Dehydroxymethylepoxyquinomicin, a novel nuclear factor-kappaB inhibitor, prevents inflammatory injury induced by interferon-gamma and histamine in NCTC 2544 keratinocytes.

Abstract

1. The novel nuclear factor (NF)-kappaB inhibitor dehydroxymethylepoxyquinomicin (DHMEQ) is a derivative of the antibiotic epoxyquinomicin C from Amycolatopsis sp. that has been found to inhibit tumour necrosis factor (TNF)-alpha-induced activation of NF-kappaB by suppressing nuclear translocation of NF-kappaB. The aim of the present study was to determine the effects of DHMEQ on interferon (IFN)-gamma- and histamine-activated NCTC 2544 keratinocytes. 2. Keratinocytes were stimulated or not with 200 U/mL IFN-gamma and 10(-4) mol/L histamine in the absence or presence of different concentrations of DHMEQ (1, 5 and 10 microg/mL) or hydrocortisone (10(-5) mol/L), which was used as a reference anti-inflammatory drug. After 48 h, each sample was tested for the presence of intercellular adhesion molecule (ICAM)-1 by western blot analysis, as well as for the release of monocyte chemoattractant protein (MCP)-1, RANTES and interleukin (IL)-8 using specific sandwich ELISAs. To verify the effect of DHMEQ on cell viability of non-stimulated NCTC 2544 keratinocytes, the 3-(4,5-dimethyl-2 thiazoyl)-2,5-diphenyl-2H-tetrazolium bromide (MTT) assay was used. 3. The results showed that 10 microg/mL DHMEQ potently inhibited ICAM-1 production (by 50%), as well as the release of MCP-1 (to 25% of control), RANTES (to 5% of control) and IL-8 (to 2% of control). The results of the MTT assay indicated that DHMEQ has no effect on cell viability. 4. In conclusion, DHMEQ inhibits the IFN-gamma- and histamine-induced activation of the keratinocyte cell line NCTC 2544. The anti-inflammatory effects of DHMEQ could be exploited by applying the drug topically alone or in combination with sub-toxic concentrations of anti-inflammatory drugs to producer a synergistic effect.

• Authors: Venera Cardile, Massimo Libra, Silvia Caggia, Giuseppina Frasca, Kazuo Umezawa, Franca Stivala, Maria Clorinda Mazzarino, Ylenia Bevelacqua, Marinella Coco, Grazia Malaponte
• Journal: Clinical and experimental pharmacology & physiology (Clin Exp Pharmacol Physiol) Vol. 37 Issue 7 Pg. 679-83 (Jul 2010) ISSN: 1440-1681 [Electronic] Australia
• PMID: 20337659 (Publication Type: Journal Article)

Chemical References

• Anti-Inflammatory Agents
• Anti-Inflammatory Agents, Non-Steroidal
• Benzamides
• CCL2 protein, human
• Chemokine CCL2
• Chemokine CCL5
• Cyclohexanones
• Interleukin-8
• NF-kappa B
• dehydroxymethylepoxyquinomicin
• Intercellular Adhesion Molecule-1
• Histamine
• Interferon-gamma
• Hydrocortisone

Topics

• Anti-Inflammatory Agents (pharmacology)
• Anti-Inflammatory Agents, Non-Steroidal (pharmacology)
• Benzamides (pharmacology)
• Cell Line
• Chemokine CCL2 (metabolism)
• Chemokine CCL5 (analysis)
• Cyclohexanones (pharmacology)
• Histamine (pharmacology)
• Humans
• Hydrocortisone (pharmacology)
• Inflammation (immunology, prevention & control)
• Intercellular Adhesion Molecule-1 (metabolism)
• Interferon-gamma (pharmacology)
• Interleukin-8 (analysis)
• Keratinocytes (drug effects, immunology)
• NF-kappa B (antagonists & inhibitors)