Dysregulation of in vitro cytokine production by monocytes during sepsis.

Abstract

The production by monocytes of interleukin-la (IL-la), interleukin-1lj# ), , and tumor necrosis factor alpha (TNFa) in intensive care unit (ICU) patients with sepsis syndrome (n = 23) or noninfectious shock (n = 6) is reported. Plasma cytokines, cell-associated cytokines within freshly isolated monocytes and LPS-induced in vitro cytokine production were assessed at admission and at regular intervals during ICU stay. TNFa and IL-6 were the most frequently detected circulating cytokines. Despite the fact that IL-la is the main cytokine found within monocytes upon in vitro activation of cells from healthy individuals, it was very rarely detected within freshly isolated monocytes from septic patients, and levels of cell-associated IL-1,@ were lower than those of TNFa. Cell-associated IL-1,6 and TNFa were not correlated with corresponding levels in plasma. Upon LPS stimulation, we observed a profound decrease of in vitro IL-la production by monocytes in all patients, and of IL-1if, IL-6, and TNFa in septic patients. This reduced LPS-induced production of cytokines was most pronounced in patients with gram-negative infections. Finally, monocytes from survival patients, but not from nonsurvival ones recovered their capacity to produce normal amounts of cytokines upon LPS stimulation. In conclusion, our data indicate an in vivo activation of circulating monocytes during sepsis as well as in noninfectious shock and suggest that complex regulatory mechanisms can downregulate the production of cytokines by monocytes during severe infections.

Sepsis-induced suppression of lung innate immunity is mediated by IRAK-M

“…It is also apparent that septic insults initiate concurrent or sequential antiinflammatory cascades during the course of sepsis, which likely mitigates the extent of inflammation and tissue injury. This antiinflammatory response, referred to as compensatory antiinflammatory response syndrome (CARS), is also believed to contribute to the increased susceptibility of critically ill patients to secondary nosocomial infections, due in part to sepsis-induced leukocyte "immunoparalysis" (2,5,8,11,(32)(33)(34)(35)(36). Interestingly, mortality is higher in patients with sepsis who display evidence of monocyte deactivation (2).…”

“…Interestingly, mortality is higher in patients with sepsis who display evidence of monocyte deactivation (2). Furthermore, monocytes isolated from patients who went on to survive their septic event were found to regain LPS responsiveness (2). At present, the molecular mechanisms underlying the immunoparalysis of sepsis remain poorly characterized.…”

“…One of the manifestations of sepsis-induced immunosuppression is macrophage dysfunction (1)(2)(3)(4)(5). Clearance of bacterial pathogens from the lung is largely dependent upon effective innate immune responses.…”

“…When the number of bacteria overwhelms the macrophage's bactericidal capabilities, the ability to mount an effective antimicrobial response requires the cytokine-mediated recruitment of neutrophils. Monocytes isolated from septic patients and experimental animals with sepsis have decreased phagocytic ability, reduced bactericidal activity, and attenuated proinflammatory cytokine production in response to ex vivo LPS stimulation (1)(2)(3)(4)(5)(7)(8)(9)(10)(11).…”

Pulmonary and Systemic Endotoxin Tolerance in Preterm Fetal Sheep Exposed to Chorioamnionitis

“…In contrast, endotoxin tolerance may inhibit host responses to invading pathogens. Endotoxin tolerance increases the risk of infections and mortality and thus is maladaptive in the intensive care setting (42). Approximately 25% of very low birth weight preterm neonates develop postnatal nosocomial sepsis (43).…”