title: Synthetic melanin suppresses production of proinflammatory cytokines.
abstract: An overproduction of proinflammatory cytokines mediates the damaging sequelae of inflammation in pathologic conditions such as rheumatoid arthritis, graft-vs-host reaction, cachexia, and sepsis syndrome. We examined the cytokine regulatory activity of synthetic melanin, exemplified by biosynthetic l-glycine-l-tyrosine-based polymer (ME-1) and chemosynthetic dihydroxyphenylalanine-based polymer (MC-1). At nontoxic concentrations, both compounds effectively (>/=60%) and reversibly suppressed the production of tumor necrosis factor (TNF), even when applied after stimulation of human peripheral blood monocytes with lipopolysaccharide (LPS). The inhibitory activity of melanin was selective with regard to cytokine response but not inducer- or cell-type-specific. In addition to TNF, melanin inhibited production of interleukin (IL)-1beta, IL-6, and IL-10 but not granulocyte-macrophage colony-stimulating factor by the LPS-stimulated monocytes. Melanin was equally effective in inhibiting production of TNF by monocytes stimulated with the purified protein derivative of Mycobacterium tuberculosis and production of IL-6 by IL-1alpha-stimulated human fibroblasts and endothelial cells. Northern blot analysis, mRNA stability determination, immunoprecipitation studies on metabolically labeled intracellular TNF, and pulse chase experiments revealed that melanin reduced efficiency of mRNA translation. The finding that melanin arrests ongoing cytokine synthesis suggests that this compound may be useful as an adjunct therapy for conditions showing involvement of proinflammatory cytokines.
authors.affiliation: Pharmaceutical Discovery Division, SRI International, Menlo Park, California 94025, USA.
authors.forename: N
authors.initials: N
authors.lastname: Mohagheghpour
authors.forename: N
authors.initials: N
authors.lastname: Waleh
authors.forename: S J
authors.initials: SJ
authors.lastname: Garger
authors.forename: L
authors.initials: L
authors.lastname: Dousman
authors.forename: L K
authors.initials: LK
authors.lastname: Grill
authors.forename: D
authors.initials: D
authors.lastname: Tusé
mesh_terms: D002470:Cell Survival / Q000187:drug effects; D002478:Cells, Cultured; D016207:Cytokines / Q000096:biosynthesis / Q000235:genetics / Q000378:metabolism*; D004730:Endothelium, Vascular / Q000166:cytology / Q000187:drug effects / Q000378:metabolism; D005347:Fibroblasts / Q000187:drug effects / Q000378:metabolism; D016178:Granulocyte-Macrophage Colony-Stimulating Factor / Q000096:biosynthesis; D006801:Humans; D007378:Interleukins / Q000096:biosynthesis / Q000235:genetics / Q000378:metabolism; D007980:Levodopa / Q000378:metabolism; D008070:Lipopolysaccharides / Q000276:immunology; D008543:Melanins / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology*; D008970:Molecular Weight; D009000:Monocytes / Q000166:cytology / Q000187:drug effects / Q000276:immunology / Q000378:metabolism; D011108:Polymers / Q000737:chemistry / Q000378:metabolism; D014176:Protein Biosynthesis / Q000187:drug effects / Q000235:genetics; D011499:Protein Processing, Post-Translational / Q000187:drug effects; D020871:RNA Stability / Q000187:drug effects; D012333:RNA, Messenger / Q000235:genetics / Q000378:metabolism; D013379:Substrate Specificity; D014373:Tuberculin / Q000276:immunology; D014409:Tumor Necrosis Factor-alpha / Q000096:biosynthesis / Q000737:chemistry / Q000235:genetics / Q000378:metabolism
chemical_list: D016207:Cytokines; D007378:Interleukins; D008070:Lipopolysaccharides; D008543:Melanins; D011108:Polymers; D012333:RNA, Messenger; D014373:Tuberculin; D014409:Tumor Necrosis Factor-alpha; D007980:Levodopa; D016178:Granulocyte-Macrophage Colony-Stimulating Factor