Novel anti-inflammatory peptides from the region of highest similarity between uteroglobin and lipocortin I

Abstract

Significant future developments in the effective treatment of inflammatory diseases may arise from non-toxic dual inhibitors of both cyclooxygenase and lipoxygenase pathways in the arachidonate cascade1. Inhibition of phospholipase A2 (PLA2) (EC 3.1.1.4), may provide such a dual action and recent research has concentrated on the role of PLA2-inhibitory proteins as possible anti-inflammatory agents. Blastokinin2 or uteroglobin3 is a steroid-induced rabbit secretory protein with PLA2-inhibitory activity. Its biochemical and biological properties have been extensively studied4–14 and its crystallographic structure has been resolved at 1.34 Å (refs 15, 16). Lipocortins are a family of related proteins17–22, which, it has been suggested, mediate the anti-inflammatory effects of glucocorticoids (for a review, see ref. 23). Some proteins of this group have been purified24–25 and the complementary DNA sequences of two human lipocortins are known25,26. Lipocortins inhibit PLA2in vitro17–21,24–29, although their mechanism of action is still unclear24–29,30,31. Recombinant lipocortin I inhibits eicosanoid synthesis in isolated perfused lungs from the guinea pig32. Here, we report that synthetic oligopeptides corresponding to a region of high amino-acid sequence similarity between uteroglobin and lipocortin I have potent PLA2 inhibitory activity in vitro and striking anti-inflammatory effects in vivo.