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Studies on the Mechanism of Corticosteroid-induced Lymphocytolysis

Departments of Biochemisty [R. W. T., A. F. B.], and Pathology [L. H. C.], and Cancer Research Centre [R. W. T., A. F. B.], University of British Columbia, Vancouver 8, British Columbia, Canada

When cells of the thymus or corticosteroid-sensitive mouse lymphosarcoma P1798S are treated in vitro with 0.27 µM cortisol in tissue culture medium with 10% serum or 0.5% human albumin, nuclear damage occurs that ends with karyorrhexis. The steroid-resistant subline P1798R does not show these changes.

Corticosteroid-sensitive lymphocytes that undergo lysis differ from the resistant subline in several respects with regard to changes in fatty acid metabolism. Corticosteroid treatment in vivo for 2 hr raised the free fatty acid (FFA) pool in thymus and P1798S cells, while decreasing it in P1798R cells. In vitro, cortisol had no effect on the uptake of ¹⁴C-labeled palmitic acid but decreased oxidation of this acid by 46 and 17% in thymus and P1798S, respectively, while increasing it 9% in P1798R.

After sensitive P1798S cells were incubated in a medium that contained FFA calculated to be equivalent to that accumulated after steroid treatment, electron microscopy revealed that certain effects of corticosteroids could be reproduced by fatty acids of chain length C-9 and higher, namely, nuclear edema, focal dissolution and disintegration of the nuclear membrane and, ultimately, karyolysis. Steroid-resistant cells show cytological changes only at 10-fold higher concentrations of FFA.

On the basis of these results, the following scheme is proposed as the mechanism by which cytolysis occurs in corticosteroid-sensitive lymphoid tissues:

¹ The studies reported are from a thesis submitted to the University of British Columbia at Vancouver in partial fulfillment of the requirements for the degree of Doctor of Philosophy. Recipient of a Medical Research Council of Canada Studentship. Present address: Department of Experimental Therapeutics, Roswell Park Memorial Institute, New York State Department of Health, Buffalo, N. Y. 14203.

² Recipient of a Killam Predoctoral Fellowship.

Received 2/21/72. Accepted 10/18/72.