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Abstract
Expression of many pro-inflammatory cytokines is controlled by the NF-kappaB signaling
pathway. NF-kappaB is induced by LPS through activation of TLR4. Melanins extracted
from fungal, plant and human sources modulate cytokine production and activate NF-kappaB
pathway. We showed that a herbal melanin (HM) from Nigella sativa L. modulates cytokine
production and suggested it as a ligand for TLR4. In this study we investigated the
possibility that the HM-induced cytokine production is via an NF-kappaB signaling
pathway. We found that HM induced the degradation of IkappaBalpha, a key step in the
activation of NF-kappaB. Moreover, addition of IkappaB kinase (IKK) specific inhibitors
effectively inhibited the observed HM-induced production of IL-8 and IL-6 by TLR4-transfected
HEK293 cells and THP-1 cells. Our results have also shown that HM induced cleavage
of caspase 8, and that this cleavage was partially abrogated by IKK inhibitors. We
suggest that HM can modulate the inflammatory response by inducing IL-8 and IL-6 production
via TLR4-dependent activation of the NF-kappaB signaling pathway.