In Vivo Exposure to High or Low Cortisol Has Biphasic Effects on Inflammatory Response Pathways of Human Monocytes

In 1949, Hench et al. surprised most of the medical community by reporting that glucocorticoids (GCs) suppress inflammation in humans.1 Their report, and a subsequent half century of research, effectively eclipsed decades of previous work by Selye and others who observed, in animals, stimulatory effects from GCs.2 Given the range of symptoms and pathophysiologic events that are caused by inflammation, it is not surprising that clinicians and researchers have chosen to search primarily for the antiinflammatory effect of GCs. Recently, human inflammatory responses have gained new levels of clinical significance with the emergence of the Systemic Inflammatory Response Syndrome (SIRS) and related conditions as a leading cause of death in hospitalized patients.3 No widely accepted treatment for this highly lethal condition is available, and overall mortality from SIRS continues to increase.4 Recent studies suggest that some patients may benefit from GC therapy of SIRS if they are in a (patho)physiologic state termed “relative adrenocortical insufficiency” but these studies have not been confirmed and it is still unclear which patients may benefit from GC treatment and whether the benefit is due to suppression of inflammation. Interestingly, Selye used the term “relative adrenocortical insufficiency” as early as 19405 in a conceptual framework in which cortisol was understood to stimulate the resistance of an organism to the effects of injury. Studies completed within the past 15 yr have used modern laboratory methods to reveal, at the cellular and molecular level, and often in a dose-dependent manner, stimulatory as well as suppressive effects of GCs on immune activity (Sapolsky et al. for recent review and definitions6). Perhaps most importantly, several studies report biphasic effects of GCs on the release of inflammatory mediators such as tumor necrosis factor-α (TNF-a), interleukin-6 (IL-6),7 acute phase proteins,8 and plasma macrophage migration inhibitory factor in vivo.9 These studies raise an important clinical question: Do all in vivo concentrations of cortisol have suppressive effects on human innate immune responses or do GC effects on immunity vary depending upon GC concentration? In this study we hypothesized that diurnal concentrations of cortisol support innate immune responses and that acute in vivo GC depletion would consequently act to decrease inflammatory responsiveness of circulating immune effector cells. Experimentally, we first either increased or decreased in vivo cortisol concentrations. Peripheral blood monocytes were then examined for their responses to the in vivo treatments and to further stimulation in vitro.