Interleukin-18 (IFNgamma-inducing factor) induces IL-8 and IL-1beta via TNFalpha production from non-CD14+ human blood mononuclear cells.

Abstract

IL-18 is synthesized as a precursor molecule without a signal peptide but requires the IL-1beta converting enzyme (ICE, caspase-1) for cleavage into a mature peptide. Human precursor IL-18 was expressed, purified, and cleaved by ICE into a 18-kD mature form. Mature IL-18 induced IL-8, macrophage inflammatory protein-1alpha, and monocyte chemotactic protein-1 in human peripheral blood mononuclear cells in the absence of any co-stimuli. Blocking IL-1 with IL-1 receptor antagonist resulted in a 50% reduction in IL-8. Neutralization of TNF with TNF binding protein resulted in a 66% reduction in IL-1beta, an 80% reduction of IL-8, and an 88% reduction in mean TNFalpha mRNA. In purified CD14+ cells but not CD3+/CD4+, IL-18 induced gene expression and synthesis of IL-8 and IL-1beta. TNFalpha production was induced in the non-CD14+ population and there was no induction of TNFbeta by IL-18. In purified natural killer cells, IL-18 induced IL-8 that was also inhibited by TNF binding protein. IL-18 did not induce antiinflammatory cytokines, IL-1Ra, or IL-10, although IL-18 induction of TNFalpha was inhibited by IL-10. In the presence of IFNgamma, IL-18-induced TNFalpha was enhanced and there was an increase in the mature form of IL-1beta. We conclude that IL-18 possesses proinflammatory properties by direct stimulation of gene expression and synthesis of TNFalpha from CD3+/CD4+ and natural killer cells with subsequent production of IL-1beta and IL-8 from the CD14+ population.

Role of interleukin‐18 in experimental group B streptococcal arthritis

“…It might directly act on synovial macrophages and articular chondrocytes. In fact, in vitro experiments have demonstrated that IL-18 induces the release of proinflammatory cytokines from macrophages and the release of matrix metalloproteinases and glycosaminoglycans by articular cartilage, supporting a possible direct contribution of IL-18 in joint destruction (17). But, by inducing MIP-2 production, IL-18 might enhance the local influx of polymorphonuclear cells, which, in turn, secrete MIP-1␣ with consequent recruitment of mononuclear cells.…”

“…Pro-IL-18 expression has been detected in antigen-presenting cells such as activated macrophages, Kupffer cells (11), and dendritic cells (14), as well as articular chondrocytes (15) and osteoblasts (16). IL-18 induces the production of proinflammatory cytokines such as TNF␣ and IL-1 (17). Furthermore, IL-18 stimulates the proliferation of activated T cells and inhibits the formation of osteoclast-like cells (16).…”

Expression of interleukin‐18 in human ovarian carcinoma and normal ovarian epithelium: Evidence for defective processing in tumor cells

“…30 In keeping with previous reports of IL-18 expression in epithelial layers that line the mucosal surface of the body, we report for the first time that normal ovarian epithelial cells express both IL-18 and ICE and have the potential to produce mature IL-18. Since this cytokine has been implicated in the upregulation of TNF-␣ and IFN-␥ expression in T and NK cells, 31 it is likely that IL-18 may contribute to the amplification of cytokine production during inflammatory or immune responses occurring in ovarian tissue. 876 IL-18 and ICE expression has also been reported in normal colon mucosal cells, where IL-18 may contribute to local immunity.…”

Adenoviral delivery of IL-18 binding protein C ameliorates Collagen-Induced Arthritis in mice

“…2,3 Production of this proinflammatory cytokine induces IFNg, TNFa and IL-1b secretion and enhances cytotoxic activity of NK cells. [4][5][6] A broad range of immuno-regulatory cells, including activated macrophages and dendritic cells but also stromal like cells such as keratinocytes, and osteoblasts, can produce IL-18. [7][8][9] Similar to IL-1, IL-18 is present in cells as a precursor protein, which has to be cleaved to an 18-kDa mature glycoprotein by IL-1b converting enzyme (ICE, caspase-1).…”