneous miscarriage specimens when compared to healthy controls (p = 0.172). Double-immunofluorescence identified decidual stroma cells as IL-18 expressing cells. Correlation analysis showed a significant negative correlation of IL-18 protein expression and gestational age in healthy controls (r = -,745, p = 0.034). Also, a positive correlation of IL-18 and maternal age was observed in patients suffering from recurrent pregnancy loss (r =, 894, p = 0.041). ConclusionOur results indicate that IL-18 expression might be necessary in early gestation but requires a tight regulation for a successful ongoing pregnancy. In the present study we observed that a significant upregulation of IL-18 in the decidua was restricted to patients with recurrent miscarriage and therefore might be interesting as a diagnostic marker. Further studies need to evaluate the exact pathophysiological mechanisms.

Interleukin-18 Is a Prognostic Marker and Plays a Tumor Suppressive Role in Colon Cancer.

Interleukin-18 (IL-18) belongs to the IL-1 family and is an essential proinflammatory and immune regulatory cytokine. The present study was designed to investigate the expression and function of IL-18 in colon cancer. In clinical analyses, mRNA and protein expressions of IL-18 were decreased in tissues of colon cancer patients. This decreased expression of IL-18 was significantly correlated with the tumor size (P = 0.001) and American Joint Committee on Cancer (AJCC) stage (P = 0.013). Patients with IL-18-positive tumors had a better survival rate than patients with IL-18-negative tumors. Moreover, upregulation of IL-18 inhibited colon cancer cell proliferation. Our data suggest that the decreased expression of IL-18 in colon cancer was associated with prognosis and tumor proliferation. IL-18 may be considered a novel tumor suppressor and a potential therapeutic target for colon cancer patients.

Microglia-Astrocyte Cross Talk through IL-18/IL-18R Signaling Modulates Migraine-like Behavior in Experimental Models of Migraine

Interleukin-18 (IL-18) is an important regulator of innate and immune responses, and is involved in the pain process, including neuropathic and cancer pain. The current study demonstrated that inflammatory soup (IS) dural infusions elicited the activation of microglia and astrocytes. In comparison, IS dural infusions induced the upregulation of IL-18 and IL-18R in microglia and astrocytes, respectively. Blocking the IL-18 signaling pathway attenuated nociceptive behavior. In comparison, blocking IL-18 signaling also suppressed the activation of astrocytes and nuclear factor-kappa B (NF-κB). IL-18 dural infusions induced nociceptive behavior and glia activation. IL-18 is a product of the activation of microglial toll-like receptor 4 (TLR4), and it acted on IL-18R expressed in astrocytes. Subsequently, it stimulated the activation of nuclear factor-kappa B (NF-κB), leading to the activation of astrocytes. In conclusion, IL-18-mediated microglia/astrocyte interactions in the medullary dorsal horn likely contribute to the development of hyperpathia or allodynia induced by migraines.

Lung injury induced by Bisphenol A: A food contaminant, is ameliorated by selenium supplementation

Bisphenol A (BPA), a widely used industrial chemical, is known to disrupt endocrine function. This study aimed to investigate the impact of chronic exposure to BPA on the lung tissue of adult male rats as well as any possible alleviating effects resulting from selenium (Se) treatment. Chronic exposure to BPA resulted in prominent inflammation and oxidative stress responses as evidenced by an increase in levels of malondialdehyde (MDA), reduced concentrations of superoxide dismutase (SOD), and upregulation of Interleukin-18 (IL-18) expression in lung tissue. In addition, chronic exposure led to modulation of the fibrosis-related gene expression, as we observed augmented follistatin-like1 (FSTL1) expression and diminished a disintegrin and metalloproteinase with thrombospondin motif 5 (ADAMTS5) expression. Se treatment remarkably mitigated changes in the expression of these dysregulated markers of lung injury. The biochemical changes were consistent with the histopathological findings, where cellular infiltration and inflammatory fibrotic changes were observed following BPA administration and a lessening of these effects with concomitant Se treatment. Taken together, the results from the study reveal that chronic exposure to BPA may promote the development of pulmonary inflammatory diseases with possible induction of lung fibrosis. Se treatment effectively suppressed oxidative stress, inflammation, and fibrosis, suggesting that Se has the potential to be used as a therapeutic agent in the treatment of pulmonary inflammatory diseases.

