A Bovine Whey Protein Extract Stimulates Human Neutrophils to Generate Bioactive IL-1Ra through a NF-κB- and MAPK-Dependent Mechanism

Abstract

Innate immunity depends on the efficiency of neutrophils to be activated rapidly to restore homeostasis. It can benefit from priming agents that enhance neutrophil capacity to respond more efficiently to a subsequent stimulation. Among natural products, a bovine whey protein extract (WPE) has been shown to prime normal human blood neutrophils by enhancing their chemotaxis, phagocytosis, oxidative burst, and degranulation. These leukocytes are also an important source of cytokines, some of which have antiinflammatory functions. We investigated the role of WPE, as well as its mechanisms of action, on the production of interleukin (IL)-1 receptor antagonist (IL-1Ra) by neutrophils in vitro. WPE dose-dependently stimulated de novo synthesis and release of IL-1Ra by normal human blood neutrophils. Among the major proteins present in WPE, β-lactoglobulin (β-LG) and α-lactalbumin (α-LA) were the only active components. They had additive effects that exactly reproduced those of WPE. Similarly to WPE, they also stimulated the accumulation of IL-1β, IL-8, IL-6, macrophage inflammatory protein (MIP)-1α, MIP-1β, and tumor necrosis factor-α. However, neutrophils incubated with WPE, β-LG, and α-LA produced IL-1Ra in excess of IL-1β and the ratio IL-1Ra:IL-1β increased linearly. The amounts of IL-1Ra stimulated by WPE or β-LG + α-LA significantly reduced the IL-1 activity in EL4 cells. Inhibitors of p38 and extracellular signal-regulated kinases (ERK)1/2 mitogen-activated protein kinase, and nuclear factor-κB cascades reduced neutrophil production of IL-1Ra. Our data suggest that WPE, through β-LG + α-LA, has immunomodulatory properties and the potential to increase host defenses.