Dysregulation of in vitro cytokine production by monocytes during sepsis.

TLDR

The study measured IL‑1α, IL‑1β, IL‑6, and TNFα production by monocytes in ICU patients with sepsis or noninfectious shock, assessing plasma, cell‑associated, and LPS‑stimulated cytokine levels at admission and over the ICU course. Septic patients showed low circulating IL‑1α, frequent TNFα and IL‑6, and a marked suppression of LPS‑induced IL‑1α, IL‑1β, IL‑6, and TNFα production—especially in gram‑negative infections—while survivors’ monocytes regained cytokine responsiveness, suggesting in vivo activation followed by regulatory down‑regulation during severe infection.

Abstract

The production by monocytes of interleukin-1 alpha (IL-1 alpha), interleukin-1 beta (IL-1 beta), interleukin-6 (IL-6), and tumor necrosis factor alpha (TNF alpha) 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. TNF alpha and IL-6 were the most frequently detected circulating cytokines. Despite the fact that IL-1 alpha 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 beta were lower than those of TNF alpha. Cell-associated IL-1 beta and TNF alpha were not correlated with corresponding levels in plasma. Upon LPS stimulation, we observed a profound decrease of in vitro IL-1 alpha production by monocytes in all patients, and of IL-1 beta, IL-6, and TNF alpha 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.