Anti‑inflammatory effects of leaf and branch extracts of honeyberry (Lonicera caerulea) on lipopolysaccharide‑stimulated RAW264.7 cells through ATF3 and Nrf2/HO‑1 activation.

Honeyberry (Lonicera caerulea) has long been used as a traditional medicine in China, Japan and northern Russia. Functional studies of honeyberry have mainly focused on the fruits, which have been reported to exert various pharmacological activities, including anti‑inflammatory activity, with limited or no studies on the other parts of the plant, such as the leaves and branches. In the present study, the anti‑inflammatory effects of extracts of the leaves (HBL), branches (HBB) and fruit (HBF) of honeyberry plant were evaluated in lipopolysaccharide (LPS)‑stimulated RAW264.7 cells. HBL and HBB significantly inhibited the production of pro-inflammatory mediators in LPS‑stimulated RAW264.7 cells, and the inhibitory effects of HBL and HBB were stronger than those of HBF. HBL and HBB blocked the nuclear accumulation of p65 independently of IκB‑α. HBL did not inhibit the phosphorylation of ERK1/2 or p38; however, HBB effectively inhibited the phosphorylation of p38 but not ERK1/2. HBL and HBB increased the expression of heme oxygenase‑1 (HO‑1) protein by inducing the nuclear accumulation of nuclear factor erythroid 2‑related factor 2 (Nrf2) through the activation of the reactive oxygen species (ROS)/p38 pathway; the reduction in inducible nitric oxide synthase (iNOS) and interleukin‑1β (IL‑1β) expression by HBL and HBB was inhibited by HO‑1 knockdown. In addition, HBL and HBB increased the expression of activating transcription factor‑3 (ATF3), and the reduction in iNOS and IL‑1β expression by HBL and HBB was inhibited by ATF3 knockdown. Collectively, HBL and HBB inhibited LPS‑induced nuclear factor‑κB activation by blocking the nuclear accumulation of p65, increasing HO‑1 expression through activation of the ROS/p38/Nrf2 pathway, and increasing ATF3 expression. Furthermore, HBB inhibited LPS‑induced p38 phosphorylation. These findings suggest that HBL and HBB may have great potential as natural products for the development of anti‑inflammatory drugs.