Production of functional IL-18 by different subtypes of murine and human dendritic cells (DC): DC-derived IL-18 enhances IL-12-dependent Th1 development

Abstract

IL-18 is a recently described cytokine that shares biological activities with IL-12 in driving the development of Th1-type T cells. As dendritic cells (DC) are very potent inducers of T cell proliferation and differentiation we wondered whether they utilize IL-18 as a factor driving Th1 development. We demonstrate by Northern blot and reverse transcription-PCR that various subtypes of human and murine DC as well as the DC-line XS contain IL-18 mRNA. When supernatants of either enriched Langerhans cells (LC) or bone marrow-derived DC were analyzed for production of IL-18 protein, IL-18 production was detected in an IL-18-specific ELISA. To assess whether the IL-18 protein released by DC is functional, we performed a sensitive bioassay using the IL-18-dependent stimulation of concanavalin A-stimulated T cells. Both, supernatants from bone marrow-derived DC and enriched LC induced IFN-+ production in the T cells. This production was partially inhibitable by addition of anti-IL-18 antiserum. In a TCR-transgenic mouse system we further demonstrate that DC-derived IL-18 potentiates IL-12-dependent Th1 development. Using DC derived from IL-12 knockout animals, we show that DC-derived IL-18 by itself is not capable of inducing Th1 cell differentiation. Together the data demonstrate that subtypes of DC are able to release functional IL-18 that is able to induce IFN-+ production and Th1 differentiation in primed T cells.

IL-18 induces the differentiation of Th1 or Th2 cells depending upon cytokine milieu and genetic background

“…These results therefore provide a novel mechanism for the induction of Th2 cell development and suggest that the term IGIF underestimates the true functional role of IL-18. Our findings also imply that IL-18, innately produced by cells of the monocyte and dendritic [30] cell lineages coincident with initial antigen stimulation, could play an influential role at an early stage of commitment by naive CD4 + T cells to the Th1 or Th2 pathway. Our results could also explain at a single-cell level the recent observation that IL-18 inhibits diabetes development in non-obese diabetic mice by counter-regulation of Th1-dependent destructive insulitis [31].…”

Localization of interleukin-18 and its receptor in somatotrophs of the bovine anterior pituitary gland

“…IL-18, similar to IL-1β with which it shares structural homology, is produced as a 24 kDa inactive precursor lacking a signal peptide and is cleaved by endoprotease IL-1β-converting enzyme (ICE; caspase-1) to generate a biologically active, mature 18 kDa moiety (Gu et al 1997). Later, the cytokine was described as being produced not only by immune cells but also by non-immune cells such as dendritic cells (Stoll et al 1998), keratinocytes (Stoll et al 1997), osteoblasts (Udagawa et al 1997), adrenal cortex cells (Conti et al 1997), intestinal epithelial cells (Pizarro et al 1999), microglial cells (Prinz and Hanisch 1999), habenula and ependymal cells, synovial cells (Gracie et al 2003) and hypothalamus. Besides the stimulation of IFN-γ release from T helper type 1 (Th1) cells, IL-18 has the ability to directly stimulate the gene expression and synthesis of tumor necrosis factor alpha (TNF-α) from CD3 + / CD4 + and NK cells with subsequent production of IL-1β and IL-8 from the CD14 + cells (Puren et al 1998).…”

Altered dendritic cell function in response to sera of common variable immunodeficiency patients

“…IL-18 is a recently described cytokine that shares biological activities with IL-12 in driving the development of T helper1-type T cells. It has been demonstrated that DCs are capable of secreting functional IL-18 that is able differentiate Th0 cells into Th1 [35]. Both IL-12 and IL-18 are being produced by macrophages and DCs in response to microbial stimulation and act in a synergistic manner on T cells, polarizing them into Th1.…”