Interleukin-18 expression increases in response to neurovascular damage following soman-induced status epilepticus in rats.

BackgroundStatus epilepticus (SE) can cause neuronal cell death and impaired behavioral function. Acute exposure to potent acetylcholinesterase inhibitors such as soman (GD) can cause prolonged SE activity, micro-hemorrhage and cell death in the hippocampus, thalamus and piriform cortex. Neuroinflammation is a prominent feature of brain injury with upregulation of multiple pro-inflammatory cytokines including those of the IL-1 family. The highly pleiotropic pro-inflammatory cytokine interleukin-18 (IL-18) belongs to the IL-1 family of cytokines and can propagate neuroinflammation by promoting immune cell infiltration, leukocyte and lymphocyte activation, and angiogenesis and helps facilitate the transition from the innate to the adaptive immune response. The purpose of this study is to characterize the regional and temporal expression of IL −18 and related factors in the brain following SE in a rat GD seizure model followed by localization of IL-18 to specific cell types.MethodsThe protein levels of IL-18, vascular endothelial growth factor and interferon gamma was quantified in the lysates of injured brain regions up to 72 h following GD-induced SE onset using bead multiplex immunoassays. IL-18 was localized to various cell types using immunohistochemistry and transmission electron microscopy. In addition, macrophage appearance scoring and T-cell quantification was determined using immunohistochemistry. Micro-hemorrhages were identified using hematoxylin and eosin staining of brain sections.ResultsSignificant increases in IL-18 occurred in the piriform cortex, hippocampus and thalamus following SE. IL-18 was primarily expressed by endothelial cells and astrocytes associated with the damaged neurovascular unit. The increase in IL-18 was not related to macrophage accumulation, neutrophil infiltration or T-cell appearance in the injured tissue.ConclusionsThese data show that IL-18 is significantly upregulated following GD-induced SE and localized primarily to endothelial cells in damaged brain vasculature. IL-18 upregulation occurred following leukocyte/lymphocyte infiltration and in the absence of other IL-18-related cytokines, suggesting another function, potentially for angiogenesis related to GD-induced micro-hemorrhage formation. Further studies at more chronic time points may help to elucidate this function.

Involvement of spinal microglia and interleukin-18 in the anti-nociceptive effect of dexmedetomidine in rats subjected to CCI

Dexmedetomidine, a selective alpha 2-adrenoceptor (α2AR) agonist, has provided significant analgesia in neuropathic pain. However, its underlying molecular mechanism has not been fully elucidated. In the present study, we found that intrathecal administration of dexmedetomidine alleviated mechanical allodynia induced by chronic constriction injury (CCI), and pretreatment with BRL44408 significantly reversed the dexmedetomidine-induced anti-nociceptive effect. Western blotting revealed that dexmedetomidine reduced the activation of microglia and the upregulation of interleukin-18 (IL-18) protein expression in the ipsilateral lumbar spinal dorsal horn, while BRL44408 pretreatment significantly blocked these effects of dexmedetomidine. Immunocytochemistry/immunohistochemistry indicated that the α2A-adrenoceptor was localised to microglia in primary culture, and IL-18 predominantly colocalised with the microglial marker Iba-1 in the dorsal horn of the spinal cord. These results suggest that the IL-18 signalling pathway in microglia may be involved in the anti-nociceptive effect of dexmedetomidine in rats subjected to CCI.

Simvastatin attenuates the additive effects of TNF-α and IL-18 on the connexin 43 up-regulation and over-proliferation of cultured aortic smooth muscle cells

