Artikel
Effects of tocilizumab on neutrophil survival and function
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Veröffentlicht: | 1. September 2015 |
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Gliederung
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Introduction: The synovial tissue in rheumatoid arthritis (RA) represents a hypoxic environment with up-regulated pro-inflammatory cytokines and cellular infiltrates including neutrophils. Although inhibition of the IL-6 receptor pathway by tocilizumab is a potent treatment for RA, it may also cause unwanted effects such as an occasionally high grade neutropenia.
Here, we analyzed the impact of tocilizumab on survival, mediator secretion, oxidative burst, phagocytosis, and energy availability of neutrophils under normoxic versus hypoxic conditions.
Methods: Human neutrophils were purified, pre-treated with varying doses of tocilizumab and, for comparison, dexamethasone or vehicle/human IgG and stimulated with LPS alone, LPS plus IL-6, or left unstimulated. Cells were then incubated under normoxic (18%O2) or hypoxic (1%O2) conditions and subsequently analyzed.
Results: Both neutrophil survival and energy availability were significantly decreased by tocilizumab in a dose-dependent manner in LPS-stimulated cells, but to a greater extent under normoxia as compared to hypoxia. We also found LPS-stimulated oxidative burst and phagocytosis of neutrophils to be higher under hypoxic versus normoxic conditions, but this difference was reduced by tocilizumab. Finally, we observed that tocilizumab affected neutrophil mediator secretion as a function of oxygen availability.
Conclusion: Tocilizumab is known for both beneficial effects and a higher incidence of neutropenia when treating RA patients. Our results suggest that both effects can at least in part be explained by a reduction in neutrophil survival, a dose-dependent inhibition of a hypoxia-induced oxidative burst and phagocytosis of infiltrating hypoxic neutrophils and alteration of mediator secretion.