Sulfur Compounds Inhibit High Glucose-Induced Inflammation by Regulating NF-κB Signaling in Human Monocytes

Abstract

High glucose-induced inflammation leads to atherosclerosis, which is considered a major cause of death in type 1 and type 2 diabetic patients. Nuclear factor-kappa B (NF-κB) plays a central role in high glucose-induced inflammation and is activated through toll-like receptors (TLRs) as well as canonical and protein kinase C-dependent (PKC) pathways. Non-toxic sulfur (NTS) and methylsulfonylmethane (MSM) are two sulfur-containing natural compounds that can induce anti-inflammation. Using Western blotting, real-time polymerase chain reaction, and flow cytometry, we found that high glucose-induced inflammation occurs through activation of TLRs. An effect of NTS and MSM on canonical and PKC-dependent NF-κB pathways was also demonstrated by western blotting. The effects of proinflammatory cytokines were investigated using a chromatin immunoprecipitation assay and enzyme-linked immunosorbent assay. Our results showed inhibition of the glucose-induced expression of TLR2 and TLR4 by NTS and MSM. These sulfur compounds also inhibited NF-κB activity through reactive oxygen species (ROS)-mediated canonical and PKC-dependent pathways. Finally, NTS and MSM inhibited the high glucose-induced expression of interleukin (IL)-1β, IL-6, and tumor necrosis factor-α and binding of NF-κB protein to the DNA of proinflammatory cytokines. Together, these results suggest that NTS and MSM may be potential drug candidates for anti-inflammation therapy.

Natural Sulfurs Inhibit LPS-Induced Inflammatory Responses through NF-κB Signaling in CCD-986Sk Skin Fibroblasts

“…NTS is a form of non-toxic mineral sulfur. Studies have shown the ability of NTS to enhance growth hormone signaling via the JAK2/STAT5b/IGF-1 axis and to produce anti-inflammatory effects against hyperglycemia in human monocytes [22,35]. MSM is another sulfur-containing natural compound with…”

“…NTS is a form of non-toxic mineral sulfur. Studies have shown the ability of NTS to enhance growth hormone signaling via the JAK2/STAT5b/IGF-1 axis and to produce anti-inflammatory effects against hyperglycemia in human monocytes [ 22 , 35 ]. MSM is another sulfur-containing natural compound with various anti-inflammatory activities [ 38 ] and exercise-induced stress in racing horse muscle cells via p53-mediated SDHA/HPRT1 expression [ 39 ].…”

“…Study of MSM in an animal model also showed no toxicity, remaining healthy and vigorous to a concentration of 6–8 g/kg/day through oral administration [ 40 ]. In our previous studies on toxicity analysis of MSM in human monocytes, THP-1 cells suggested very low or negligible cytotoxicity in THP-1 cells by 200 mM MSM [ 22 ]. We also studied cytotoxic effects of MSM in bone marrow-derived macrophages isolated from mice, finding no toxicity up to 200 mM MSM [ 41 ].…”

“…The noncanonical NF-κB pathway activates in response to specific stimuli and TNF receptor superfamily ligands and activates p52/RelB NF-κB complex [ 21 ]. Protein kinase C-dependent α (PKC-α) takes part in cell growth and differentiation and plays a key role in inflammation by acting as a signaling mediator between TLRs and NF-κB [ 22 ]. In inflammation, PKC-α regulates IL-1β release through ERK1/2 and p38 MAPK phosphorylation, which then activates NF-κB signaling and production of inflammatory cytokines TNF-α and IL-6 [ 23 , 24 ].…”

“…Non-toxic sulfur (NTS) has been used in livestock feed to enhance immunity and meat quality, and studies have shown that oral administration of NTS in rats does not induce cell death [ 33 , 34 ]. NTS exhibits anti-inflammatory activity against human THP-1 cells [ 22 ] and enhances growth hormone signaling in mouse C2C12 cells [ 35 ].…”