Synthetic melanin suppresses production of proinflammatory cytokines

An overproduction of proinflammatory cytokines mediates the damaging sequel ae of inflammation in pathologic conditions such as rheumatoid arthritis, g raft-vs-host reaction, cachexia, and sepsis syndrome. We examined the cytok ine regulatory activity of synthetic melanin, exemplified by biosynthetic L -glycine-L-tyrosine-based polymer (ME-1) and chemosynthetic dihydroxyphenyl alanine-based polymer (MC-1), At nontoxic concentrations, both compounds ef fectively (greater than or equal to 60%) and reversibly suppressed the prod uction of tumor necrosis factor (TNF), even when applied after stimulation of human peripheral blood monocytes with lipopolysaccharide (LPS), The inhi bitory activity of melanin was selective with regard to cytokine response b ut not inducer- or cell-type-specific. In addition to TNF, melanin inhibite d production of interleukin (IL)-1 beta, IL-6, and IL-10 but not granulocyt e-macrophage colony-stimulating factor by the LPS-stimulated monocytes. Mel anin was equally effective in inhibiting production of TNF by monocytes sti mulated with the purified protein derivative of Mycobacterium tuberculosis and production of IL-6 by IL-1 alpha-stimulated human fibroblasts and endot helial cells. Northern blot analysis, mRNA stability determination, immunop recipitation studies on metabolically labeled intracellular TNF, and pulse chase experiments revealed that melanin reduced efficiency of mRNA translat ion. The finding that melanin arrests ongoing cytokine synthesis suggests t hat this compound may be useful as an adjunct therapy for conditions showin g involvement of proinflammatory cytokines, (C) 2000 Academic Press.