Revisited anti-inflammatory activity of matricine in vitro: Comparison with chamazulene

The proazulene matricine (1) is present in chamomile flower heads and has been proven to exhibit strong in vivo anti-inflammatory activity. In contrast to other secondary metabolites in chamomile preparations like its degradation product chamazulene (2), no plausible targets have been found to explain this activity. Therefore we revisited 1 regarding its in vitro anti-inflammatory activity in cellular and molecular studies. Using ICAM-1 as a marker for NF-kappa B activation, it was shown that ICAM-1 protein expression induced by TNF-alpha and LPS, but not by IFN-gamma, was remarkably inhibited by 1 in endothelial cells (HMEC-1). Inhibition was concentration-dependent in a micromolar range (10-75 mu M) and did not involve cytotoxic effects. At 75 mu M expression of the adhesion molecule ICAM-1 was down to 52.7 +/- 3.3% and 20.4 +/- 1.8% of control in TNF-alpha and LPS-stimulated HMEC-1, respectively. In contrast, 2 showed no activity. Quantitative RT-PCR experiments revealed that TNF-alpha-induced expression of the ICAM-1 gene was also reduced by 1 in a concentration-dependent manner, reaching 32.3 +/- 62% of control at 100 mu M matricine. Additional functional assays (NF-kappa B promotor activity and cytoplasm to nucleus translocation) confirmed the inhibitory effect of 1 on NF-kappa B signaling. Despite the fact that 1 lacks an alpha,beta-unsaturated carbonyl and is thus not able to act via a Michael reaction with electron rich SH groups of functional biological molecules, data gave strong evidence that 1 inhibits NF-kappa B transcriptional activity in endothelial cells by an hitherto unknown mechanism and this may contribute to its well-known anti-inflammatory activity in vivo. (C) 2015 Elsevier B.V. All rights reserved.