Abstract
Mutolide an anti-inflammatory compound was isolated from the coprophilous fungus Lepidosphaeria sp. (PM0651419). The compound mitigated LPS-induced secretion of pro-inflammatory cytokines TNF-α and IL-6 from THP-1 cells as well as human peripheral blood mononuclear cells (hPBMCs). Mutolide also inhibited secretion of another pro-inflammatory cytokine IL-17 from anti-hCD3/anti-hCD28 stimulated hPBMCs. NF-κB is the major transcription factor involved in the secretion of pro-inflammatory cytokines including IL-17. Mechanistic evaluations revealed that mutolide inhibited induced NF-κB activation and translocation from cytoplasm into the nucleus. However, mutolide did not significantly affect activity of p38 MAPK enzyme, a serine/threonine kinase involved in cell cycle proliferation and cytokine secretion. These results indicate that mutolide may exert its anti-inflammatory effect via NF-κB inhibition. Oral administration of mutolide at 100 mg/kg showed significant inhibition of LPS-induced release of TNF-α from Balb/c mice in an acute model of inflammation. Our results highlight the anti-inflammatory properties of mutolide and suggest that further evaluation in a chronic model of inflammation is required to confirm the potential of mutolide as a druggable candidate for the treatment of inflammatory diseases.Electronic supplementary materialThe online version of this article (doi:10.1186/s40064-015-1493-6) contains supplementary material, which is available to authorized users.
Highlights
Inflammation is a complex response to harmful stimuli like microbial infection, endotoxin exposure, damaged cells or irritants
Fungal metabolites are known potential anti-inflammatory agents and act on targets such as iNOS, NF-κB, AP-1, JAK, STAT, cytokines, cyclooxygenase (COX-1 and COX-2), 3β-HSD, XO and PLA2: Rutilins A and B isolated from Hypoxylon rutilum, an inhibitor of NO production(Quang et al 2006), Gliovirin isolated from Trichoderma harzianum, an inhibitor of inducible TNF-α expression (Rether et al 2007), Panepoxydone isolated from Lentinus crinitus, an inhibitor of NF-κB activation (Erkel et al 1996), Phomol isolated from Phomopsis sp. inhibitor of edema in the mouse ear assay (Weber et al 2004), Ergoflavin isolated from an endophytic fungus of Mimosops elengi, an inhibitor of human TNF-α and IL-6 (Deshmukh et al 2009), are but a few examples
In this study, we demonstrated the anti-inflammatory potential of mutolide isolated from the coprophilous fungus Lepidosphaeria sp. (PM0651419)
Summary
Inflammation is a complex response to harmful stimuli like microbial infection, endotoxin exposure, damaged cells or irritants. Lipopolysaccharide (LPS), which is produced by Gram negative bacteria, binds to CD14/ TLR4/MD2 receptor complex, especially in monocytes, dendritic cells, macrophages and B cells. This results in activation of a complex biochemical cascade that promotes the recruitment of MyD88, activation of protein kinases, recruitment of the adaptor protein TRAF6, and subsequent activation and translocation of NF-κB and AP-1 into the nucleus. A number of studies have reported that natural products show anti-inflammatory activity by controlling the levels of various inflammatory cytokines or inflammatory mediators including TNF-α, IL-6, IL-1β, NF-κB, JAK, STAT, NO, iNOS, COX-1 and COX-2 (Debnath et al 2013; Gautam and Jachak 2009). Fungal metabolites are known potential anti-inflammatory agents and act on targets such as iNOS, NF-κB, AP-1, JAK, STAT, cytokines, cyclooxygenase (COX-1 and COX-2), 3β-HSD, XO and PLA2: Rutilins A and B isolated from Hypoxylon rutilum, an inhibitor of NO production(Quang et al 2006), Gliovirin isolated from Trichoderma harzianum, an inhibitor of inducible TNF-α expression (Rether et al 2007), Panepoxydone isolated from Lentinus crinitus, an inhibitor of NF-κB activation (Erkel et al 1996), Phomol isolated from Phomopsis sp. inhibitor of edema in the mouse ear assay (Weber et al 2004), Ergoflavin isolated from an endophytic fungus of Mimosops elengi, an inhibitor of human TNF-α and IL-6 (Deshmukh et al 2009), are but a few examples
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