Inhibition of inflammatory cytokine production and lymphocyte proliferation by structurally different sesquiterpene lactones correlates with their effect on activation of NF-kappa B

Many sesquiterpene lactones (S1s) are known to possess anti-inflammatory ac tivities. To gain further insight into their structure-activity relationshi ps and the molecular mechanism of action, four germacranolide sesquiterpene lactones which differ in the skeleton and the number of reactive centers ( 4 beta ,15-epoxy-miller-9E-enolide (1), 15-acetoxy-eremantholide B (2), a m ixture of 15-(isovaleroyl)/15-(2-methyl-butyryl)-2-alpha -acetoxy-miguanin (3), and 15-(2-hydroxy)-isobutyryloxy-micrantholide (4)) were investigated for their effect on production of proinflammatory cytokines (interleukin-1 beta [IL-1 beta], IL-6, and tumor necrosis factor-alpha [TNF-alpha]) as wel l as proliferation of concanavalin A (Con A) and lipopolysaccharide (LPS)-s timulated mouse lymphocytes. Compounds 1 and 3 which possess an alpha -meth ylene-gamma -lactone function and a conjugated carbonyl group induced a hal f-maximal inhibition of cytokine synthesis in adherent mouse peritoneal exs udate cells at micromolar concentrations (IC50 0.69-1.70 muM), while compou nd 4 which contains only an alpha -methylene-gamma -lactone residue was les s active (IC50 : 8.38 muM). Interestingly, compound 2, which carries only a conjugated keto group, displayed a potency similar to those of the bifunct ional compounds I and 3. All four S1s suppressed proliferation of murine ly mphocyte at IC50 concentrations between 0.22 and 5.03 muM. The rank order o f potency was 1 = 2 > 3 > 4. Generally, the growth of LPS-stimulated cells was more strongly influenced than those of Con A-activated lymphocytes. Thi s effect was particularly pronounced with 4. Inhibitory concentrations corr elated well with those necessary for inhibition of the transcription factor nuclear factor KB (NF-kappaB) observed in a previous investigation. Theref ore, it can be assumed that NF-KB may be involved in the suppressive effect of S1s on cytokine production and lymphocyte proliferation. (C) 2001 Elsev ier Science Inc. All rights reserved.