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Interplay between IFN-gamma and IL-6 signaling governs neutrophil trafficking and apoptosis during acute inflammation

Rachel M McLoughlin1, Janusz Witowski, Rachel L Robson

  • 1Institute of Nephrology, University of Wales College of Medicine, Heath Park, Cardiff, CF14 4XN, United Kingdom.

The Journal of Clinical Investigation
|August 20, 2003
PubMed

Insights

Interferon-gamma (IFN-γ) is crucial for controlling neutrophil (PMN) movement and clearance during inflammation. It modulates Interleukin-6 (IL-6) signaling via its soluble receptor (sIL-6R) to enhance PMN apoptosis and removal.

Area of Science:

  • Immunology
  • Inflammation research
  • Innate immunity

Background:

  • Neutrophil (PMN) recruitment and clearance are vital for host defense and resolving inflammation.
  • Interferon-gamma (IFN-γ) is a key cytokine in immune regulation.
  • Interleukin-6 (IL-6) signaling, particularly through its soluble receptor (sIL-6R), plays a role in inflammatory processes.

Purpose of the Study:

  • To investigate the role of IFN-γ in controlling neutrophil infiltration and apoptosis.
  • To elucidate the interplay between IFN-γ, IL-6 signaling, and neutrophil trafficking.
  • To understand how IFN-γ influences the resolution of inflammation.

Main Methods:

  • Utilized IFN-γ-deficient (IFN-γ-/-) and IL-6-deficient (IL-6-/-) mouse models.
  • Induced peritoneal inflammation to study neutrophil recruitment.
  • Administered IFN-γ and a soluble IL-6 receptor-IL-6 fusion protein (HYPER-IL-6) to modulate cytokine signaling.
  • Analyzed leukocyte infiltrate and neutrophil apoptosis.

Main Results:

  • IFN-γ deficiency impaired initial neutrophil recruitment and suppressed IL-1β and IL-6 expression.
  • IFN-γ signaling reconstitution restored neutrophil infiltration, IL-6 levels, and chemokine expression.
  • HYPER-IL-6 attenuated PMN influx in IFN-γ-/- mice, while IFN-γ had no effect in IL-6-/- mice.
  • Neutrophil apoptosis was impaired in the absence of IFN-γ and IL-6 due to aberrant sIL-6R signaling.

Conclusions:

  • IFN-γ critically regulates both neutrophil recruitment and clearance phases of innate immunity.
  • IFN-γ controls PMN infiltration and promotes apoptosis by modulating IL-6/sIL-6R signaling.
  • These findings highlight a significant role for IFN-γ in effective resolution of inflammation.

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