HUMAN INTERLEUKIN-1 INHIBITOR

A specific inhibitor of Interleukin-1 (IL-1) in humans has recently been identified that is present in the urine of some normal individuals, but is found in elevated amounts in the urine of patients with fever and certain other pathological conditions. It is a glycoprotein of approximately 30 Kd. that specifically inhibits (IL-1) induced thymocyte proliferation, but also interacts with IL-1 in its effects on fibroblast prostaglandin synthesis. The proposed study is a comprehensive analysis of the structure, physiology, and function of this newly described molecule. A biochemical purification scheme using a variety of chromatographic procedures will be developed in order to purify the IL-1 inhibitor to homogeneity. Purified inhibitor will be used for structural analyses employing either standard biochemical methods or molecular cloning methodology. Purified inhibitor will also be used to produce polyclonal or monoclonal, monospecific antibodies. These antibodies will be utilized to set up a sensitive and specific immunoassay for the inhibitor. The spectrum of activity of the IL-1 inhibitor will continue to be investigated, by analyzing its effects on a number of IL-1 mediated events in vitro including fibroblast prostaglandin and collagenase synthesis, hepatocyte production of acute phase serum proteins, and T cell activation. Its effect in vivo will also be investigated utilizing assays for IL-1 induced pyrogenicity and adjuvanticity. Its immunosuppressive effects on in vivo cell mediated and humoral immunity will also be analyzed. The mechanism of action of the inhibitor will be investigated, including its effect on IL-1 induced expression of IL-2 receptors or IL-2 production, and cell cycle shift, as well as the role of arachidonic acid metabolism. Potential effects on the IL-1 molecule itself including direct binding or prevention of IL-1 interaction with target cells will also be studied. The cell source of the IL-1 inhibitor will also be determined, as well as its relationship to acute phase serum proteins, other urine or serum proteins, and other IL-1 inhibitors. The long range objectives of this study are to determine the mechanism and role of the inhibitor as a physiological regulator of immunity and inflammation in humans.