Antiinflammatory and immunosuppressive effects

Suppression of inflammatory and immune reactions and treatment of cancers of the lymphoid system are among the major applications of glucocorticoids. As noted above, despite early assumptions that such 'pharmacological' effects had no physiological basis, it is now clear that they are as physiological as are the effects on glucose metabolism. For example, induction of adrenal insufficiency in experimental animals (by adrenalectomy or administration of the glucocorticoid antagonist RU486) enhances inflammatory and immune reactions, showing that these reactions are physiologically regulated by endogenous glucocorticoids. Studies by Sternberg and coworkers also strongly suggest that dysregulation of the HPA axis can result in autoimmunity.

Anti-inflammatory and immunosuppressive actions of glucocorticoids are now known to be closely related, affecting nearly all cells that participate in immunity and inflammation and sharing fundamental cellular and molecular mechanisms that are under glucocorticoid influence. Glucocorticoids dramatically alter the distribution of leukocytes, markedly decreasing blood counts of lymphocytes, monocytes, eosinophils and basophils within 1-3 h of glucocorticoid administration. Recent work has shown that changes in blood leukocytc distribution result from glucocorticoid interaction with the type II adrenal steroid receptor. While neutrophil counts rise in the blood, glucocorticoids decrease the accumulation of leukocytes at inflammatory sites. Glucocorticoids also kill lymphocytes, largely by the initiation of apoptosis, a striking effect that is applied in the treatment of lymphocytic leukemias and lymphomas.

Numerous reactions that are fundamental to immunity - antigen-induced T and B cell proliferation, early B cell differentiation, antigen presentation, NK activity, differentiation and activation of macrophages - are suppressed by glucocorticoids. Although some of these are probably direct effects on the target cell being measured, others certainly involve indirect effects resulting from glucocorticoid regulation of intermediary molecules. In the past 20 years, the ability to glucocorticoids to inhibit the production of various inflammatory enzymes and cytokines, by mechanisms such as those outlined above, began to be recognized. Table 1 contains a partial list of mediators which are obligatory components of immune and inflammatory reactions

Table 1 Glucocorticoid regulation of mediators involved in immunity and inflammation

Increased mRNA and/or protein Annexin I (lipocortin-1) pa-Adrenergic receptor Macrophage inhibitory factor Decreased mRNA and/or protein

Interleukins 1, 2, 3, 4, 5, 6, 8, 11, 12, 13 (immune cytokines)

TNFa, GM-CSF, RANTES, MIP-1a, SCF (inflammatory cytokines/chemokines)

iNOS (inducible nitric oxide synthetase)

COX-2 (inducible cyclooxygenase)

cPLA2 (inducible phospholipase)

Endothelin-1 (bronchoconstrictor)

ICAM-1, VCAM-1 (adhesion molecules)

Collagenase, elastase, plasminogen activator (proteases)

Bradykinin, serotonin, histamine (inflammatory mediators)

and whose production is inhibited by glucocorticoids. Glucocorticoids also inhibit some effects of these mediators, such as responses of lymphocytes to IL-2 and of eosinophils to IL-3, IL-5, GM-CSF and IFNy. By blocking communication via cytokines, glucocorticoids cut off signals required for clonal expansion and differentiation of antigen-specific T and B cells, as well as signals which activate effector functions that participate in inflammatory reactions. It seems likely, therefore, that a principal mechanism through which glucocorticoids control immune and inflammatory reactions is by suppressing cytokines and other mediators.

The complexity of the interplay between glucocorticoids and inflammatory mediators is evidenced bv the increased expression of certain cytokine receptors in response to glucocorticoids, and probably by altered expression of glucocorticoid receptors induced by some cytokines. How might such effects fit with the models presented in Figures 3 and 4? Basal levels of glucocorticoid, and possibly the surge which occurs early in an immune response, may initially enhance the actions of cytokines by increasing expression of cytokine receptors. As cytokine concentrations rise, they act on the HPA to stimulate even higher levels of glucocorticoids which restrain further cytokine production unless very strong inflammatory signals persist. Normally, elimination of the antigen and resolution of the inflammation allows cytokine production to cease so that both cytokines and glucocorticoids return to basal levels. However, sustained inflammation with continued high levels of cytokines can persist in spite of high levels of glucocorticoid. This outcome might result in part from cytokine-induced reduction in glucocorticoid receptor expression, a mechanism postulated by some to contribute to steroid-resistant asthma.

See also: Anti-Inflammatory (nonsteroidal) drugs;

Arachidonic acid and the leukotrlenes; Immunosuppression; Annexins (llpocortins).

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