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Leukocytes come into intimate contact with the venular endothelium as they extravasate from blood to the interstitium during inflammation. In exteriorized tissues, the number of leukocytes rolling along the vessel wall was markedly increased in adrenalectomized and metyrapone-treated animals, relative to sham-operated and normal animals. During the development of an acute, local inflammatory response, rollers were numerically decreased and a stronger adhesion of the cells to the endothelium, with a concomitant migration into tissues, was observed. Adhesion and migration were much more marked in adrenalectomized and metyrapone-treated animals than in controls, suggesting that secreted glucocorticoids exert a suppressive effect on leukocyte-endothelial interactions. The increased number of rolling leukocytes in adrenalectomized and metyrapone-treated animals apparently resulted in more cells available to migrate into inflamed tissues. The effect appears to involve receptor occupancy and induction of gene expression because normal animals receiving the steroid antagonist RU 38 486, actinomycin D, or cycloheximide behaved as adrenalectomized or metyrapone-treated animals. Administration to adrenalectomized animals of a monoclonal antibody to the membrane glycoprotein complex CD18 did not affect the number of rolling cells, but dramatically reduced the number of adherent or migrated leukocytes. It is suggested that secreted glucocorticoids, in addition to an effect on rolling behavior of circulating leukocytes, might also modulate the activity of the glycoprotein complex CD18 on white blood cells. The ultimate consequence is a restrictive effect on cell emigration in inflammation.

Leucopenia induced by the administration of methotrexate reduced the volume of inflammatory exudate and the number of cells entering the pleural cavity during a 4-h carrageenin pleurisy when compared with that of non-leucopenic controls. The depressed response was partially but markedly restored when leucopenic animals were intravenously injected, immediately before the initiation of pleurisy, with spleen lymphocytes (or their products) obtained from normal, adrenal-demedullated or mock-operated rats. In contrast spleen lymphocytes (or their products) obtained from adrenalectomized rats or from rats receiving metyrapone, an inhibitor of adrenal glucocorticoid biosynthesis, were completely inactive. It is concluded that in physiologic concentrations glucocorticoids are essential for the production of lymphocyte-derived factors involved in the development of acute, non-immune inflammation. In pharmacologic concentrations, however, glucocorticoids suppress the release of such pro-inflammatory factors.