ABSTRACT
Interleukin-1 (IL-1) -alpha and -beta are potent regulators of inflammatory responses. The naturally occurring interleukin-1 receptor antagonist (IL-1ra) is effective in vitro and in vivo in modulating biological responses to IL-1. We have previously reported the discovery of IL-1 antagonist peptides from the search of phage display libraries. Further characterization of this group of peptides has led to a 15-mer, AF12198, Ac-FEWTPGWYQJYALPL-NH2 (J represents the unnatural amino acid, 2-azetidine-1-carboxylic acid), with both in vitro and in vivo IL-1 antagonist activity. AF12198 selectively binds the human type I IL-1 receptor but not the human type II receptor or the murine type I receptor. In vitro, AF12198 inhibits IL-1-induced IL-8 production by human dermal fibroblasts with a half-maximal inhibition concentration or IC50 of 25 nM and IL-1-induced intercellular adhesion molecule-1 (ICAM-1) expression by endothelial cells with an IC50 of 9 nM. When given as an intravenous infusion to cynomolgus monkeys, AF12198 blocks ex vivo IL-1 induction of IL-6 and down modulates in vivo induction of IL-6. This is the first small molecule to show IL-1 receptor antagonist activity in vivo.
Subject(s)
Interleukin-1/antagonists & inhibitors , Peptides/pharmacology , Proteins/pharmacology , Receptors, Interleukin-1/antagonists & inhibitors , Amino Acid Sequence , Animals , Cells, Cultured , Dose-Response Relationship, Drug , E-Selectin/biosynthesis , Humans , Intercellular Adhesion Molecule-1/biosynthesis , Interleukin 1 Receptor Antagonist Protein , Macaca fascicularis , Mice , Peptide Library , Peptides/metabolism , Proteins/metabolism , Sialoglycoproteins/metabolism , Species SpecificityABSTRACT
The purpose of this study was to investigate the effect of nonsurgical stress on plasma glucose, insulin and glucagon in the ewe and fetus. Plasma glucose, insulin and glucagon were measured before and after a 2 min period of verbal and physical startling of much greater magnitude than that to which we ewe is exposed during routine blood drawing. Studies were completed on 5 fed ewes, 5 fasted ewes and on 4 fetuses of fasted ewes. There were no significant differences after a startling compared to the control values. Thus, there appears no need to allow the ewe a prolonged period (more than 1-2 weeks) to become accustomed to handling by humans before chronic metabolic studies involving serum glucose, insulin and glucagon are undertaken.
