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A Role for Corticosteroid-Binding Globulin in Delivery of Cortisol to Activated Neutrophils^*

GEOFFREY L. HAMMOND, CAROLYN L. SMITH, NIGEL A. M. PATERSON and WILLIAM J. SIBBALD

Departments of Obstetrics and Gynecology (G.L.H., C.L.S.) and Medicine (N.A.M.P., W.J.S.), University of Western Ontario, Victoria Hospital London, Ontario, N6A 4G5 Canada

Address all correspondence and requests for reprints to: Geoffrey L. Hammond, Ph.D., Department of Obstetrics and Gynecology, University of Western Ontario, 375 South Street, London, Ontario, N6A 4G5 Canada.

In human blood, cortisol is transported by a plasma protein known as corticosteroid-binding globulin (CBG). As anticipated from primary structure comparisons of CBG and ₁-proteinase inhibitor (A1-PI), CBG acts as a substrate for neutrophil elastase. However, unlike A1-PI, CBG does not alter the activity of this enzyme, but is cleaved by it at a single location close to its carboxy-terminus, and this reduces its molecular size by 5 kDa with the concomitant release of more than 80% of CBG-bound cortisol. Three small molecular size fragments are detected after elastase cleavage, and carbohydrate analysis of these fragments suggests that they represent the same polypeptide fragment which has been differentially glyco-sylated. To assess the biological significance of these observations, CBG was incubated with either mononuclear cells or granulocytes obtained from patients with acute inflammation (sepsis) and from a normal volunteer. Only granulocytes from septic patients reduced the mol wt of CBG by about 5 kDa and destroyed its steroid-binding activity. Preincubation with A1-PI prevented this, which demonstrates that neutrophil elastase plays a key role in this event. These results suggest a physiological role for CBG in the delivery of cortisol to sites of inflammation.

^* This work was supported by grants from the Medical Research Council of Canada and the Ontario Lung Association.

OCTRF Research Scholar.

Supported by an Ontario Graduate Scholarship.

Received June 23, 1989.

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