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and IL-10 production by primed human monocytes following interaction with oxidatively modified autologous erythrocytes
Departments of
* Anatomy, Cell Biology & Injury Sciences, and
Pediatrics, University of Medicine and Dentistry of New Jersey, New Jersey Medical School, Newark, New Jersey
Correspondence: Zoltán Spolarics, M.D., Ph.D., Associate Professor, UMDNJ-New Jersey Medical School, 185 South Orange Ave., MSB G-626, Newark, NJ 07103. E-mail: spolaric{at}umdnj.edu
The presence of dysfunctional/damaged red blood cells (RBCs) has
been associated with adverse clinical effects during the
inflammatory response. The aim of this study was to elucidate whether
oxidatively modified, autologous RBCs modulate monocyte cytokine
responses in humans. Monocyte tumor necrosis factor 
(TNF-) and
IL-10 production was measured in whole blood from healthy volunteers
using ELISA and flow cytometry. Oxidatively modified RBCs (15 mM
phenylhydrazine, 1 h, OX-RBC) or vehicle-treated RBCs (VT-RBC)
opsonized by autologous serum were administered alone or in combination
with one of three priming agents: E. coli
lipopolysaccharide (LPS, 0.2 ng/ml), zymosan A (1 mg/ml), or phorbol
12-myristate 13-acetate (PMA, 50 ng/ml). OX-RBC or VT-RBC alone did not
result in the release of TNF- or IL-10. LPS, zymosan, and PMA caused
marked and dose-dependent increases in TNF- and IL-10 production.
Addition of OX-RBC augmented the LPS-, zymosan-, and PMA-induced
TNF- release by approximately 100%. OX-RBC augmented LPS- and
zymosan-induced IL-10 release by 400–600%. Flow cytometry analyses
showed that monocytes were responsible for TNF- and IL-10 production
in whole blood. The presence of OX-RBC alone increased the complexity
of CD14+ monocytes but caused no cytokine production. LPS alone induced
cytokine production without altering cell complexity. After the
combined (OX-RBC+LPS) treatment, monocytes of high complexity were
responsible for TNF- production. The presence of mannose or
galactose (at 10–50 mM) did not alter the observed augmentation of
cytokine production by OX-RBC, suggesting that lectin receptors are not
involved in the response. These studies indicate that the interaction
between damaged autologous erythrocytes and monocytes has a major
impact on the cytokine responses in humans. An augmented cytokine
production by the mononuclear phagocyte system may adversely affect the
clinical course of injury and infections especially in genetic or
acquired RBC diseases or after transfusions.
Key Words: red blood cells • cytokines • oxidative stress • macrophage • host response • inflammation
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