Abstract
BackgroundBee venom therapy has been used to treat inflammatory diseases including rheumatoid arthritis in humans and in experimental animals. We previously found that bee venom and melittin (a major component of bee venom) have anti-inflammatory effect by reacting with the sulfhydryl group of p50 of nuclear factor-kappa B (NF-κB) and IκB kinases (IKKs). Since mitogen activated protein (MAP) kinase family is implicated in the NF-κB activation and inflammatory reaction, we further investigated whether activation of MAP kinase may be also involved in the anti-inflammatory effect of melittin and bee venom.MethodsThe anti-inflammatory effects of melittin and bee venom were investigated in cultured Raw 264.7 cells, THP-1 human monocytic cells and Synoviocytes. The activation of NF-κB was investigated by electrophoretic mobility shift assay. Nitric oxide (NO) and prostaglandin E2 (PGE2) were determined either by Enzyme Linked Immuno Sorbent Assay or by biochemical assay. Expression of IκB, p50, p65, inducible nitric oxide synthetase (iNOS), cyclooxygenase-2 (COX-2) as well as phosphorylation of MAP kinase family was determined by Western blot.ResultsMelittin (0.5–5 μg/ml) and bee venom (5 and 10 μg/ml) inhibited lipopolysaccharide (LPS, 1 μg/ml) and sodium nitroprusside (SNP, 200 μM)-induced activation of c-Jun NH2-terminal kinase (JNK) in RAW 264.7 cells in a dose dependent manner. However, JNK inhibitor, anthra [1,9-cd]pyrazole-6 (2H)-one (SP600215, 10–50 μM) dose dependently suppressed the inhibitory effects of melittin and bee venom on NF-κB dependent luciferase and DNA binding activity via suppression of the inhibitory effect of melittin and bee venom on the LPS and SNP-induced translocation of p65 and p50 into nucleus as well as cytosolic release of IκB. Moreover, JNK inhibitor suppressed the inhibitory effects of melittin and bee venom on iNOS and COX-2 expression, and on NO and PGE2 generation.ConclusionThese data show that melittin and bee venom prevent LPS and SNP-induced NO and PGE2 production via JNK pathway dependent inactivation of NF-κB, and suggest that inactivation of JNK pathways may also contribute to the anti-inflammatory and anti-arthritis effects of melittin and bee venom.
Highlights
Bee venom therapy has been used to treat inflammatory diseases including rheumatoid arthritis in humans and in experimental animals
We previously found that bee venom and its major component, melittin inhibited lipopolysaccharide (LPS), tumor necrosis factor-α (TNF-α), and sodium nitroprusside (SNP)-induced nuclear factorkappa B (NF-κB) activation by preventing p50 translocation through interaction of melittin and sulfhydryl residue of p50 and/or inhibitory κB (IκB) kinases (IKKα and IKKβ), and that these inhibit inflammatory reaction in the development of rheumatoid arthritis [4,5] through reduction of large amounts of nitric oxide (NO) and prostaglandins (PGs) which are synthesized systemically in animal models of arthritis and in patients with rheumatoid arthritis [6,7,8,9,10]
Melittin inhibited LPS and SNP-induced activation of Jun NH2-terminal kinase (JNK) in RAW 264.7 cells We previously found that bee venom and its major component, melittin inhibits LPS, TNF-α and SNP-induced inflammatory responses through inactivation of NF-κB and IKKs signals [4,5]
Summary
Bee venom therapy has been used to treat inflammatory diseases including rheumatoid arthritis in humans and in experimental animals. We previously found that bee venom and its major component, melittin inhibited lipopolysaccharide (LPS), tumor necrosis factor-α (TNF-α), and sodium nitroprusside (SNP)-induced NF-κB activation by preventing p50 translocation through interaction of melittin and sulfhydryl residue of p50 and/or IκB kinases (IKKα and IKKβ), and that these inhibit inflammatory reaction in the development of rheumatoid arthritis [4,5] through reduction of large amounts of nitric oxide (NO) and prostaglandins (PGs) which are synthesized systemically in animal models of arthritis and in patients with rheumatoid arthritis [6,7,8,9,10]. Potent inhibitors of IKKs preventing NF-κB activity through blockage of IκB release can be useful for the treatment of inflammatory diseases such as rheumatoid arthritis (RA) [15,16,17,18]
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