Abstract
IL-32γ is a multifunctional cytokine involved in various inflammatory and auto-immune diseases in which neutrophils can affect the evolution of these diseases. To persist at inflammatory sites, neutrophils require inhibition of their rapid and constitutive apoptosis, an inhibitory effect that phlogogenic cytokines support. To date, the effects of IL-32γ on neutrophils remain unknown. We demonstrate that IL-32γ delays, in a dose-dependent manner, the spontaneous apoptosis of human blood neutrophils by activating mainly p38 MAPK through rapid p38 phosphorylation. PI3-K and ERK1/2 MAPK are also involved, but to a lesser extent. Most of cytokines that induce retardation of neutrophil apoptosis activate the expression of MCL-1 at both mRNA and protein levels. IL-32γ added to human blood neutrophils in vitro is associated with sustained levels of MCL-1 protein. This effect in neutrophils corresponds to a decrease of MCL-1 protein degradation without any effect on MCL-1 mRNA levels. The sustained levels of MCL-1 induced by IL-32γ are only abrogated by the p38β MAPK inhibitor SB202190. Additionally, IL-32γ induces a reduction in caspase 3 activity in neutrophils. In conclusion, IL-32γ affects human blood neutrophils in vitro by increasing their survival, suggesting that this cytokine could have profound effects on the deleterious functions of neutrophils in several diseases.
Highlights
Neutrophils are terminally differentiated cells that, in homeostatic conditions, constitutively undergo apoptosis in vivo and in vitro [1]
Knowing that IL-32 contributes to inflammation in rheumatoid arthritis, inflammatory bowel disease and cancer [43,46,47], chronic diseases in which neutrophils are implicated, we investigated the effect of IL-32c, the longest and the most active isoform, on neutrophil apoptosis
IL-32c reduced the levels of active pancaspase in a dose-dependent manner, which indicated an inhibitory effect of IL-32c on neutrophil apoptosis (Figure 1D)
Summary
Neutrophils are terminally differentiated cells that, in homeostatic conditions, constitutively undergo apoptosis in vivo and in vitro [1]. Circulating neutrophils can be considered as resting cells that remain in the blood a few hours only [2]. This short circulatory lifespan can greatly increase during infection and inflammation in response to secretion of cytokines and growth factors. These situations delay apoptosis of neutrophils, the lifespan of which can be extended to a few days. Neutrophil apoptosis is delayed in vitro by various cytokines including granulocyte-macrophage colonystimulating factor (GM-CSF), G-CSF, interleukin-1 (IL-1), IL-4 or IL-6 [3,4,5,6]. Retardation of neutrophil apoptosis by cytokines, inflammatory mediators or microorganisms could, lead to persistent inflammation and tissue damage induced by secretion of cytotoxic molecules such as reactive oxidants and proteases [7,8,9]
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