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1000
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Abstract/Summary
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BACKGROUND: During inflammation, immune cells produce cytokines, chemokines and prostaglandins. This results in acute or chronic inflammation, which favor the development of degenerative diseases such as diabetes, obesity or cardiovascular diseases. Inflammatory processes are modulated by intrinsic and external factors. External factors are supposed to act via similar modes of action as do endogenous molecules and mediators. Both endogenous ligands and nutrient-derived metabolites might modify the extent and status of the cellular and systemic response during inflammation. Therefore, the biological activity of endogenous mediators was compared with nutrition-derived substances. METHODS: Murine macrophages (RAW264.7 cells), in vitro differentiated human promyeloid THP-1 cells and peripheral blood leukocytes (PBL) were stimulated with LPS in the presence of z-ligustilide (LIG) or the endogenous PPARγ ligand 15deoxyΔ12,14-prostaglandin J2 (15d–PGJ2). Secretion of mediators of inflammation was measured by EIA, the Griess reaction and multiplex ELISA (Luminex®). Gene expression was quantified by real-time PCR. Nuclear translocation of NF-κB was measured by cytometric techniques. RESULTS: LPS-activated RAW264.7 cells produced nitric oxide (NO), COX2-dependent prostaglandin E2 (PGE2), interleukins and chemokines. LIG concentration-dependently reduced the production of nitric oxide (NO) and PGE2, although it did not match the inhibitory potential of 15d–PGJ2. LIG inhibited the secretion of cytokines (IL-1α, IL-6, TNF-α) and differentiation factors (GM-CSF) in murine macrophages. It blunted the production of CCL2/MCP-1, but did not alter the secretion of CCL5/RANTES. LIG reduced mRNA levels of pro-inflammatory cytokines (e.g. TNF-α, IL-1α, IL-6), chemokines (CCL4/MIP-1β), and pro-inflammatory enzymes (iNOS). Similarly, LIG robustly impaired inflammatory mediators (e.g. CCL2/MCP-1, CCL3-MIP-1α, CCL4/MIP-1β, CXCL10/IP-10, IL-12p70, TNF-α) of LPS-activated human THP-1 cells and PBLs. Unexpectedly, it augmented the production of IL-1β, IL-6 and GM-CSF in PBLs. CONCLUSIONS: LIG diminished the extent of the inflammatory response measured by the production of different mediators or metabolites (NO, PGE2, interleukins, cytokines, chemokines). LIG acted at the transcriptional level and targeted the NF-κB signaling pathway. Since LIG and the anti-inflammatory prostaglandin 15d–PGJ2 share most of the analyzed biological features, we infer that they have similar modes of action. Hence, LIG acts as an anti-inflammatory prostaglandin and modulates cytokine- and chemokine-dependent inflammatory responses.
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