Academic journal article Psychologische Beiträge

Negative Feedback Control of Inflammatory Leukocyte Recruitment by Stress-Induced Glucocorticoid Secretion

Academic journal article Psychologische Beiträge

Negative Feedback Control of Inflammatory Leukocyte Recruitment by Stress-Induced Glucocorticoid Secretion

Article excerpt


Exogenously administered glucocorticoids downregulate inflammatory host response, i.e. by inhibition of adhesion molecule expression on leukocyte surfaces. Here, possible associations between the trauma-induced endogenous secretion of cortisol and the expression of neutrophil adhesion molecules (L-selectin/CD62L, CD 11 lb, CD54) were studied in humans. Standardized elective hip arthroplasty was investigated as an exemplary condition of acute traumatic stress. In 20 patients, blood for quantification of cortisol and adrenocorticotropic hormone was obtained at minutes 10, 20, 30, 60, hours 1, 2, 4 and 10 and days 1,3 and 7. Expression of L-selectin/CD62L, CD1 lb and CD54 on neutrophil surfaces was determined preoperatively, and postoperatively at hours 1, 2, 3, 4, and 10 and at days 1 and 3. Secretion of both, adrenocorticotropic hormone and cortisol was significantly increased between 1-10 hours after onset of tissue injury. Compared to baseline values, CDllb expression was increased at hour 1 and normalized after day 1, whereas L-selectin/CD62L expression, mirroring this pattern was decreased until day 1. Patients with high endogenous glucocorticoid secretion exhibited significantly decreased expression selectively of L-selectin/CD62L. This inverse association between stress-induced cortisol secretion and expression of Lselectin/CD62L is consistent with a role of this neuroendocrine response as a negative feedback loop to attenuate exaggerated inflammatory leukocyte recruitment.

Key words: inflammation, host response, glucocorticoid.

Tissue injury, caused by trauma, ischemia, or burns non-specifically induces inflammatory and neuroendocrine changes in relation to its extent (1). The key event of the inflammatory response is the focal recruitment of polymorphonuclear neutrophils (PMNs) at sites of tissue irritation, aimed to eradicate devitalized tissue and to prevent secondary microbial invasion by virtue of their cytotoxic products such as oxygen free radicals, cytokines or proteases (2,3). Focal extravasation of PMNs into injured tissue occurs through several sequential steps. Initially, L-selectin (CD62L) on leukocyte surfaces interacts with endothelial counterreceptors, e.g. poorly characterized sialyl-Lewis`-bearing oligosaccharides, creating a marginating pool of PMNs that roll along the blood vessel wall in search of inflammatory signals (4,5). At this point, PMNs can still shed their L-selectin receptors and detach from the endothelium and contribute to the circulating pool since "LowL-selectin-PMNs" have decreased endothelial adherence (6). However, inflammatory signals on irritated tissue, e.g. leukotriene B4, platelet activating factor, or cytokines cause enhancement of the surface expression and avidity of the IiZ integrin MAC- 1 consisting of a B subunit (CDllb) linked to a 13 subunit (CD18). The interaction between this integrin and counterreceptors expressed on the surface of activated endothelial cells (e.g. ICAM-1, CD54) results in high-affinity binding of PMNs, which is finally followed by their transendothelial migration into the parenchyma (4).

Glucocorticoids belong to the most potent and widely used antiinflammatory drugs (7,8). An important mechanism of their action is the inhibition of leukocyte accumulation. In vitro, dexamethasone and hydrocortisone reduce adhesion between leukocytes and endothelium (9). In turn, the steroid receptor antagonist RU-486, that prevents translocation of ligated glucocorticoid receptor to the nucleus, completely abolishes these effects (10).

Exogenous glucocorticoids are, however, only artificial agonists mimicking the release of endogenous cortisol. Tissue injury-associated stress response is characterized by a strong endogenous glucocorticoid secretion (1). The aim of this longitudinal study was to test the hypothesis that the stress-induced endogenous glucocorticoid secretion is strong enough to interfere with adhesion between PMNs and endothelial cells in vivo. …

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