Glucocorticoids and the Th1/Th2 Balance

I. J. Elenkov

Clinical Neuroendocrinology Branch, National Institute of Mental Health, National Institutes of Health, Bethesda, MD 20892, U.S.A.

Immune responses are regulated by antigen-presenting cells (APC) -monocytes/macrophages and dendritic cells, and by natural killer (NK) cells that are components of innate immunity, and by the recently described T helper (Th) lymphocyte subclasses Th1 and Th2, that are components of adaptive (acquired) immunity. Th1 cells primarily secrete IFN-γ, IL-2 and TNFβ, which promote cellular immunity, whereas Th2 cells secrete a different set of cytokines, primarily IL-4, IL-10 and IL-13 which promote humoral immunity. Naive CD4⁺ (antigen-inexperienced) Th0 cells are clearly bipotential and serve as precursors of Th1 and Th2 cells. Among the factors currently known to influence the differentiation of these cells towards Th1 or Th2, cytokines produced by cells of the innate immune system are the most important. Thus, IL-12, produced by activated monocytes/macrophages or other APCs, is a major inducer of Th1 differentiation and hence cellular immunity. This cytokine acts in concert with NK-derived IFN-γ to further promote Th1 responses. APC-derived IL-12 and TNFα in concert with natural killer (NK) cell and Th1-derived IFN-γ stimulate the functional activity of T cytotoxic cells (Tc), NK cells and activated macrophages, which are the major components of cellular immunity. The type 1 cytokines IL-12, TNFα and IFN-γ also stimulate the synthesis of nitric oxide (NO) and other inflammatory mediators that drive chronic delayed type inflammatory responses. Because of these crucial and synergistic roles in inflammation IL-12, TNFα and IFN-γ are considered the major pro-inflammatory cytokines. Th1 and Th2 responses are mutually inhibitory. Thus, IL-12 and IFN-γ inhibit Th2 cells activities, while IL-4 and IL-10 inhibit Th1 responses. IL-4 and IL-10 promote humoral immunity by stimulating the growth and activation of mast cells and eosinophils, the differentiation of B cells into antibody-secreting B cells, and B cell immunoglobulin switching to IgE. Importantly, these cytokines also inhibit macrophage activation, T-cell proliferation and the production of pro-inflammatory cytokines. Therefore, the Th2 (type 2) cytokines IL-4 and IL-10 are the major anti-inflammatory cytokines.

Previous studies have shown that glucocorticoids suppress the production of TNFα, IFN-γ and IL-2 in vitro and in vivo in animals and humans. These early observations, in the context of the broad clinical use of glucocorticoids, initially led to the conclusion that stress hormones are, in general, immunosuppressive. Recent evidence indicates, however, that systemically, glucocorticoids cause selective suppression of Th1 responses and a shift towards Th2-mediated humoral immunity, rather than generalized immunosuppression. Thus, recent evidence indicates that glucocorticoids also act through their classic cytoplasmic/nuclear receptors on APCs to suppress the production of the main inducer of Th1 responses IL-12 in vitro and ex vivo. Since IL-12 is extremely potent in enhancing IFN-γ and inhibiting IL-4 synthesis by T cells, the inhibition of IL-12 production by APCs may represent a major mechanism by which glucocorticoids affect the Th1/Th2 balance. Thus, glucocorticoid-treated monocytes/macrophages produce significantly less IL-12, leading to their decreased capacity to induce IFN-γ production by antigen-primed CD4⁺ T cells. This is also associated with an increased production of IL-4 by T cells, probably resulting from disinhibition from the suppressive effects of IL-12 on Th2 activity. Furthermore, glucocorticoids potently downregulate the expression of IL-12 receptors on T and NK cells. This explains why human peripheral blood mononuclear cells (PBMCs) stimulated with immobilized anti-CD3 lose their ability to produce IFN-γ in the presence of glucocorticoids. Thus, although glucocorticoids may have a direct suppressive effect on Th1 cells, the overall inhibition of IFN-γ production by these cells appears to result mainly from the inhibition of IL-12 production by APCs and from the loss of IL-12 responsiveness of NK and Th1 cells.

It is particularly noteworthy that glucocorticoids have no effect on the production of the potent anti-inflammatory cytokine IL-10 by monocytes; yet, lymphocyte-derived IL-10 production appears to be upregulated by glucocorticoids. Thus, rat CD4⁺ T cells pretreated with dexamethasone exhibit increased levels of mRNA for IL-10. Similarly, during experimental endotoxemia or cardiopulmonary bypass, or in multiple sclerosis patients having an acute relapse, treatment with glucocorticoids is associated with increased plasma IL-10 secretion. This could be the result of a direct stimulatory effect of glucocorticoids on T cell IL-10 production and/or a block on the restraining inputs of IL-12 and IFN-γ on monocyte/lymphocyte IL-10 production. In contrast to catecholamines, glucocorticoids have a direct effect on Th2 cells by upregulating their IL-4, IL-10 and IL-13 production.

Although interest in the Th2 response was initially directed at its protective role in helminthic infections and its pathogenic role in allergy, this response may have important regulatory functions in countering the tissue-damaging effects of macrophages and Th1 cells. Thus, systemically, an excessive immune response, when circulating pro-inflammatory cytokines are high, or local inflammation through stimulation of the afferent vagus nerve fibers, stimulate the hypothalamic-pituitary-adrenal (HPA) axis. The subsequent release of glucocorticoids may trigger a mechanism that inhibits Th1 but potentiates Th2 responses. This important feed-back mechanism may protect the organism from ”overshooting” with type 1/pro-inflammatory cytokines and other products of activated macrophages with tissue damaging potential.