1. Section on Developmental Genetics, Human Genetics Branch, National Institute of Child Health and Human Development, National Institutes of Health, Bethesda, Maryland, 20892, USA
2. ^*To whom correspondence should be addressed.

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 studied^4–14 and its crystallographic structure has been resolved at 1.34 Å (refs 15, 16). Lipocortins are a family of related proteins^17–22, 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 purified^24–25 and the complementary DNA sequences of two human lipocortins are known^25,26. Lipocortins inhibit PLA₂ in vitro^{17–21,24–29}, although their mechanism of action is still unclear^{24–29,30,31}. 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.