The major Boswellia serrata active 3-acetyl-11-keto-β-boswellic acid strengthens interleukin-1α upregulation of matrix metalloproteinase-9 via JNK MAP kinase activation

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Background Boswellia serrata gum resin has attracted pharmacological interest as an alternative antinflammatory. Purpose We studied the application of an ethanolic extract of the resin and its main active 3-O-acetyl-11-keto-β-boswellic acid (AKBA) against inflammatory degeneration of skin extracellular matrix. Study design We compared the effects of the extract and AKBA on the activity of MMP-2 and MMP-9 (72-kDa and 92-kDa type IV collagenases) in HaCaT keratinocytes exposed to interleukin-1α (IL-1α) as a skin inflammation model. Methods MMP activity in cell conditioned medium was assayed by gelatin zymography, while NF-KB and MAP kinase activations were evaluated by Western blotting. Results IL-1α (10 ng/ml) upregulated MMP-9 but not MMP-2 in HaCaT cells. The extract, used at 2.3, 4.6 and 9.3 µg/ml, had no effect, but in combination with IL-1α showed MMP-9 inhibition at the lowest dose and increased upregulation at the highest one. AKBA alone, at the same concentrations (corresponding to 5, 10, and 20 µM), did not stimulate MMP-9, but together with IL-1α induced an increased upregulation at the lowest dose that progressively disappeared at higher doses. WB analysis showed that IL-1α induced phosphorylation of NF-κB p65, while AKBA abolished this effect at 20 µM, but conversely increased it at 5 µM. Screening of MAP kinase phosphorylation showed a combined activation of IL-1α/AKBA on JNK, while the JNK inhibitor SP600125 abolished MMP-9 upregulation induced by IL-1α/AKBA. Conclusion The enhancing effect of IL-1α/AKBA on MMP-9 at low AKBA concentration seems to involve the activation of JNK-mediated NF-κB pathway. Conversely, the extract inhibits the IL-1α effect at low doses, but not at higher ones, where AKBA and possibly other β-boswellic acids reach concentrations that potentiate the effect of IL-1α. The extract at low doses could protect the skin against degenerative processes of extracellular matrix, while keto-β-boswellic acids seem unsuitable for this purpose.

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