Postgrad Med J: first published as 10.1136/pgmj.52.612.631 on 1 October 1976. Downloaded from Postgraduate Medical Journal (October 1976) 52, 631-633.

Anti-inflammatory action of corticosteroids M. W. GREAVES M.D., M.R.C.P.

Institute of Dermatology, University of London

Summary The anti-inflammatory action of corticosteroids is com- plex. At a cellular level, they cause redistribution of granulocytes, resulting in increased circulating granu- locytes and reduced tissue pools. They also cause lymphopenia. The significance of these phenomena in relation to the anti-inflammatory activity of steroids is unknown. The most obvious pharmacological effects of corticosteroids are seen on blood vessels. They cause adrenergically mediated vasoconstriction and .'Fq,,:t;^.A^~~~~~~;rE .> i due to non-competitive antagonism of vasodilation Protected by copyright. prostaglandin E and bradykinin. t~~A4 W~~ Prostaglandin formation is inhibited by cortico- steroids but whether this is due to an effect on enzymic synthesis or release is uncertain. Corticosteroids -iiL' 8 l " ;' '. . .A -'' .'.. stabilize the lysosomal membrane preventing release 4 of enzymes in vitro but the of lysosomal significance FIG. 1. Simple representation of inflammatory response. this in vivo is debatable. A =mast cell, B =polymorphonuclear, C =monocyte. THE corticosteroids differ from almost all other responses to injury leads to spontaneous remission. anti-inflammatory drugs in that they are capable of It may well be that the pharmacological and cellular inhibiting virtually all the components of inflam- mechanisms involved in the natural termination of mation. It is proposed to deal with the anti-inflam- inflammation are just as important in terms of matory action of corticosteroids on three interrelated understanding the pathology and therapy of in-

components of the inflammatory response: (i) flammation as the mechanisms involved in its pro- http://pmj.bmj.com/ inflammatory cells; (ii) blood vessels; (iii) release or duction. formation of mediators. The initial phase of the inflammatory response Before embarking on this scheme it is worth con- is due to released histamine from the tissue mast sidering some general features common to most cell. Experiments with cytotoxic polymorphonuclear inflammatory responses. Figure 1 shows an in- depleting agents (Willoughby and Spector, 1968) flammatory response in its simplest form. The re- suggest that polymorphs, if involved, may play only sponse to injury is bimodal. There is an initial a minor part in the delayed response because granu- transitory increase in vasoactivity which soon lopenic animals show a normal delayed response. on September 24, 2021 by guest. dwindles. It is soon followed by a gradual rise to a On the other hand, the appearance of mediators of sustained plateau of vasodilatation or increased per- the delayed response appears to be associated with meability. The delayed phase of the reaction finally mononuclear leucocytes. dwindles after about 24 hr or more. The biphasic The interactions of the mediators of the delayed reaction can be identified clinically although it is often reaction are probably very complex. The E prosta- overlooked. In the skin an immediate transitory glandins (PGE) and the F prostaglandins (PGF), erythematous phase occurs after short wavelength both of which are present in the delayed inflam- u.v. irradiation, to be followed by the characteristic matory response, act in opposition to each other, delayed 'sunburn' erythema. PGE causing vasodilatation and PGF causing vaso- Much effort has gone into the identification of constriction (Crunkhorn and Willis, 1971). The mediators which bring about this dual response. spontaneous resolution of inflammation could well However, the natural history of most inflammatory be a result of an increase in the proportion of F Postgrad Med J: first published as 10.1136/pgmj.52.612.631 on 1 October 1976. Downloaded from 632 M. W. Greaves

