Gamma-irradiated resveratrol negatively regulates LPS-induced MAPK and NF-κB signaling through TLR4 in macrophages

• Gamma-irradiation induced the appearance of several new peaks of resveratrol.
• Gamma-irradiated resveratrol did not exert cytotoxicity to macrophages.
• Gamma-irradiated resveratrol inhibited the pro-inflammatory mediators.
• Gamma-irradiated resveratrol induced an inhibition of MAPKs and NF-κB.
• Gamma-irradiated resveratrol inhibited TLR4 signaling pathways.

Resveratrol was irradiated at various doses of 15, 30, 50, and 70 kGy for the development of physiological functionalities through modification of the structural properties. Gamma irradiation induced a decrease in the resveratrol peak, and the appearance of several new peaks by gamma irradiation was gradually increased up to 70 kGy. Gamma-irradiated resveratrol did not exert cytotoxicity to macrophages in dose ranges from 15 to 70 kGy; therefore, 70 kGy gamma-irradiated resveratrol was used as the maximum dose throughout subsequent experiments. Treatment of LPS-stimulated macrophages with 70 kGy gamma-irradiated resveratrol resulted in a dose-dependent decrease in iNOS-mediated NO, PGE2, and pro-inflammatory cytokine level, such as TNF-α, IL-6 and IL-1β. 70 kGy gamma-irradiated resveratrol significantly inhibited cyclooxygenase-2 levels, as well as the expression of cell surface molecules, such as CD80 and CD86, in LPS-induced macrophages. Furthermore, the inhibitory action of these pro-inflammatory mediators occurred through an inhibition of MAPKs (ERK1/2, p38 and JNK) and NF-κB signaling pathways based on a toll-like receptor 4 in macrophages, which may be closely mediated with the radiolysis products of resveratrol transformed by gamma-irradiation. From these findings, it seems likely that gamma irradiation can be an effective tool for a reduction of the toxicity and play a potent role in the treatment of inflammatory disease.