In addition to stimulating IFN-γ synthesis, IL-18 also possesses inflammatory effects by inducing synthesis of the proinflammatory cytokines TNF and IL-1β and the chemokines IL-8 and macrophage inflammatory protein-1α. We hypothesized that neutralization of IL-18 would have a beneficial effect in lethal endotoxemia in mice. IL-1β converting enzyme (ICE)-deficient mice, lacking the ability to process mature IL-18 and IL-1β, were completely resistant to lethal endotoxemia induced by LPS derived from either Escherichia coli or Salmonella typhimurium. In contrast, both wild-type and IL-1β−/− mice were equally susceptible to the lethal effects of LPS, implicating that absence of mature IL-18 or IFN-γ but not IL-1β in ICE−/− mice is responsible for this resistance. However, IFN-γ-deficient mice were not resistant to S. typhimurium LPS, suggesting an IFN-γ-independent role for IL-18. Anti-IL-18 Abs protected mice against a lethal injection of either LPS. Anti-IL-18 treatment also reduced neutrophil accumulation in liver and lungs. The increased survival was accompanied by decreased levels of IFN-γ and macrophage inflammatory protein-2 in anti-IL-18-treated animals challenged with E. coli LPS, whereas IFN-γ and TNF concentrations were decreased in treated mice challenged with S. typhimurium. In conclusion, neutralization of IL-18 during lethal endotoxemia protects mice against lethal effects of LPS. This protection is partly mediated through inhibition of IFN-γ production, but mechanisms involving decreased neutrophil-mediated tissue damage due to the reduction of either chemokines (E. coli LPS) or TNF (S. typhimurium LPS) synthesis by anti-IL-18 treatment may also be involved.
Screening for variants in TPMT did not reduce the proportions of patients with hematologic ADRs during thiopurine treatment for IBD. However, there was a 10-fold reduction in hematologic ADRs among variant carriers who were identified and received a dose reduction, compared with variant carriers who did not, without differences in treatment efficacy. ClinicalTrials.gov number: NCT00521950.
SUMMARYInduction of expression of adhesion molecules is a crucial step in in¯ammation. The role of interleukin-18 (IL-18) in induction of various adhesion molecules was investigated in freshly isolated peripheral blood mononuclear cells and human monocyte and T-cell lines. IL-18 selectively up-regulated intercellular adhesion molecule-1 (ICAM-1) expression on freshly isolated human monocytes, but not on lymphocytes. The expression of other adhesion molecules was not in¯uenced. Induction of ICAM-1 by IL-18 was dependent on endogenous tumour necrosis factor-a (TNF-a), and IL-12 had an additive effect on that of IL-18. No changes in adhesion molecule expression were observed on the monocytic cell line THP-1 and on the T-cell lines HSB-2 and Jurkat J16. In addition, induction of ICAM-1 on monocytes by lipopolysaccharide was slightly, but signi®cantly, inhibited by blockade of either endogenous IL-18 or TNF-a with IL-18 binding protein or TNF binding protein, respectively. Blocking IL-1 effects with IL-1 receptor antagonist did not in¯uence ICAM-1 levels. In conclusion, IL-18 selectively up-regulates the expression of ICAM-1 on monocytes, and this contributes to the proin¯ammatory effects of this cytokine.
Despite the importance of interferon (IFN)-gamma, tumor necrosis factor (TNF), and interleukin (IL)-18 for host defense against candidiasis, the pathways leading to their stimulation by Candida albicans are unclear. In a whole-blood model, IL-18 neutralization by IL-18 binding protein decreased C. albicans-induced IFN-gamma synthesis by 72%. Similarly, neutralization of IL-12 or IL-1beta by either neutralizing antibodies or IL-1 receptor antagonist also reduced (by 65%) IFN-gamma production. Neutralization of TNF by TNF binding proteins resulted in only a 36% reduction of IFN-gamma synthesis. In contrast, production of TNF and IL-8 was largely unaffected by these cytokine inhibitors. Thus, C. albicans stimulates IFN-gamma production in an IL-18-, IL-12-, and IL-1beta-dependent manner, whereas production of TNF and IL-8 is independent of these cytokines. Blocking the biologic activities of IL-18, IL-12, and IL-1beta in patients (e.g., for treatment of autoimmune diseases) may result in increased susceptibility to C. albicans infection.
scite is a Brooklyn-based organization that helps researchers better discover and understand research articles through Smart Citations–citations that display the context of the citation and describe whether the article provides supporting or contrasting evidence. scite is used by students and researchers from around the world and is funded in part by the National Science Foundation and the National Institute on Drug Abuse of the National Institutes of Health.