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Cytokines use different intracellular mechanisms to upregulate the membrane expression of CX3CR1 in human monocytes

Cecilia Analia Panek1, Andrea Cecilia Bruballa1, Gonzalo Ezequiel Pineda1

  • 1Laboratorio de Patogénesis e Inmunología de Procesos Infecciosos, Instituto de Medicina Experimental, Consejo Nacional de Investigaciones Científicas y Técnicas- Academia Nacional de Medicina, Buenos Aires, Argentina.

Molecular Immunology
|February 19, 2019
PubMed

Insights

Interleukin-10 (IL-10) and Interferon-gamma (IFN-γ) prevent CX3CR1 loss in monocytes. IL-10 increases CX3CR1 mRNA stability, while both cytokines activate STAT pathways, up-regulating CX3CR1 expression.

Area of Science:

  • Immunology
  • Cell Biology

Background:

  • Fractalkine receptor (CX3CR1) expression on monocytes (Mo) is crucial for homeostasis and disease.
  • Previous studies showed CX3CR1 levels decrease with culture and dendritic cell differentiation, but increase with macrophage differentiation.
  • Soluble factors like LPS, IL-10, and IFN-γ influence CX3CR1 expression, but intracellular pathways remain unclear.

Purpose of the Study:

  • To investigate the effects of anti-inflammatory cytokines (IL-4, IL-13, IL-10) alone or with IFN-γ on CX3CR1 expression in human monocytes.
  • To elucidate the intracellular mechanisms, including STAT and PI3K pathways, by which IL-10 and IFN-γ regulate CX3CR1 levels.

Main Methods:

  • Human monocytes were cultured with various cytokines (IL-4, IL-13, IL-10, IFN-γ) and their effects on CX3CR1 expression were analyzed.
  • Intracellular signaling pathways, including STAT phosphorylation and mRNA stability, were investigated using chemical inhibitors and molecular biology techniques.
  • CX3CR1 protein and mRNA levels were quantified to assess the impact of different treatments.

Main Results:

  • Only IL-10 and IFN-γ, when used separately, prevented the down-modulation of CX3CR1 during monocyte culture.
  • Combined IL-10 and IFN-γ treatment resulted in the highest cell-surface CX3CR1 expression, suggesting synergistic effects.
  • IL-10 and IFN-γ induced PI3K-dependent phosphorylation of STAT3 and STAT1, respectively, which was essential for their effects on CX3CR1.
  • IL-10 uniquely increased CX3CR1 mRNA levels by enhancing mRNA stability in a PI3K-dependent manner.

Conclusions:

  • IL-10 and IFN-γ differentially regulate CX3CR1 expression in human monocytes through distinct intracellular mechanisms.
  • Both cytokines converge on PI3K-dependent STAT activation to up-regulate CX3CR1 protein.
  • IL-10 additionally enhances CX3CR1 expression by increasing mRNA stability, highlighting a unique regulatory role.

Keywords:
CX3CR1IFN-γIL-10MonocytesSTAT1STAT3mRNA

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