Nutritional control of IL-23/Th17-mediated autoimmune disease through HO-1/STAT3 activation

Abstract

The nutritional curcumin (CUR) is beneficial in cell-mediated autoimmune diseases. The molecular mechanisms underlying this food-mediated silencing of inflammatory immune responses are poorly understood. By investigating antigen-specific immune responses we found that dietary CUR impairs the differentiation of Th1/Th17 cells in vivo during encephalomyelitis and instead promoted Th2 cells. In contrast, feeding CUR had no inhibitory effect on ovalbumin-induced airway inflammation. Mechanistically, we found that CUR induces an anti-inflammatory phenotype in dendritic cells (DC) with enhanced STAT3 phosphorylation and suppressed expression of Il12b and Il23a. On the molecular level CUR readily induced NRF2-sensitive heme oxygenase 1 (HO-1) mRNA and protein in LPS-activated DC. HO-1 enhanced STAT3 phosphorylation, which enriched to Il12b and Il23a loci and negatively regulated their transcription. These findings demonstrate the underlying mechanism through which a nutritional can interfere with the immune response. CUR silences IL-23/Th17-mediated pathology by enhancing HO-1/STAT3 interaction in DC.

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“…Following the decreased DNA-binding activity of STAT3, also the expression of IL-1β and TNF-α were significantly downregulated after treatment with curcumin [ 63 ]. More recently, low concentrations (7.5 μM) of curcumin have been found to induce in vitro an anti-inflammatory profile in DCs enhancing the phosphorylation and the activity of STAT3, thus suggesting a biphasic effect of curcumin on STAT3 modulation depending on the range of curcumin concentrations [ 64 ]. This observation is quite intriguing and has been also observed when curcumin has been used together with opioids, the drugs of choice for the alleviation of acute and chronic pain and opioid tolerance.…”

A review of the mechanisms of action of dimethylfumarate in the treatment of psoriasis

“…The immunomodulatory effects of DMF in experimental settings of autoimmune inflammatory disorders such as multiple sclerosis (MS) are thought to be mediated through both Nrf2‐dependent and Nrf2‐independent pathways . Pharmacological activation of Nrf2 may be a major strategy against MS, other inflammatory diseases and against cancer . Nrf2 is also important to protect keratinocytes from oxidative damage and DMF is a potent inducer of HO‐1 in human keratinocytes cultured in vitro .…”

“…In DCs, DMF treatment stimulates apoptosis and DMF has also been shown to inhibit the activation of STAT1 and to impair IL‐12 production; its effect on STAT1 depends on the DCs’ intracellular GSH level . In addition, Nrf2‐dependent induction of HO‐1 enhances STAT3 activation in DC, a negative regulator of Il23a transcription . Additional studies to examine the antioxidant properties of DMF and its consequences on signalling pathways in more depth are desirable.…”

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“…In EAE induced by the MOG-peptide 35–55 in C57BL/6 mice, CD4+ Th17 cells are present both in the periphery and in the inflamed central nervous system [ 50 ] and amelioration of EAE by curcumin treatment was through inhibition of IL-17 production [ 39 ]. Further studies indicated that dietary curcumin inhibited the differentiation of pro-inflammatory Th1/Th17 cells in vivo during encephalomyelitis and instead promoted Th2 cells [ 51 ]. Curcumin appeared to silence IL-23/Th17-mediated pathology in EAE by enhancing HO-1/STAT3 interaction in dendritic cells (DCs) [ 51 ].…”

“…Further studies indicated that dietary curcumin inhibited the differentiation of pro-inflammatory Th1/Th17 cells in vivo during encephalomyelitis and instead promoted Th2 cells [ 51 ]. Curcumin appeared to silence IL-23/Th17-mediated pathology in EAE by enhancing HO-1/STAT3 interaction in dendritic cells (DCs) [ 51 ].…”