IL-1β Processing in Host Defense: Beyond the Inflammasomes

Stimulation and release of proinflammatory cytokines is an essential step for the activation of an effective innate host defense, and subsequently for the modulation of adaptive immune responses. Interleukin-1β (IL-1β) and IL-18 are important proinflammatory cytokines that on the one hand activate monocytes, macropages, and neutrophils, and on the other hand induce Th1 and Th17 adaptive cellular responses. They are secreted as inactive precursors, and the processing of pro-IL-1β and pro-IL-18 depends on cleavage by proteases. One of the most important of these enzymes is caspase-1, which in turn is activated by several protein platforms called the inflammasomes. Inflammasome activation differs in various cell types, and knock-out mice defective in either caspase-1 or inflammasome components have an increased susceptibility to several types of infections. However, in other infections and in models of sterile inflammation, caspase-1 seems to be less important, and alternative mechanisms such as neutrophil-derived serine proteases or proteases released from microbial pathogens can process and activate IL-1β. In conclusion, IL-1β/IL-18 processing during infection is a complex process in which the inflammasomes are only one of several activation mechanisms

Enhanced viral clearance in interleukin-18 gene-deficient mice after pulmonary infection with influenza A virus

T helper 1 driven immune responses facilitate host defence during viral infections. Because interleukin-18 (IL-18) mediates T helper 1 driven immune responses, and since mature IL-18 is up-regulated in human macrophages after influenza virus infection in vitro, it has been suggested that IL-18 plays an important role in the immune response to influenza. To determine the role of IL-18 in respiratory tract infection with influenza, IL-18 gene-deficient (IL-18(–/–)) and normal wildtype mice were intranasally inoculated with influenza A virus. Influenza resulted in an increase in constitutively expressed IL-18 in the lungs of wildtype mice. The clearance of influenza A was inhibited by IL-18, as indicated by reduced viral loads on day 8 and day 12 after infection in IL-18(–/–) mice. This enhanced viral clearance correlated with increased CD4(+) T-cell activation in the lungs as reflected by CD69 expression on the cell surface. Surprisingly, interferon-γ (IFN-γ) levels were similar in the lungs of IL-18(–/–) mice and wildtype mice. Intracellular IFN-γ staining revealed similar expression levels in lung-derived natural killer cells, CD4(+) and CD8(+) T cells, indicating that IFN-γ production is IL-18-independent during influenza virus infection. Tumour necrosis factor-α production by CD4(+) T cells was significantly lower in IL-18(–/–) mice than in wildtype mice. Our data indicate that endogenous IL-18 impairs viral clearance during influenza A infection

Cytokine responses and regulation of interferon-gamma release by human mononuclear cells to Aspergillus fumigatus and other filamentous fungi.

Contains fulltext : 48233.pdf (publisher's version ) (Closed access)There is substantial evidence that the production of proinflammatory cytokines is important in host resistance to invasive aspergillosis. Knowledge of the host response towards other filamentous fungi is scarce, as most studies have focused on Aspergillus fumigatus. In addition, interferon-gamma (IFNgamma) plays a crucial role in the control of invasive aspergillosis, but little is known about the regulation of IFNgamma after stimulation of mononuclear cells by A. fumigatus. Cytokine responses to four different Aspergillus spp., Scedosporium prolificans, and a Rhizopus oryzae strain were compared for their ability to induce the release of tumour necrosis factor-alpha (TNFalpha) and interleukin(IL)-6 by human monocytes. S. prolificans induced significantly more TNFalpha and IL-6 release compared to A. fumigatus, while the various Aspergillus spp. induce comparable levels of these cytokines. By using specific cytokine inhibitors we were able to show that endogenous IL-1, but not IL-18 and TNFalpha was required for IFNgamma and IL-10 release upon stimulation with A. fumigatus hyphae, whereas conidia induced IFNgamma stimulation is independent of these cytokines

Toll-like Receptor 2 Ligands on the Staphylococcal Cell Wall Downregulate Superantigen-induced T Cell Activation and Prevent Toxic Shock Syndrome

Staphylococcal superantigens are pyrogenic exotoxins that cause massive T cell activation leading to toxic shock syndrome and death. Despite the strong adaptive immune response induced by these toxins, infections by superantigen-producing staphylococci are very common clinical events. We hypothesized that this may be partly a result of staphylococcal strains having developed strategies that downregulate the T cell response to these toxins. Here we show that the human interleukin-2 response to staphylococcal superantigens is inhibited by the simultaneous presence of bacteria. Such a downregulatory effect is the result of peptidoglycan-embedded molecules binding to Toll-like receptor 2 and inducing interleukin-10 production and apoptosis of antigen-presenting cells. We corroborated these findings in vivo by showing substantial prevention of mortality after simultaneous administration of staphylococcal enterotoxin B with either heat-killed staphylococci or Staphylococcus aureus peptidoglycan in mouse models of superantigen-induced toxic shock syndrome