Lipocortin and the mechanism of action of the glucocorticoids

Abstract

The glucocorticoids inhibit our 'defence reactions' at many levels. One way in which they achieve this is by inhibiting the synthesis of chemicals involved in the promotion of the inflammatory response. The production of many mediators involved in the response to infection, injury, haemorrhage or metabolic disturbances are under glucocorticoid control such that elevated levels of hormone in the blood suppresses their formation. In many cases the action of these mediators is blocked as well. It might be thought that the glucocorticoids act simply by decreasing the synthesis rate of these protein regulators of inflammation such as the lymphokines, or of the enzymes which make prostaglandins. Whilst this undoubtedly does occur, another mechanism is also employed: that is, the glucocorticoid-induced synthesis of inhitibory proteins. Lipocortin (and possibly other related proteins) then is a sort of 'second messenger' of the glucocorticoids. It is only one of many such regulatory proteins but it is an important one, controlling as it does the mediators which promote development of the symptoms of the inflammatory response. It is undoubtedly the significant component of the inbuilt mechanism for terminating the inflammatory response which the physician exploits, for when he gives his patients relatively large doses of steroids to control an inflammatory response, he is in reality increasing the synthesis of these 'second mesenger' proteins such as lipocortin to a near maximum. All the early studies on lipocortin were performed in vitro, that is under conditions in which steroids were not normally present. Under these circumstances the generation and appearance of lipocortin seemed absolutely dependent upon the presence of glucocorticoids in the perfusing medium. These findings have led some to the erroneous notion that lipocortin was only present following treatment with exogenous steroids. Of course, all healthy mammals have circulating glucocorticoids and thus it is more rational to expect that lipocortin is a normal constituent of plasma and tissues (as indeed it appears to be), although the amount present in the cells can be increased by raising the concentration of endogenous or exogenous steroids. There has been a corresponding change in our appreciation of the function of lipocortin. Originally, it was regarded mainly as an 'anti-inflammatory protein' but today it seems more likely that this protein is present in most cells, and that its function is to control phospholipase A2 activity and to allow lipid hydrolysis only under strictly defined circumstances. This reversible inhibitory function of lipocortin could well be controlled by the phosphorylation and dephosphorylation cycle described above. Naturally, during inflammation, phospholipase is substantially activated and thus there is a requirement for a greater than normal supply of the inhibitory protein, hence the relationship between the rate of synthesis and the release of steroid hormones. The discovery, characterisation, islation, sequencing and cloning of lipocortin has opened up an entirely new and exciting chapter in cell biology and also holds out a strong promise for the future of anti-inflammatory therapy. In addition to their beneficial clinical effects, steroids produce a wide spectrum of side effects which preclude the use of these drugs for long periods of time except in the very seriously ill. These side effects are caused by changes in the transcription of specific genes in the same way as the anti-inflammatory effects. It has long been an article of a faith of scientists working in this are that if we could identify and isolate the 'second messengers' of steroid action that are responsible for the anti-inflammatory effects, it should be possible to produce drugs which possess many of the beneficial action of steroids without incurring the heavy penalty of side effects. The real value of this work is that it enables us to take our first stpes in that direction.