Cytolethal and growth inhibitory effects of glucocorticoids on human lymphoid cells
Robertson, Alison Mary Grey
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Glucocorticoids cause the regression of certain lymphoid tumours, though the precise mechanism by which this is achieved is still not fully understood. Consequently, I studied the action of a glucocorticoid, methylprednisolone (MPS), on human lymphoid cell lines as a possible in vitro model for this effect. MPS induced both a cytolethal and growth inhibitory response in these cells, which I have defined on a kinetic and morphological basis. The cytolethal response - measured by the ability of live cells to exclude nigrosine after treatment over 48hr - was dose-dependent, occurring around 10 MPS. Maximal lethal effects occurred only on continuous exposure of the cells to MPS. Morphological changes, as observed by light and electron microscopy, were consistent with apoptosis followed by autolysis, with increased nigrosine uptake correlating closely with onset of autolysis. A low background level of apoptosis and autolysis was also present in control cultures. The growth inhibitory response - measured by an increase in population doubling time after treatment over several days - was dose-dependent, occurring within the concentration range 10 M - 10 Si MPS. Again, continuous exposure to MPS was necessary for the response to be maintained. Morphological changes resulting from sub lethal damage were seen in mitochondria by electron microscopy; in addition a small increase in the number of apoptotic and autolytic cells was observed by light microscopy. Cell cycle kinetic analysis.revealed that growth inhibition was a stable effect caused by a blockage of cells in G^ (or Gq); I was unable to determine whether blocked cells were committed to death or maintained the ability to return to cycle. A correlation was made between my own results and biochemical studies performed on human lymphoid cell lines by other workers in our research group. The relationship between in vitro and in vivo responses to glucocorticoids was also discussed.