IL-1β induces dendritic cells to produce IL-12

Abstract

The cytokine IL-12, a product of dendritic cells (DC), plays a major role in cellular immunity, notably by inducing lymphocytes to produce IFN-gamma. Microbial products, T cell signals and cytokines induce the production of IL-12. Here, IL-1 beta is identified as a new IL-12-inducing agent, acting conjointly with CD40 ligand (CD40L) on human monocyte-derived DC in vitro. The effects of IL-1 beta were dose dependent, specifically blocked by neutralizing antibodies, and were observed both in immature and mature DC. Immature DC secreted more IL-12 than mature DC, but the effects of IL-1 beta were not due to a block of DC maturation as determined by analysis of DC surface markers. The mechanisms of action of IL-1 beta could be contrasted to that of other inducers of IL-12 such as IFN-gamma and lipopolysaccharide (LPS). Either IL-1 beta or IFN-gamma co-induced IL-12 with CD40L but conjointly, IL-1 beta, CD40L and IFN-gamma synergized, inducing very high levels of IL-12. The effects of IL-1 beta differed from those of LPS in that IL-1 beta, unlike LPS, could not induce IL-12 solely after IFN-gamma priming; and when combined with CD40L, IL-1 beta, unlike LPS, induced little IL-10. The mechanism of action of IL-1 beta involves IL-12 alpha mRNA up-regulation, and we show that the combination of CD40L and IL-1 beta induces high levels of IL-12 alpha and IL-12 beta mRNA in DC. Altogether, these results delineate a new mechanism linking adaptive and innate immune responses for the regulation of IL-12 production in DC and for the role of IL-1 beta in the development of cellular immunity.

IL-1β Enhances CD40 Ligand-Mediated Cytokine Secretion by Human Dendritic Cells (DC): A Mechanism for T Cell-Independent DC Activation

“…In that study, they demonstrate the role of IL-1␤ on enhancing CD40L-mediated IL-12p70 secretion (32). The present study also demonstrates that monocytes and MoDC were potent producers of IL-1␤ in response to intact E. coli, whereas CD34 ϩ -derived DC and PBDC were not.…”

GPL, a Novel Cytokine Receptor Related to GP130 and Leukemia Inhibitory Factor Receptor

“…Dendritic cells, which are powerful antigen-presenting cells for the immune response, were generated starting from either monocytes or CD34-positive bone marrow cells by growing them in the presence of the appropriate cytokines (26). After culture, RNAs were extracted, and the presence of GPL transcripts was searched by RT-PCR using PCR.…”

“…Reanalysis of the sorted populations indicated a purity Ͼ95%. Dendritic cell cultures were carried out as described previously in detail (25,26). Briefly, dendritic cells were generated from adherent monocytes and cultured with granulocyte/ macrophage-colony stimulating factor and IL-4 before activation with IFN-␥ (10 ng/ml), LPS (100 ng/ml), IL-1␤ (10 ng/ml), CD40 ligand (CD40L) (1 g/ml), or tumor necrosis factor (TNF)-␣ (25 ng/ml).…”

A novel RNA‐based adjuvant combines strong immunostimulatory capacities with a favorable safety profile

“…In addition to Type I IFN and Type I IFN-stimulated genes (ISGs) the adjuvant induced the upregulation of inflammasome-associated genes 36 such as IL-1b, which is described to be involved in lymphocyte activation and increased IL-12 secretion in dendritic cells. 37 Administration of RNAdjuvant V R led to potent transient induction of distinct chemokines and immune activation markers at the injection site including the "adjuvant core response genes" CCL2, CCL4, CCL5, CCL7 and CCL12. 38 In addition, a pronounced up-regulation of the CXCR3-ligands CXCL9, CXCL10 and CXCL11 was detected which functions include recruitment of CD4 1 Th1 cells, CD8…”