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

Abstract

BACKGROUND Recent studies demonstrate that glucocorticoids (GCs) have both supportive (stimulatory) and suppressive effects on immune responses, depending upon the GC concentration. Since some GC effects on inflammation are stimulatory, we hypothesized that acute in vivo GC depletion would decrease inflammatory responses of human monocytes. METHODS Monocytes were isolated from healthy volunteer participants before and after in vivo treatment with; 1) IV saline, 2) IV high dose hydrocortisone (8 μg · kg−1 · min−1) followed by oral hydrocortisone overnight, and 3) oral RU486 (200 mg at 0400 and 1600 h) to block the intracellular GC receptor and IV etomidate (1.5 mg · kg−1 · h−1) for 12 h to prevent compensatory adrenal cortisol synthesis. Plasma adrenocorticotropic hormone, plasma, and salivary cortisol were measured serially. Monocytes were tested for; 1) cytokine responses, 2) expression of CD163, CD119, and CD54, and 3) mRNA levels of GC-responsive inflammatory mediators. All measurements were made with and without in vitro stimulation of monocytes by lipopolysaccharide. RESULTS Cortisol and adrenocorticotropic hormone measurements demonstrated effective manipulation of in vivo cortisol. In vivo hypercortisolemia and in vivo GC depletion had reciprocal effects on monocyte mRNA levels of 4 important GC-responsive molecules: 1) GC receptor, CD163, interleukin-10, and suppressor of the cytokine synthesis-3. Monocyte cytokine responses and protein expression were not affected by GC depletion. CD163 expression was increased by hypercortisolemia. CONCLUSIONS Short-term GC depletion affects mRNA levels of GC-responsive molecules but does not affect monocyte protein expression or cytokine responses.

Glucocorticoids enhance the in vivo migratory response of human monocytes

“…Relative fluorescence units were assigned to these values and these data were used to generate the expression profiles delineated in the text. Consistent with our previous studies 36,37 , no changes in β-actin expression were observed with cortisol treatment excluding this as a source of bias in the analyses. The expression values of experimental genes were therefore normalized to their respective β-actin values.…”

Glucocorticoid treatment skews human monocyte differentiation into a hemoglobin-clearance phenotype with enhanced heme-iron recycling and antioxidant capacity

“…It has been shown experimentally that even stress concentrations of cortisone can increase CD163 expression, and monocytes with significantly enhanced CD163 have been detected after infusion of endotoxin in healthy persons as well as in patients with severe burn injury. [47][48][49] Therefore, it might be speculated that the stress-inducible Hb scavenger system has developed under the evolutionary pressure of infectious hemolytic diseases such as malaria. In these conditions, activation of the endogenous stress response might support monocyte/macrophage adaptation to extracellular Hb.…”

Glucocorticoids suppress cystathionine gamma-lyase expression and H2S production in lipopolysaccharide-treated macrophages

“…GCs have been shown to inhibit the release of pro-inflammatory cytokines including TNF-a, interleukin-1 (IL-1) and interleukin-6 (IL-6) [17], but promote phagocytosis of apoptotic cells by macrophages [30]. In addition, GCs have also been shown to induce changed expression of many pro-and antiinflammatory genes in human monocytes [31,32]. Recently, Li et al [33] reported that dexamethasone decreased the expression of CSE in isolated rat neutrophils.…”