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

PLoS One. 2022 Feb 3;17(2):e0263370. doi: 10.1371/journal.pone.0263370. eCollection 2022.

Abstract

The cytokine Interferon-γ (IFN-γ) exerts powerful immunoregulatory effects on the adaptive immune system and also enhances functions of the neutrophil (PMN). The clinical use of IFN-γ has been driven by the finding that its administration to patients with chronic granulomatous disease (CGD) results in decreased incidence and severity of infections. However, IFN-γ has no effect on the characteristic defect of CGD, the inability to convert oxygen to microbicidal metabolites including superoxide anion (O2-) during the phagocytosis associated oxidative burst. We administered varying doses of IFN-γ to adult volunteers and studied the effects on plasma drug levels and response molecules and PMNs isolated from blood drawn at intervals over a 96- hour period. Plasma concentrations of IFN-γ, IP-10 and neopterin, and stimulated release of O2- from PMNs exhibited dose- and time-dependent increases after IFN-γ administration. Gene expression in PMNs was altered for 2775 genes; changes occurred rapidly after administration and returned to baseline in 24-36 hours. Several genes involved with neutrophil host defense were upregulated including those for components of the O2- generating NADPH oxidase; innate-immune and Fc receptors; proteins involved in MHCI and II; a regulator of circulating PMN number; guanylate binding proteins; and a key enzyme in synthesis of an essential NOS cofactor. Coordinate changes were detected in protein levels of representative products from several of these genes. Lysates from isolated neutrophils also demonstrated a spike in NO following IFN-γ administration. IFN-γ appears to increase non-oxygen dependent microbicidal functions of PMNs which could provide strategies to compensate for deficiencies, explain its clinical benefit for CGD patients and expand therapeutic applications of IFN-γ to other disorders. Trial registration: Protocol registered in ClinicalTrials.gov, NCT02609932, Effect of IFN-γ on Innate Immune Cells.

Publication types

  • Research Support, N.I.H., Extramural
  • Research Support, Non-U.S. Gov't

MeSH terms

  • Adolescent
  • Adult
  • Chemokine CXCL10 / biosynthesis
  • Gene Expression Profiling*
  • Gene Expression Regulation*
  • Granulomatous Disease, Chronic / drug therapy*
  • Granulomatous Disease, Chronic / genetics
  • Granulomatous Disease, Chronic / metabolism*
  • Healthy Volunteers
  • Humans
  • Interferon-gamma / biosynthesis
  • Interferon-gamma / pharmacology*
  • Middle Aged
  • NADPH Oxidases / metabolism
  • Neopterin / biosynthesis
  • Neutrophils / drug effects*
  • Neutrophils / metabolism
  • Phagocytosis
  • Phenotype
  • Respiratory Burst
  • Superoxides
  • Young Adult

Substances

  • CXCL10 protein, human
  • Chemokine CXCL10
  • IFNG protein, human
  • Superoxides
  • Neopterin
  • Interferon-gamma
  • NADPH Oxidases

Associated data

  • ClinicalTrials.gov/NCT02609932