title: Herbal melanin activates TLR4/NF-kappaB signaling pathway.
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.
authors.affiliation: Department of Genetics and Pathology, Rudbeck Laboratory, Uppsala University Hospital, SE-751 85 Uppsala, Sweden.
authors.forename: Fredrik
authors.initials: F
authors.lastname: Oberg
authors.forename: Adil
authors.initials: A
authors.lastname: Haseeb
authors.forename: Matilda
authors.initials: M
authors.lastname: Ahnfelt
authors.forename: Fredrik
authors.initials: F
authors.lastname: Pontén
authors.forename: Bengt
authors.initials: B
authors.lastname: Westermark
authors.forename: Adila
authors.initials: A
authors.lastname: El-Obeid
mesh_terms: D017209:Apoptosis / Q000187:drug effects; D053181:Caspase 8 / Q000378:metabolism*; D002460:Cell Line; D006801:Humans; D051550:I-kappa B Kinase / Q000037:antagonists & inhibitors*; D020672:I-kappa B Proteins / Q000037:antagonists & inhibitors*; D015850:Interleukin-6 / Q000378:metabolism; D016209:Interleukin-8 / Q000378:metabolism; D008070:Lipopolysaccharides / Q000633:toxicity; D008543:Melanins / Q000494:pharmacology*; D009000:Monocytes / Q000187:drug effects; D000072000:NF-KappaB Inhibitor alpha; D016328:NF-kappa B / Q000378:metabolism*; D031881:Nigella sativa; D010936:Plant Extracts / Q000494:pharmacology; D012639:Seeds; D015398:Signal Transduction / Q000187:drug effects; D051197:Toll-Like Receptor 4 / Q000378:metabolism*; D014162:Transfection
chemical_list: D020672:I-kappa B Proteins; D015850:Interleukin-6; D016209:Interleukin-8; D008070:Lipopolysaccharides; D008543:Melanins; D016328:NF-kappa B; C000606204:NFKBIA protein, human; D010936:Plant Extracts; C495345:TLR4 protein, human; D051197:Toll-Like Receptor 4; D000072000:NF-KappaB Inhibitor alpha; D051550:I-kappa B Kinase; D053181:Caspase 8