Roxatidine suppresses inflammatory responses via inhibition of NF-κB and p38 MAPK activation in LPS-induced RAW 264.7 macrophages

Abstract

Roxatidine is a novel, specific, competitive H(2) -receptor antagonist that is used to treat gastric and duodenal ulcers, and which is known to suppress the growth of several tumors by reducing vascular endothelial growth factor (VEGF) expression. Nevertheless, it remains unclear whether roxatidine has anti-inflammatory effects. In this study, we the authors investigated the anti-inflammatory effect of roxatidine in lipopolysaccharide (LPS)-stimulated RAW 264.7 macrophage cells. It was found that roxatidine dose-dependently inhibited the productions of prostaglandin E(2) (PGE(2)), nitric oxide (NO), and histamine, and the protein and mRNA expressions of cyclooxygenase-2 (COX-2), inducible nitric oxide synthase (iNOS), and histidine decarboxylase (HDC). In addition, roxatidine reduced the productions and expressions of VEGF-1 and pro-inflammatory cytokines, including those of tumor necrosis factor-α (TNF-α), interleukin-1β (IL-1β), and interleukin-6 (IL-6). Electrophoretic mobility shift assays (EMSA) and reporter gene assays revealed that treatment with roxatidine attenuated the LPS-induced DNA-binding and transcriptional activity of nuclear factor kappa B (NF-κB). In addition, it was found that pretreatment with roxatidine significantly inhibited the nuclear translocations of the p65 and p50 subunits of NF-κB, and these inhibitions were not found to be associated with decreases in the phosphorylation or degradation of inhibitory kappa B-α (IκBα). Furthermore, roxatidine suppressed the phosphorylation of p38 MAP kinase, but not of IκB kinase-α/β (IKKα/β), c-Jun NH(2) -terminal kinase (JNK), or extracellular signal-regulated kinase (ERK). Taken together, these results indicate that the anti-inflammatory properties of roxatidine in LPS-treated RAW 264.7 macrophages are mediated by the inhibition of NF-κB transcriptional activity and the p38 MAP kinase pathway.

LPS-induced production of TNF-α and IL-6 in mast cells is dependent on p38 but independent of TTP

“…This was in line with results published about the substances imperatorin and roxatidine, which inhibit LPS-induced p38 but not Erk activity in RAW 264.7 macrophages. These substances were shown to downregulate TNF-α and IL-6 production in LPS-stimulated macrophages, implying dispensability for the Erk pathway in this respect [42, 43]. Interestingly, TACE-mediated processing of pre-TNF was demonstrated to be dependent on Erk signaling in LPS-stimulated macrophages [44], indicating cell type-specific regulation of TNF-α production.…”

The effect of anti-inflammatory properties of ferritin light chain on lipopolysaccharide-induced inflammatory response in murine macrophages

“…Both MAPKs and NF-κB activation are essential for the expression of various pro-inflammatory genes [26][27][28]. To investigate whether FTL inhibits the LPS-induced inflammatory response by suppressing the activation of MAPKs and NF-κB, western blot analysis was performed on LPS-stimulated RAW264.7 murine macrophages.…”

Analysis of Histamine Receptor Knockout Mice in Models of Inflammation

“…In these models, histamine deficiency accelerates neutrophil and macrophage accumulation into dermis and peritoneum, respectively, indicating an antiinflammatory effect of histamine, which can be attributed to the functional expression of H 2 R in these cells (Hasturk et al, 2006;Cho et al, 2011;Reher et al, 2012a). Neutrophils and mast cells also produce histamine upon proper stimulation [i.e., activation of Toll-like receptor 4 (TLR4) or TLR7], in a phosphatidylinositol 3-kinase-dependent manner (Smuda et al, 2011).…”