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In this study the anti-inflammatory properties of zilpaterol, a β2-adrenergic receptor (AR) agonist specifically developed as a growth promoter in cattle were investigated. Although zilpaterol has a different structure compared with the β2-AR agonists known to date, it was noted that it was able to bind to both the β2-AR (K i = 1.1 × 10-6) and the β1-AR (Ki = 1.0 × 10-5). Using lipopolysaccharide (LPS)-exposed U937 macrophages, the production of cyclic adenosine-3′, 5′-cyclic monophosphate (cAMP) and tumor necrosis factor alpha (TNF-α) were investigated. Zilpaterol inhibited TNF-α release and induced intracellular cAMP levels in a dose-dependent manner. The inhibition of TNF-α release and induction of cAMP production was mainly mediated via the β2-AR, as indicated by addition of β1- and β2-specific antagonists. The effects of zilpaterol were investigated in LPS-treated male Wistar rats after pretreatment with zilpaterol. Zilpaterol dosed at 500 μg/kg body weight reduced the TNF-α plasma levels. In conclusion, zilpaterol is a β2-adrenergic agonist and an inhibitor of TNF-α production induced by LPS both in vivo and in vitro. © 2005 Blackwell Publishing Ltd.

Two-dimensional difference gel electrophoresis (DIGE) in combination with univariate (Student's t-test) and multivariate data analysis, principal component analysis (PCA) and partial least squares discriminant analysis (PLS-DA) were used to study the anti-inflammatory effects of the β2-adrenergic receptor (β2-AR) agonist zilpaterol. U937 macrophages were exposed to the endotoxin lipopolysaccharide (LPS) to induce an inflammatory reaction, which was inhibited by the addition of zilpaterol (LZ). This inhibition was counteracted by addition of the β2-AR antagonist propranolol (LZP). The extracellular proteome of the U937 cells induced by the three treatments were examined by DIGE. PCA was used as an explorative tool to investigate the clustering of the proteome dataset. Using this tool, the dataset obtained from cells treated with LPS and LZP were separated from those obtained from LZ treated cells. PLS-DA, a multivariate data analysis tool that also takes correlations between protein spots and class assignment into account, correctly classified the different extracellular proteomes and showed that many proteins were differentially expressed between the proteome of inflamed cells (LPS and LZP) and cells in which the inflammatory response was inhibited (LZ). The Student's t-test revealed 8 potential protein biomarkers, each of which was expressed at a similar level in the LPS and LZP treated cells, but differently expressed in the LZ treated cells. Two of the identified proteins, macrophage inflammatory protein-1beta (MIP-1β) and macrophage inflammatory protein-1 alpha (MIP-1α) are known secreted proteins. The inhibition of MIP-1β by zilpaterol and the involvement of the β2-AR and cAMP were confirmed using a specific immunoassay. © 2005 American Chemical Society.