Hiromi Okigami

Endogenous cortisol determines the circadian rhythm of lipopolysaccharide-- but not lipoteichoic acid--inducible cytokine release.

To investigate the circadian rhythm of inducible cytokine release and a potential pacemaker role of endogenous cortisol, cortisol levels as well as cytokine release from ex vivo LPS‐stimulated blood were assessed at 4‐h intervals over 24 h in 11 volunteers. We found a significant diurnal variation for IFN‐γ and IL‐8, and a tendency for TNF, all inversely correlated to the serum cortisol levels, but no evidence for such a rhythm for IL‐1β and IL‐6. In vitro IC50 values for cytokine inhibition by hydrocortisone (HC) corresponded to the observed rank order for circadian rhythmicity. mRNA analyses revealed that this was due to a reduction of gene transcription. These effects of HC were significantly reversed by the glucocorticoid receptor antagonist RU486. Supplementation of HC in vivo to maintain morning cortisol levels throughout the day blunted the circadian rhythm of ex vivo LPS‐induced cytokines. Surprisingly, no significant diurnal variation for any investigated cytokine was found in the same volunteer group upon stimulation with lipoteichoic acid (LTA), the gram‐positive counterpart to LPS. Furthermore, 10–50‐fold higher HC concentrations as compared to LPS were required to block LTA‐induced cytokine release. LTA, in contrast to LPS, failed to activate Jun kinase, a reported target for HC action.

Discovery and evaluation of piperidinyl carboxylic acid derivatives as potent α4β1 integrin antagonists

Piperidinyl carboxylic acid-based derivatives were prepared as antagonists of the leukocyte cell adhesion process that is mediated through the interaction of the alpha(4)beta(1) integrin (VLA-4, very late antigen 4) and the vascular cell adhesion molecule 1 (VCAM-1). Compounds 2a-h inhibited the adhesion in a cell-based assay in the low and sub micromolar range, a pharmacokinetic study of 2d is reported.

Discovery and evaluation of terephthalic acid derivatives as potent α4β1 integrin antagonists

Terephthalic acid based derivatives containing β- and γ-amino acid residues were prepared as antagonists of the leukocyte cell adhesion process that is mediated through the interaction of the very late antigen 4 (VLA-4) and the vascular cell adhesion molecule 1 (VCAM-1). The compounds 2, 10–12, 14, and 16–17 inhibited the adhesion in a cell based assay in the low and sub micromolar range.