Glucocorticoids-All-Rounders Tackling the Versatile Players of the Immune System.

Cindy Strehl,Lisa Ehlers,Timo Gaber,Frank Buttgereit

doi:10.3389/fimmu.2019.01744

Abstract

Glucocorticoids regulate fundamental processes of the human body and control cellular functions such as cell metabolism, growth, differentiation, and apoptosis. Moreover, endogenous glucocorticoids link the endocrine and immune system and ensure the correct function of inflammatory events during tissue repair, regeneration, and pathogen elimination via genomic and rapid non-genomic pathways. Due to their strong immunosuppressive, anti-inflammatory and anti-allergic effects on immune cells, tissues and organs, glucocorticoids significantly improve the quality of life of many patients suffering from diseases caused by a dysregulated immune system. Despite the multitude and seriousness of glucocorticoid-related adverse events including diabetes mellitus, osteoporosis and infections, these agents remain indispensable, representing the most powerful, and cost-effective drugs in the treatment of a wide range of rheumatic diseases. These include rheumatoid arthritis, vasculitis, and connective tissue diseases, as well as many other pathological conditions of the immune system. Depending on the therapeutically affected cell type, glucocorticoid actions strongly vary among different diseases. While immune responses always represent complex reactions involving different cells and cellular processes, specific immune cell populations with key responsibilities driving the pathological mechanisms can be identified for certain autoimmune diseases. In this review, we will focus on the mechanisms of action of glucocorticoids on various leukocyte populations, exemplarily portraying different autoimmune diseases as heterogeneous targets of glucocorticoid actions: (i) Abnormalities in the innate immune response play a crucial role in the initiation and perpetuation of giant cell arteritis (GCA). (ii) Specific types of CD4+ T helper (Th) lymphocytes, namely Th1 and Th17 cells, represent important players in the establishment and course of rheumatoid arthritis (RA), whereas (iii) B cells have emerged as central players in systemic lupus erythematosus (SLE). (iv) Allergic reactions are mainly triggered by several different cytokines released by activated Th2 lymphocytes. Using these examples, we aim to illustrate the versatile modulating effects of glucocorticoids on the immune system. In contrast, in the treatment of lymphoproliferative disorders the pro-apoptotic action of glucocorticoids prevails, but their mechanisms differ depending on the type of cancer. Therefore, we will also give a brief insight into the current knowledge of the mode of glucocorticoid action in oncological treatment focusing on leukemia.

Highlights

Hormones enable intercellular communication as well as the exchange of information between different organ systems throughout the human body
Steroids are lipophilic hormones that are subdivided into mineralocorticoids produced in the zona glomerulosa of the adrenal cortex, glucocorticoids produced in the zona fasciculata as well as sex hormones produced in the zona reticularis and to a great extent in the gonads
These findings clearly show that our knowledge concerning the mechanisms of glucocorticoid action—including the desirable anti-inflammatory and the undesirable adverse effects—is yet insufficient

Summary

INTRODUCTION

Hormones enable intercellular communication as well as the exchange of information between different organ systems throughout the human body. RA patients present an enrichment of effector memory CD4+CD45RO+ T cells in the affected joints [89] and a massive expansion CD4+ T cell clones in synovial tissue of early disease, which suggests a local antigen-induced proliferation [90] In this context, it should be noted that blocking co-stimulation targeting CD80/CD86-CD28 interaction significantly improved the signs and symptoms of RA illustrating the importance of T cells in the pathogenesis [91]. Glucocorticoids decrease IFN-γ production by T cells from patients with rheumatoid arthritis ex vivo and in vitro mechanistically via their suppressive action on the IL-12-induced STAT4 phosphorylation and by direct protein-protein interaction with the transcription factor T-BET— described as transrepression in the introduction (Figure 3) [116,117,118,119]. IL-17 contributes to neutrophil recruitment [122] and an increase in neutrophil survival, a hallmark of RA synovial fluid promoting joint damage (Figure 2) [122,123,124]

B Cells Have Emerged as Central Players in Systemic Lupus Erythematosus

Findings

CONCLUDING REMARKS