relative to E. At the same time PGE enhances the tologists is the production of arteriolar vasocon- inflammation-producing potentiation of pharma- striction by potent glucocorticoids when applied cological actions of histamine and bradykinin topically. There is considerable evidence to indicate (Moncada, Ferriera and Vane, 1973). Thus PGE, in that the vasoconstrictor action of glucocorticoids doses which alone do not cause whealing, will is due not to a direct action but to sensitization amplify whealing due to histamine or bradykinin. of vascular muscle to noradrenaline. For example, Synergism seems to be an important factor in the guanethidine, which prevents release of noradrena- pharmacology of delayed inflammation. PGE has line from sympathetic nerve endings, prevents a further action on secretion of histamine. PGE steroid vasoconstriction (Solomon, Wentzel and causes inhibition of histamine secretion by mast cells Greenberg, 1965). Independently of this, gluco- via a negative feedback mechanism (Lichtenstein corticoids have been found to antagonize the vaso- et al., 1972). The feedback inhibition is probably dilator actions of bradykinin and PGE. Thus it can dependent upon activation of the adenyl cyclase- be said that glucocorticoids modulate the response of cyclic AMP mechanism of the mast cell via prosta- the blood vessels to naturally-occurring vasodilator glandin-specific adenylcyclase receptors. It seems and vasoconstrictor agents. The explanation for this clear that inflammation is the result of complex non-specific modulating action is unknown, but a interaction between several different mediators. plausible idea put forward by Bush (1962) suggests that glucocorticoids induce a conformational change The relationship of the anti-inflammatory action of in the receptor molecule thus preventing drug- corticosteroids to cellular changes in inflammation receptor combination. In man, neutrophilia occurs 24 hr after a systemic dose of prednisolone. This seems to be related to a The actions of glucocoiticoids at a biochemical diminution of the marginal pool of neutrophils, level especially in the lungs, which in turn is related to One of the most exciting developments in ourProtected by copyright. reduced granulocyte or possibly endothelial sticki- knowledge of the actions of anti-inflammatory drugs ness (Peters et al., 1972). Whether the anti-inflam- has been their actions on the prostaglandin syn- matory action of prednisone may be related, at least thetizing enzyme system. Prostaglandins are not in part, to diminution of the local population of normally found free or stored in tissues. They are polymorphs in an inflammatory lesion seems to be synthetized locally in response to injury. uncertain, especially in view of the animal experi- The pathway for biosynthesis of the 20-carbon ments of Willoughby and his colleagues referred to fatty acids PGE and PGF is exemplified by the path- above, which suggest that at least in some laboratory way for synthesis of PGE2 and PGF2oC from arachi- animal models, neutrophils had no more than a donic acid substrate. The source of this substrate is minor role in delayed inflammation. There is also cell membrane lipid probably released as a result of evidence listed by Ward (1966) that steroids in the action of the lysosomal enzyme phospholipase. therapeutic concentrations can inhibit neutrophil The action of a mixture of enzymes present in the chemotaxis. microsomal fraction collectively termed prosta- http://pmj.bmj.com/ The effect of corticosteroids on lymphocytes is glandin synthetase converts arachidonic acid to complex, and has been the subject of a review by PGE2 and PGF2oc by an oxygenation process. During Claman (1975). Lymphopenia occurs after a single the course of this reaction, intermediates are formed dose of prednisolone and this involves both B and including peroxides and cyclic endoperoxides. These T lymphocytes. The response of the remaining T are extremely labile, having a half-life of less than 5 lymphocytes to antigen and concanavallin A is im- min and are therefore very difficult to study. However, paired but both numbers and reactivity return to it appears they are highly active pharmacologically normal within 24 hr. The mechanism for steroid- and may be as important as PGE, and PGF2o in the on September 24, 2021 by guest. induced lymphopenia is uncertain. Lymphocyto- response to injury. lysis seems unlikely in view of the rapid return of the The important discovery made by Vane and his peripheral blood lymphocyte count to normal levels. colleagues (Vane, 1971) was that the enzymic reac- Alternatively the lowered counts may be a result of tion could be inhibited by non-steroid anti-inflam- redistribution of lymphocytes between blood and matory drugs including aspirin, indomethacin and bone marrow. There is also some in vitro and in vivo paracetamol, probably by blocking binding sites on evidence suggesting that corticosteroids in high the enzyme. He found that corticosteroids had little dosage interfere with phagocytosis by macrophages. or no action on the enzyme. He concluded that the analgesic and anti-pyretic actions of these non- The pharmacological actions of corticosteroids rele- steroid drugs was due to their ability to inhibit vant to their actions as anti-inflammatory agents prostaglandin synthetase. However, it has now An observation particularly familiar to derma- become apparent that corticosteroids do have a Anti-inflammatory steroids 633 Postgrad Med J: first published as 10.1136/pgmj.52.612.631 on 1 October 1976. Downloaded from more complex inhibitory action on PG formation. actions can be distinguished at cellular, pharma- The present author (Greaves and McDonald-Gibson, cological and biochemical levels. There are also a 1972) studied the effect of steroid and non-steroid number of other probably important modes of action anti-inflammatory drugs on prostaglandin synthetase including a stimulatory action on the adenyl cyclase- from skin. Like Vane he found that if he used a cyclic adenosine monophosphate system and on purified enzyme preparation he obtained significant histamine formation which have not been discussed dose-related inhibition of synthesis by the non- here. Because of the toxic effects of available cor- steroid drugs and none by potent steroids such as ticosteroids, new alternatives are badly needed. The fluocinolone and betamethasone. By contrast, if a difficulty with developing non-steroid anti-inflam- crude skin homogenate was used, it was possible to matory alternatives to corticosteroids is that known obtain convincing inhibition of PG biosynthesis by classes of non-steroid anti-inflammatory agents pos- corticosteroids as well as by the non-steroid drugs. sess a much more limited range of anti-inflammatory It now seems from further work by others that actions. Most effort is therefore being currently steroids, although not inhibiting the synthetizing directed towards increasing the therapeutic index of enzyme, may prevent the release of prostaglandins. existing steroids. Lewis has demonstrated inhibition of release of References prostaglandins from adipose tissue undergoing BUSH, I.E. (1962) Chemical and biological factors in the functional vasodilation as a result of hormone- activity of adrenal cortical steroids. Pharmacological evoked lipolysis (Piper and Lewis, 1975) and Levine Reviews, 13, 317. CHAYEN, J., BITENSKY, L., BUTCHER, R.G., POULTER, L.W. & (Kantrowitz et al., 1975) at Brandeis University, has UBHI, G.S. (1970) Methods for the direct measurement of shown that prostaglandin release from rheumatoid anti-inflammatory actions on human tissue maintained in synovia is inhibited in vitro by steroids. Thus, both vitro. British Journal of Dermatology, 82, Suppl. 6, 62. non-steroid and steroid anti-inflammatory drugs CLAMAN, H.N. (1975) How corticosteroids work. Journal of Allergy and Clinical Immunology, 55, 145. Protected by copyright. interfere with prostaglandin production in tissues in CRUNKHORN, P. & WILLIS, A.L. (1971) Interaction between the response to injury although they act at different prostaglandin E and F given intradermally in the rat. points in the reaction sequence. British Journal of Pharmacology, 41, 507. Corticosteroids may of course have more than one GREAVES, M.W. & MCDONALD-GIBSON, W. (1972) Prosta- action on the system. It glandin biosynthesis by human skin and its inhibition by PG-synthetizing has also corticosteroids. British Journal of Pharmacology, 46, 172. been suggested that corticosteroids may act earlier KANTROWITZ, F., ROBINSON, D.R., MCGUIRE, M.B. & on by preventing release by injury of the lysosomal LEVINE, L. (1975) Corticosteroids inhibit prostaglandin enzyme phospholipase, whose activity seems essen- production by rheumatoid synovia. Nature. London, tial for release of the prostaglandin forming substrate 258, 737. LICHTENSTEIN, L.M., GILLESPIE, E., BOURNE, H.R. & HENNEY, arachidonic acid as a prelude to prostaglandin C.S. (1972) The effects of a series of prostaglandins on in biosynthesis. vitro models of the allergic response and cellular immunity. This is an opportunity to consider the much Prostaglandins, 2, 519. argued problem of the relevance of the lysosomal MONCADA, S., FERRIERA, S.A. & VANE, J.R. (1973) Prosta- membrane stabilizing properties of glucocorticoids glandins aspirin-like drugs at the oedema of inflammation.

