Avermectin exerts anti-inflammatory effect by downregulating the nuclear transcription factor kappa-B and mitogen-activated protein kinase activation pathway.
Lipopolysaccharide (LPS) can induce mouse macrophages to produce a number of cytokines and other inflammatory mediators. Immunopharmacological studies can provide new information on the immunomodulatory activities of some drugs, including their effect on cytokine productions. For this reason, we first investigated the efficacy of avermectin on cytokine levels induced by LPS in vitro, and we found that avermectin can significantly regulate tumor necrosis factor alpha, interleukin (IL)-1beta and IL-10, but has no significant effect on IL-6. We further investigated the effects of the drug on the major signal transduction pathways associated with inflammation: nuclear transcription factor kappa-B (NF-kappaB) and the mitogen-activated protein (MAP) kinases, extracellular signal regulated kinase, p38 and c-Jun N-terminal kinase (JNK). RAW 264.7 cells were pretreated with 0.625, 1.25 or 5 mg/L avermectin 1 h prior to treatment with 1 mg/L LPS. Thirty minutes later, cells were fixed, and NF-kappaB activation was measured by immunocytochemical analysis, or cells were collected and MAP-kinase activation was measured by western blot. Signal transduction studies showed that avermectin significantly inhibits NF-kappaB p65 translocation into the nucleus and inhibits JNK and p38 phosphorylation protein expression. Therefore, avermectin may inhibit LPS-induced production of inflammatory cytokines by blocking NF-kappaB and MAP-kinase in RAW 264.7 cells.
Ci
Xinxin
X
Department of Veterinary Pharmacology, College of Animal Science and Veterinary Medicine, Jilin University, Changchun, Jilin 130062, China.
Li
Hongyu
H
Yu
Qinlei
Q
Zhang
Xuemei
X
Yu
Lu
L
Chen
Na
N
Song
Yu
Y
Deng
Xuming
X
D000818:Animals; D000893:Anti-Inflammatory Agents / Q000008:administration & dosage / Q000494:pharmacology*; D002478:Cells, Cultured; D016207:Cytokines / Q000187:drug effects / Q000378:metabolism; D004305:Dose-Response Relationship, Drug; D015536:Down-Regulation / Q000187:drug effects; D018690:Excitatory Amino Acid Agonists / Q000008:administration & dosage / Q000494:pharmacology; D007249:Inflammation / Q000188:drug therapy* / Q000503:physiopathology; D007559:Ivermectin / Q000008:administration & dosage / Q000031:analogs & derivatives* / Q000494:pharmacology; D008070:Lipopolysaccharides; D008264:Macrophages / Q000187:drug effects / Q000378:metabolism; D051379:Mice; D020928:Mitogen-Activated Protein Kinases / Q000187:drug effects / Q000235:genetics; D016328:NF-kappa B / Q000187:drug effects* / Q000235:genetics; D015398:Signal Transduction / Q000187:drug effects
D000893:Anti-Inflammatory Agents; D016207:Cytokines; D018690:Excitatory Amino Acid Agonists; D008070:Lipopolysaccharides; D016328:NF-kappa B; D007559:Ivermectin; C019264:avermectin; D020928:Mitogen-Activated Protein Kinases