Type I interferons in combination with bacterial stimuli induce apoptosis of monocyte-derived dendritic cells

Abstract

For instance, interferon ␣ (IFN-␣), which is transiently released during the first wave of innate immunity in response to bacteria and viruses, 2-10 has been reported to suppress interleukin-12 (IL-12) production of monocytes and DCs. [11][12][13][14] The superfamily of type I IFNs comprises at least 12 IFN-␣ species and a single IFN-␤ that differentially bind to a common receptor. 15 Alpha IFNs are produced in modest amounts by monocytes, macrophages, and B lymphocytes 9 and in much larger quantities by the precursors of lymphoid DCs (pDC2), 9,16,17 whereas IFN-␤ is mainly produced by fibroblasts. 18 Despite their established protective role in innate immunity because of their antibacterial and antiviral activity, 2,10,[19][20][21] there is increasing evidence that type I IFNs might also act negatively on immunity not only by abrogating IL-12 production but also by impairing DC differentiation 22 and reducing the phagocytic and oxidative activity of monocytes. 23 Other studies showed that lipopolysaccharide (LPS) has suppressive effects on monocytes and monocyte-derived DCs, 4,10 possibly in part mediated by LPS-triggered type I IFN production. A transient presence of endotoxin during the differentiation of monocyte-derived DCs abrogates IL-12 production of the resulting immature DCs on a second stimulation with LPS. 24 If permanently present during DC differentiation, it completely desensitizes the cells to all further LPS-mediated maturation signals. 25 Monocytes from septic patients were found to be hyporesponsive to LPS stimulation ex vivo, and this hyporesponsiveness was reversed during IFN-␥ treatment that also lead to clearance of sepsis, 26 suggesting that monocyte deactivation might be a major mechanism of immunosuppression. Despite these data it is unclear how DCs respond to a combination of type I IFNs and bacterial products. With the use of the culture of monocyte-derived DCs, our study revealed a strong synergistic effect between type I IFNs and products from gramnegative as well as gram-positive bacteria for the induction of apoptosis. This effect occurs if both stimuli are present together during the whole culture but also when the bacterial stimulus is added later to immature DCs generated in the presence of type I IFNs. Materials and methods Monocyte isolation and DC cultureHuman mononuclear cells were obtained from blood containing citrate as anticoagulant from healthy donors by density gradient centrifugation using

Loss of Type I IFN Receptors and Impaired IFN Responsiveness During Terminal Maturation of Monocyte-Derived Human Dendritic Cells

“…The pro-apoptotic activity of type I IFNs on DCs has been independently described by different groups (7,8,13) that observed a reduced cell recovery after DC culture in the presence of type I IFNs. In addition, it has been recently reported that type I IFNs in combination with LPS induce apoptosis of monocytederived DCs (30). Consistent with these reports we reproducibly observed a reduced number of viable cells in DC cultures after 24 h of LPS stimulation with respect to control iDCs.…”

Induction of CD83+CD14+ Nondendritic Antigen-Presenting Cells by Exposure of Monocytes to IFN-α

“…Several papers have demonstrated that type I IFNs, when added together with other cytokines, influence the DC compartment both in vitro (21,(23)(24)(25)(26)(27)(28)(29)37) and in vivo (37,38). Herein, we extended these observations by showing that in the absence of other cytokines, IFN-␣ per se prompts immunophenotypical and functional monocyte differentiation into nondendritic mature APCs.…”

“…Used in combination with classic cytokines such as GM-CSF ϩ IL-4 (21-24) or GM-CSF alone (25)(26)(27), type I IFNs influence DC generation and maturation. Numerous papers show a promoting effect of type I IFNs on DC generation (21,(23)(24)(25)(26)(27), but an inhibitory effect has also been reported (22,28,29). Even though blood and tissue resident cells can be exposed to high levels of type I IFNs during IFN-␣ therapy (14,30,31) or viral infections (11,32,33), to our knowledge the effects of type I IFNs on monocytes have never been studied in the absence of other cytokines.…”

Phagosomal signaling byBorrelia burgdorferiin human monocytes involves Toll-like receptor (TLR) 2 and TLR8 cooperativity and TLR8-mediated induction of IFN-β

“…Given that type I IFNs can shape a variety of downstream inflammatory responses through positive and/or negative regulation of the expression of hundreds of additional genes involved in secondary host defenses, TLR8 activation is likely to play a critical role in clearance of the spirochete and, most importantly, disease control. Type I IFNs also can promote inflammatory cell death of host cells (50,64), a phenomenon that we previously described in Bb-infected monocytes (4), and thus may constitute an additional mechanism for controlling spirochetal replication. Whether or not the presence of tlr8 SNPs in patients with LD affects spirochetal clearance and/or dissemination, and whether these SNPs are linked to disease progression and/or the severity of the initial clinical presentation, needs to be studied.…”