Nature. London, 246, 217. http://pmj.bmj.com/ described by Weissman (1969) to their supposed PETERS, W.P., HOLLAND, J.F., SENN, H., RHOMBERG, W. & therapeutic mode of action. There is no doubt that BANERGEL, T. (1972) Corticosteroid administration and corticosteroids have the ability to stabilize mem- localised leucocyte mobilisation in man. New England Journal of Medicine, 286, 342. branes. This has clearly been established for lyso- PIPER, P.J. & LEWIS, G.P. (1975) Inhibition of release of somal and mitochondrial membranes by Chayen prostaglandins as an explanation of some of the actions of et al. (1970) and is probably due to formation of anti-inflammatory corticosteroids. Nature. London, 254, protein-steroid-phospholipid complexes. Some 308. SOLOMON, L.M., WENTZEL, H.E. & GREENBERG, M.S. (1965) doubt has, however, been cast on the significance of Studies in the mechanism of steroid vasoconstriction. on September 24, 2021 by guest. this effect in relation to in vivo anti-inflammatory Journal of Investigative Dermatology, 44, 129. activity because of the lack of correlation between VANE, J.R. (1971) Inhibition of prostaglandin synthesis as a rank order of potency in lysosomal membrane mechanism of action for anti-inflammatory drugs. Nature. New Biology, 231, 232. stabilization and anti-inflammatory activity of WARD, P.A. (1966) The chemosuppression of chemotaxis. steroids ill vitro. Journal of Experimental Medicine, 124, 209. It must, finally, be pointed out that steroids are a WEISSMAN, G. (1969) The effect of steroid and drugs on lyso- unique class of anti-inflammatory drug in that they somes. In: Frontiers ofBiology, pp. 276-295. North Holland Publishing Co., Amsterdam. seem to inhibit most or all of the major components of WILLOUGHBY, D.A. & SPECTOR, W.G. (1968) Inflammation inflammation. Thus, it is not surprising that separate in agranulocytic rats. Nature. London, 219, 5160.