Statin therapy is known to down-regulate inflammatory activities in atheromatous tissues of animals. The aims of this study were to examine the regulatory role of interleukin-18 (IL-18) in the connexin 43 (Cx43) and the proliferation of cultured aortic smooth muscle cells (SMCs) as well as to elucidate the underlying therapeutic mechanism of simvastatin. Vytorin therapy significantly alleviated high-cholesterol diet-induced hypercholesterolemia, suppressed neointimal hyperplasia, macrophage infiltration, and Cx43 and IL-18 expression in rabbit aortic walls. In vitro study using an aortic SMC line showed that IL-18 up-regulated constitutive Cx43 expression and potentiated tumor necrosis factor-α (TNF-α)-triggered Akt and MAPK signaling pathways. Simvastatin treatment alone reduced constitutive Cx43 levels and prevented the TNF-α-induced IL-18 up-regulation. Mechanistic investigation using kinase-specific inhibitors showed that simvastatin pretreatment attenuated TNF-α-elicited Akt and ERK1/2 phosphorylation, whereas PI3K and all MAPK activities were also implied in the additive effect of TNF-α and IL-18 on Cx43 up-regulation. Proliferation assay indicated that IL-18 stimulated SMC proliferation and synergized the TNF-α-stimulated cell proliferation. Likewise, simvastatin treatment suppressed the SMC over-proliferation induced not only by TNF-α alone, but also by simultaneous treatment with TNF-α and IL-18. The suppression of simvastatin in SMC proliferation was not mediated through mitochondrial related pro-apoptogenesis under both scenarios. In conclusion, simvastatin attenuates the additive effects of TNF-α and IL-18 on Cx43 up-regulation and over-proliferation of aortic SMCs, mainly through the blockade of Akt signaling pathway. These findings may fortify the rationale underlying the atheroprotective mechanism of statin therapy.

Increased expression of interleukin-18 in the trigeminal spinal subnucleus caudalis after inferior alveolar nerve injury in the rat

Interleukin-18 (IL-18) is an important regulator of innate and immune responses, and is known to be expressed in various types of cells and upregulated in pathological conditions including tissue injury and inflammation, suggesting it has both proinflammatory and compensatory roles. Here we show that IL-18 was increased in microglia in the trigeminal spinal subnucleus caudalis (Vc) after peripheral nerve injury. We used a trigeminal neuropathic pain model in which the withdrawal threshold of maxillary whisker pad skin was significantly decreased after inferior alveolar nerve transection, and observed a striking increase in IL-18 expression in the Vc around the obex area from 3d and continued until 14d after nerve injury. The IL-18 labeled cells were largely colocalized with Iba1, suggesting this upregulation occurred in hyperactive microglia. We also found that the IL-18 induction coexisted with phosphorylated p38 MAPK, indicating a possible role of p38 in the regulation of IL-18. Our findings are the first report that injury of trigeminal nerve induced IL-18 upregulation in activated microglia in the Vc, suggesting a possible role of IL-18 in orofacial neuropathic pain.

Interleukin-18 upregulation is associated with the use of steroids in patients with ulcerative colitis

Interleukin-18 upregulation is associated with the use of steroids in patients with ulcerative colitis

Interleukin-18-Related Genes Are Induced during the Contraction Phase but Do Not Play Major Roles in Regulating the Dynamics or Function of the T-Cell Response toListeria monocytogenesInfection

Proinflammatory cytokines, such as gamma interferon (IFN-gamma), impact aspects of T-cell responses after infection, including expansion, contraction, and memory formation. Interleukin-18 (IL-18) functions as a proinflammatory cytokine by stimulating the production of IFN-gamma from multiple cell types and accentuating the development of Th1 CD4 T-cell responses. Focused microarray analyses revealed upregulation of IL-18 and IL-18 receptor genes in CD8 T cells during the contraction phase. Based on these findings we investigated if and how signaling through the IL-18 receptor influences the development and kinetics of antigen (Ag)-specific CD8 and CD4 T-cell responses following infection. IL-18Ralpha(-/-) and IL-18(-/-) mice developed frequencies and total numbers of Ag-specific CD8 T cells after Listeria monocytogenes infection that were similar to those of wild-type C57BL/6 mice. The kinetics of expansion, contraction, and memory CD8 T-cell maintenance were also similar. When IL-18Ralpha deficiency was isolated to Ag-specific CD8 T cells, the kinetics of the expansion and contraction phases were also normal. These basic findings were confirmed by examining the response to vaccinia virus infection. In contrast, the expansion of Ag-specific CD4 T cells was slightly curtailed by the absence of IL-18Ralpha; however, contraction and the maintenance of memory were not altered. Importantly, both memory Ag-specific CD8 and CD4 T cells generated in the absence of IL-18Ralpha expanded appropriately after secondary antigen exposure and were protective, indicating that signaling through the IL-18 receptor is not required for normal T-cell response kinetics and survival of immunized mice challenged with a lethal L. monocytogenes infection.

