Increased and Long-Term Generation of Dendritic Cells with Reduced Function from IL-6-Deficient Bone Marrow

Abstract

The importance of IL-6 in dendritic cell (DC) development and function has not been well defined. To establish the role of IL-6, we studied bone marrow-derived DC (BMDC) and freshly isolated splenic DC from IL-6−/−-transgenic mice. We found that although IL-6−/− bone marrow had a similar composition to that of wild-type (WT) mice, it generated up to 10 times more DC when cultured in GM-CSF. The difference persisted even when IL-6−/− and WT bone marrow were cultured together, excluding the possibility that the effects were simply due to different cytokine microenvironments. In comparison to WT BMDC, IL-6−/− BMDC captured at least as much Ag, had an equivalent surface phenotype, and matured similarly in response to LPS or CpG. However, IL-6−/− BMDC induced less T cell allostimulation and Ag-specific T cell activation, but only the former was related to their inability to generate IL-6. Although WT bone marrow cultures died within 4 wk, IL-6−/− cultures continued to generate BMDC for >120 days, although the BMDC became immature and less functional. In vivo, we found that IL-6−/− mice had similar numbers and types of splenic DC as WT mice, both normally and after treatment with either Flt-3 ligand or GM-CSF. These findings demonstrate that IL-6 has profound effects on DC development in vitro, although the number and subtype composition of DC are unaffected by the absence of IL-6 in vivo. Furthermore, secretion of IL-6 is critical to certain DC functions.

Biliary Obstruction Selectively Expands and Activates Liver Myeloid Dendritic Cells

“…We found that LPS increased the alloproliferation in all groups (Fig. 5B), which was consistent with our previous findings showing that IL-6 increases the allostimulation of both bone marrow and freshly isolated splenic DCs (22). Notably, though, liver myeloid DCs from BDL-treated mice remained significantly more stimulatory.…”

Pregnancy Impairs the Innate Immune Resistance toSalmonella typhimuriumLeading to Rapid Fatal Infection

“…Neutrophils are the main source of early IFN-␥ production critical for activation of NK cells. Furthermore, IL-6 also has complex differential effects on differentiation and activation of dendritic cells and macrophages (49,50). Thus, the overt production of IL-6 may have lead to the deleterious consequence of lack of sufficient recruitment of inflammatory cell types in the systemic compartments of pregnant ST-infected hosts.…”

Ischemic Injury Enhances Dendritic Cell Immunogenicity via TLR4 and NF-κB Activation

“…2B-D, IL-1b production was also elevated in DCs at 12 h post-isc treatment (p = 0.014); at 24 h, IL-12(p40) and TNF-a were released at significantly higher levels by isc DCs as compared with ctrl DCs (p , 0.0006); it should also be noted that TNF-a production has been shown to be subject to negative feedback inhibition via PGE upregulation as well as posttranscriptional mRNA destabilization, which may account for the decrease in TNF-a levels observed at 24 h compared with 12 h (38-41). IL-6 production is known to be increased following activation of TLR4, thereby leading to an inflammatory response (19,(42)(43)(44). This increase in IL-6 may thus serve to enhance the immune response initiated by DCs following isc injury.…”