Selective MyD88-dependent pathway inhibition by the cyanobacterial natural product malyngamide F acetate

• Published in: European journal of pharmacology Vol. 629; no. 1; pp. 140 - 146
• Main Authors: Villa, Francisco A., Lieske, Kelly, Gerwick, Lena
• Format: Journal Article
• Language: English
• Published: Amsterdam Elsevier B.V 10.03.2010; Elsevier
• Subjects: Animals; Anti-Inflammatory Agents - chemistry; Anti-Inflammatory Agents - pharmacology; Biological and medical sciences; Biological Products - chemistry; Biological Products - pharmacology; Cell Line; Cyanobacteria; Cyanobacteria - chemistry; Cyclohexanones - chemistry; Cyclohexanones - pharmacology; Cytokines - genetics; Drug Evaluation, Preclinical; Fatty Acids, Monounsaturated - chemistry; Fatty Acids, Monounsaturated - pharmacology; Gene Expression Regulation - drug effects; IL-6 (interleukin 6); Lyngbya majuscula; Malyngamide F acetate; Marine; Marine natural product; Medical sciences; Mice; MyD88-dependent; Myeloid Differentiation Factor 88 - metabolism; Nitric Oxide - biosynthesis; NO (nitric oxide); Pharmacology. Drug treatments; Structure-Activity Relationship; TNF-α (tumor necrosis factor alpha); NO (nitric oxide); TNF-α (tumor necrosis factor alpha); Malyngamide F acetate; MyD88-dependent; Marine natural product; IL-6 (interleukin 6); Cytokine; Natural product; Natural compound; Interleukin 6; Marine environment; Nitric oxide; Tumor necrosis factor α
• ISSN: 0014-2999; 1879-0712
• DOI: 10.1016/j.ejphar.2009.12.002

In response to evolutionary selective pressure, prokaryotes have developed a rich array of secondary metabolites, some of which may be inhibitory to the innate immune system and the inflammatory response in vertebrates. We utilized the RAW264.7 macrophage cell line stimulated with LPS in a nitric oxide (NO) assay to screen for compounds with immunomodulatory activities from a library of marine natural products, and found that the malyngamide structure class, found commonly in the marine cyanobacterium Lyngbya majuscula, has potent activity. Several of the malyngamides were found to possess IC50 values of 5.4–18 µM. Malyngamide F acetate exhibited strong concentration-dependent anti-inflammatory activity in the NO assay with an IC50 of 7.1 µM and with no cytotoxicity at the concentrations tested. Subsequent real-time PCR of selected genes revealed a unique cytokine profile after LPS stimulation (TLR4) with decreased expression of iNOS, IL-1β, IL-6, and IL-10, but increased TNF-α expression. Additional experiments utilizing CpG and Poly I:C stimulation to selectively activate the MyD88-dependent and -independent pathways via TLR9 and TLR3 substantiated the finding that malyngamide F acetate selectively inhibits the MyD88-dependent pathway. To our knowledge, this is the first report of a natural product inhibiting the MyD88-dependent pathway.