Regulatory effects of beta-2-microglobulin on reactive oxygen species generation in polymorphonuclear cells

Beta-2-microglobulin (β2m) constitutes the invariant light chain of the major histocompatibility complex class I (MHC I) and is present on all nucleated cells, as well as in biological fluids, platelets and neutrophil granules. Immune cells can increase their production and secretion of β2m in response to cytokines such as IFN-γ, IFN-α, and TNF-α. Elevated β2m levels can be detected in various inflammatory, autoimmune, infectious and malignant diseases, often correlating with poor prognosis and reduced survival. So far, no specific functions have been agreed on for soluble β2m.

In the present study, we investigated the effects of exogenous β2m and two proteolytically processed forms, cK58β2m and dK58β2m, on ROS production in polymorphonuclear leukocytes (PMNs). β2m was shown to enhance ROS generation triggered by latex beads, while cK58β2m and dK58β2m suppressed both baseline ROS levels and responses to latex beads, TNF-α, and fMLF. Among these, dK58β2m was generally the most potent inhibitor. The inhibitory effect of cK58β2m and dK58β2m was also confirmed in DMSO-differentiated HL-60 cells, a neutrophil-like cell line. Furthermore, treatment with dK58β2m impaired the recruitment of p47phox and p67phox to the plasma membrane following fMLF stimulation, two key subunits of the NADPH oxidase complex responsible for superoxide anion production in neutrophils. This may explain the reduced ROS production observed in cells treated with dK58β2m.

Taken together, these results suggest that β2m, cK58β2m and dK58β2m can regulate ROS generation in PMNs and highlight a potential role for β2m in modulating the innate immune response through control of ROS production.