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Roxatidine suppresses inflammatory responses via inhibition of NF‐κB and p38 MAPK activation in LPS‐induced RAW 264.7 macrophages
Author(s) -
Cho EuJin,
An HyoJin,
Shin JiSun,
Choi HyeEun,
Ko Jane,
Cho YoungWuk,
Kim HyungMin,
Choi JungHye,
Lee KyungTae
Publication year - 2011
Publication title -
journal of cellular biochemistry
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.028
H-Index - 165
eISSN - 1097-4644
pISSN - 0730-2312
DOI - 10.1002/jcb.23294
Subject(s) - p38 mitogen activated protein kinases , mapk/erk pathway , kinase , nitric oxide synthase , chemistry , microbiology and biotechnology , vascular endothelial growth factor , iκbα , tumor necrosis factor alpha , protein kinase a , electrophoretic mobility shift assay , nitric oxide , nf κb , pharmacology , signal transduction , cancer research , biology , biochemistry , endocrinology , gene expression , organic chemistry , vegf receptors , gene
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. J. Cell. Biochem. 112: 3648–3659, 2011. © 2011 Wiley Periodicals, Inc.