Syringin from Tinospora crispa downregulates pro-inflammatory mediator production through MyD88-dependent pathways in lipopolysaccharide (LPS)-induced U937 macrophages

Syringin, a phenylpropanoid glycoside, has exhibited numerous biological properties including inhibitory activities against various immune and inflammatory disorders. In this study, syringin isolated from Tinospora crispa was evaluated for its ability to down-regulate activated nuclear factor-kappa B (NF‐κB), phosphoinositide-3-kinase-Akt (PI3K‐Akt) and mitogen‐activated protein kinases (MAPKs) signal transducing networks in U937 macrophages activated by lipopolysaccharide.

The attenuating effects of syringin on the productions of prostaglandin E2 (PGE2), cyclooxygenase-2 (COX-2), interleukin-1β (IL-1β), and tumor necrosis factor-α (TNF-α), and the expressions of signaling molecules of the signaling pathways were investigated by using ELISA, Western blot, and qRT-PCR.

Syringin downregulated the NF-κB, MAPKs, and PI3K‐Akt signal networks by significantly reducing PGE₂ production in the macrophages via suppression of COX-2 gene and protein expression levels. It also reduced TNF-α and IL-1β secretion and their mRNA expression, suppressed phosphorylation of NF-κB (p65), IKKα/β, and IκBα, and restored ability of IκBα to degrade. Syringin dose-dependently attenuated Akt, p38 MAPKs, JNK, and ERK phosphorylation. Also, the expression of corresponding upstream signaling molecules toll-like receptor 4 (TLR4) and myeloid differentiation primary response gene 88 (MyD88) were down-regulated in response to syringin treatment.

The suppressive effect of syringin on the inflammatory signaling molecules in MyD88-dependent pathways suggested it’s potential as a drug candidate for development into an agent for treatment of various immune-mediated inflammatory disorders.