A Stress-Induced, Superoxide-Mediated Caspase-1 Activation Pathway Causes Plasma IL-18 Upregulation

Psychological/physical stresses are known to cause relapses of autoimmune and inflammatory diseases. To reveal a mechanism by which noninflammatory stresses affect host defenses, responses to immobilization stress in mice were investigated, focusing on the role of a multifunctional cytokine, interleukin-18 (IL-18). In the adrenal cortex, the stress induced IL-18 precursor proteins (pro-IL-18) via adrenocorticotropic hormone (ACTH) and a superoxide-mediated caspase-1 activation pathway, resulting in conversion of pro-IL-18 to the mature form, which was released into plasma. Inhibitors of caspase-1, reactive oxygen species, and P38 mitogen-activated protein kinase (MAPK) suppressed stress-induced accumulation of plasma IL-18. These inhibitors also blocked stress-induced IL-6 expression. This, together with the observation that IL-6 was not induced in IL-18-deficient mice, showed that IL-6 induction by stress is dependent on IL-18. In stressed organisms, IL-18 may influence pathological and physiological processes. Controlling the caspase-1 activating pathway to suppress IL-18 levels may provide preventative means against stress-related disruption of host defenses.

Macrophage-derived interleukin-18 in experimental renal allograft rejection

Interleukin 18 (IL-18) is primarily a macrophage-derived, pro-inflammatory cytokine. As macrophages can act as effector cells in acute rejection, we examined the role of IL-18 in a rat model of acute renal allograft rejection. Life-sustaining orthotopic DA to Lewis allograft and Lewis-Lewis isograft kidney transplants were performed. In the same model, macrophage-depleted animals, achieved with liposomal-clodronate therapy, were also studied. Macrophage (ED1+) accumulation and IL-18 expression was assessed by immunohistochemistry. CD11b+ cells (macrophages) were isolated from kidney and spleen by micro beads. Real-time PCR was used to assess IL-18 and INF-gamma mRNA expression in tissue and cell isolates. Allografts, but not isografts, developed severe tubulo-interstitial damage and increased serum creatinine by day 5 (P<0.001). Immunohistochemistry revealed a greater ED1+ cell accumulation in day 5 allografts compared with isografts (P<0.001). IL-18 mRNA expression was increased 3-fold in allografts compared to isografts (P<0.001). Accordingly, IL-18 protein was increased in allografts (P<0.001), and was predominantly expressed by ED1+ macrophages. CD11b+ macrophages isolated from allografts had a 6-fold upregulation of IL-18 mRNA expression compared to isograft macrophages (P<0.001). Macrophage depletion resulted in a marked attenuation of allograft rejection, ED1+ and IL-18+ cells were significantly reduced (P<0.05) as was IL-18 mRNA expression (29.28+/-2.85 vs 62.48+/-3.05, P<0.001). INF-gamma mRNA expression (P<0.01) and iNOS (P<0.001) production were also significantly reduced in the macrophage-depleted animals. This study demonstrates that IL-18 is significantly increased during acute rejection and is principally produced by intra-graft macrophages. We hypothesize that IL-18 upregulation may be an important macrophage effector mechanism during the acute rejection process.

Upregulation of interleukin-18 expression in mouse primary keratinocytes induced to differentiate by calcium.

Interleukin-18 (IL-18) is an immunomodulatory cytokine that stimulates interferon-gamma production by T helper cells. Recently, basal keratinocytes have been shown to constitutively express IL-18, and IL-18 expression increases in the suprabasal keratinocytes in psoriatic lesions. In the study reported here we showed that in mouse epidermis, IL-18 immunoreactivity was markedly increased in the granular and cornified layers. To further investigate whether differentiated keratinocytes synthesize more IL-18, we examined the expression of mouse IL-18 in primary mouse keratinocytes induced to differentiate by calcium, an in vitro cell culture system mimicking keratinocyte differentiation in the epidermis. We demonstrated that IL-18 mRNA and protein in cultured keratinocytes were increased by calcium treatment in a time- and dose-dependent manner. The upregulation of IL-18 was associated with an increase in keratinocyte differentiation markers, and was dependent on the synthesis of new RNAs and proteins. However, the IL-18 protein in the cytoplasm was predominantly in the precursor form, and no increase in IL-18 activity was detected in the culture medium treated with calcium. Furthermore, blocking the calcium-induced keratinocyte differentiation with protein kinase C inhibitor inhibited the upregulation of IL-18 expression. These findings suggest that IL-18 is synthesized in keratinocytes mainly in the inactive precursor form, and its expression is upregulated as basal keratinocytes differentiate in the epidermis.