An Fc Gamma Receptor-Mediated Upregulation of the Production of Interleukin 10 by Intravenous Immunoglobulin in Bone-Marrow-Derived Mouse Dendritic Cells Stimulated with LipopolysaccharideIn Vitro

Abstract

Intravenous immunoglobulin (IVIG), a highly purified immunoglobulin fraction prepared from pooled plasma of several thousand donors, increased anti-inflammatory cytokine IL-10 production, while decreased proinflammatory cytokine IL-12p70 production in bone-marrow-derived mouse dendritic cells (BMDCs) stimulated with lipopolysaccharide (LPS). The changes of cytokine production were confirmed with the transcription levels of these cytokines. To study the mechanisms of this bidirectional effect, we investigated changes of intracellular molecules in the LPS-induced signaling pathway and observed that IVIG upregulated ERK1/2 phosphorylation while downregulated p38 MAPK phosphorylation. Using chemical inhibitors specific to protein kinases involved in activation of Fc gamma receptors (FcγRs), which mediate IgG signals, we found that hyperphosphorylation of ERK1/2 and Syk phosphorylation occurred after stimulation of BMDC with LPS and IVIG, and the increasing effect on IL-10 production was abolished by these inhibitors. Furthermore, an antibody specific to FcγRI, one of FcγRs involved in immune activation, inhibited IVIG-induced increases in IL-10 production, but not IL-12p70 decreases, whereas the anti-IL-10 antibody restored the decrease in IL-12p70 induced by IVIG. These findings suggest that IVIG induced the upregulation of IL-10 production through FcγRI activation, and IL-10 was indispensable to the suppressing effect of IVIG on the production of IL-12p70 in LPS-stimulated BMDC.

Pediatric tolerogenic DCs expressing CD4 and immunoglobulin‐like transcript receptor (ILT)‐4 secrete IL‐10 in response to Fc and adenosine

“…6). It has been reported previously that IVIG triggers the production of IL-10 in bone-marrow derived macrophages by binding to FcγRI and stimulating ERK1/2 phosphorylation [27]. Adenosine production in inflamed tissues results in A 2A R activation and cyclic AMP production [15].…”

Therapeutic normal IgG intravenous immunoglobulin activates Wnt-β-catenin pathway in dendritic cells

“…DCs play a crucial role as professional antigen presenting cells in balancing the immune response and tolerance. Investigations on the mode of action of IVIG have revealed that it inhibits the activation of both human and murine DCs and the production of inflammatory cytokines 19,23,27 The ability of IVIG to suppress DC activation also had impact on the DC-mediated T cell responses and the pathogenesis of autoimmune diseases 19,20,55,61,62 . The signaling pathway(s) that are implicated in the regulation of DC functions by IVIG is not well understood.…”

“…It is interesting to note that IVIG has been reported to suppress the inflammatory cytokines in DCs and reciprocally regulate Tregs and effector Th1/Th17 responses in vitro, in vivo in EAE model, and in treated autoimmune patients [19][20][21][22][23][24][25][26][27][28][29][30][31][32][33] . In view of reports on the central role of β-catenin/Wnt pathway in mediating these anti-inflammatory effects, we hypothesized that IVIG induces the activation of β-catenin/Wnt pathway to exert antiinflammatory effects.…”

On the modelling and analysis of the regulatory network of dengue virus pathogenesis and clearance

“…IFNα/β can also lead to induction of SOCS [67]. DENV by its ADE (Antibody dependent enhancement) mechanism through FcR signalling [16,73,19] up regulates IL-10 production [32,17].…”

“…A new hypothesis termed as intrinsic ADE, suggests that DENV internalization via FcγR results in the induction of interleukin- 55 10 (IL-10) production, biased T-helper-1 (Th)1 to Th2 response and suppression of innate immunity, which leads to both high levels of antibodies (Abs) and viral load in dengue patients [94,39]. Fujii et al in a recent study, suggested the up-regulation of IL-10 levels via FcγR [32]. As a consequence of ADE, complementary mechanism to higher viremia may be explained as FcγR mediated DENV entry due to suppressed antiviral immune response.…”