In vivo interferon-gamma induced changes in gene expression dramatically alter neutrophil phenotype.

Area of Science:

• Immunology
• Cell Biology
• Pharmacology

Background:

• Interferon-gamma (IFN-γ) is used clinically for chronic granulomatous disease (CGD) patients to reduce infections.
• IFN-γ does not correct the primary defect in CGD, which is impaired oxidative burst.
• Understanding IFN-γ's effects on neutrophils (PMNs) is crucial for its therapeutic application.

Purpose of the Study:

• To investigate the dose- and time-dependent effects of IFN-γ administration on human volunteers.
• To analyze changes in plasma biomarkers and neutrophil function and gene expression.
• To explore the mechanisms behind IFN-γ's clinical benefits in CGD.

Main Methods:

• Adult volunteers received varying doses of IFN-γ.
• Blood samples were collected over 96 hours to measure plasma IFN-γ, IP-10, neopterin, and PMN O2- release.
• PMN gene expression, protein levels, and nitric oxide (NO) production were analyzed.

Main Results:

• Plasma levels of IFN-γ, IP-10, and neopterin increased dose- and time-dependently.
• Stimulated O2- release from PMNs showed a dose- and time-dependent increase.
• Gene expression in PMNs was significantly altered, with rapid changes and recovery within 24-36 hours. Upregulated genes included those for NADPH oxidase components, immune receptors, and NOS cofactor synthesis.
• Increased NO production was observed in neutrophil lysates.

Conclusions:

• IFN-γ administration modulates innate immune responses in neutrophils.
• IFN-γ enhances non-oxygen dependent microbicidal functions of PMNs.
• These findings provide a rationale for IFN-γ's efficacy in CGD and suggest broader therapeutic potential.