NF-κB, p38 MAPK, ERK1/2, mTOR, STAT3 and increased glycolysis regulate stability of paricalcitol/dexamethasone-generated tolerogenic dendritic cells in the inflammatory environment

Abstract

Tolerogenic dendritic cells (tDCs) may offer an intervention therapy in autoimmune diseases or transplantation. Stable immaturity and tolerogenic function of tDCs after encountering inflammatory environment are prerequisite for positive outcome of immunotherapy. However, the signaling pathways regulating their stable tolerogenic properties are largely unknown. In this study, we demonstrated that human monocyte-derived tDCs established by using paricalcitol (analogue of vitamin D2), dexamethasone and monophosphoryl lipid A exposed for 24h to LPS, cytokine cocktail, polyI:C or CD40L preserved reduced expression of co-stimulatory molecules, increased levels of inhibitory molecules ILT-3, PDL-1 and TIM-3, increased TLR-2, increased secretion of IL-10 and TGF-β, reduced IL-12 and TNF-α secretion and reduced T cell stimulatory capacity. tDCs further induced IL-10-producing T regulatory cells that suppressed the proliferation of responder T cells. In the inflammatory environment, tDCs maintained up-regulated indoleamine 2, 3 dioxygenase but abrogated IκB-α phosphorylation and reduced transcriptional activity of p65/RelA, RelB and c-Rel NF-κB subunits except p50. Mechanistically, p38 MAPK, ERK1/2, mTOR, STAT3 and mTOR-dependent glycolysis regulated expression of ILT-3, PDL-1 and CD86, secretion of IL-10 and T cell stimulatory capacity of tDCs in the inflammatory environment. Stability of tDCs in the inflammatory environment is thus regulated by multiple signaling pathways.

JAK/STAT Blockade Alters Synovial Bioenergetics, Mitochondrial Function, and Proinflammatory Mediators in Rheumatoid Arthritis

“…In addition to this potential mechanistic link, STAT‐3 has recently been demonstrated to be a direct transcriptional activator of HK2 . This direct effect of STAT‐3 activation on glycolysis through up‐regulation of HK2 has been described previously in cancer cells, including those of the breast, ovary, and bladder . Similarly, inhibition of STAT‐3 by small interfering RNA significantly decreases HK2 protein, glucose consumption, and lactate production in human hepatocellular carcinoma cells .…”

PRL-3 improves colorectal cancer cell proliferation and invasion through IL-8 mediated glycolysis metabolism

“…Besides, activation of several signal pathways was found to be involved in chronic inflammation such as NF-κB (32). Notably, recent studies revealed that activation of NF-κB increased glycolysis in the inflammatory environment (33). In the present study, we integrated the association between IL-8 and glycolysis.…”

Lipopolysaccharide‐primed heterotolerant dendritic cells suppress experimental autoimmune uveoretinitis by multiple mechanisms

“…Interestingly, there are considerable experimental data showing that pre‐treatment of DC with LPS generates cells that promote tolerance rather than immunity15, 26, 27, 28, 29, 30, 31, 32 although the mechanism of tolerance induction in DC is not fully understood. Lipopolysaccharide‐activated macrophages and DC become refractory to further stimulation with LPS,33 a phenomenon known as endotoxin tolerance (ET), which has been attributed to various factors including: (i) the blockade of intracellular signalling events and subsequent gene re‐programming; (ii) up‐regulation of anti‐inflammatory cytokines like interleukin‐10 (IL‐10) and transforming growth factor‐ β (TGF‐ β ); and (iii) down‐regulation of surface expression of the TLR4 receptor 34.…”