Interleukin (il)-18 binding protein deficiency disrupts natural killer cell maturation and diminishes circulating il-18

Robert Z. Harms, Austin J. Creer, Kristina M. Lorenzo-Arteaga, Katie R. Ostlund, Nora E Sarvetnick

Research output: Contribution to journalArticle

11 Citations (Scopus)

Abstract

The cytokine interleukin (IL)-18 is a crucial amplifier of natural killer (NK) cell function. IL-18 signaling is regulated by the inhibitory effects of IL-18 binding protein (IL-18BP). Using mice deficient in IL-18BP (IL-18BPKO), we investigated the impact of mismanaged IL-18 signaling on NK cells. We found an overall reduced abundance of splenic NK cells in the absence of IL-18BP. Closer examination of NK cell subsets in spleen and bone marrow using CD27 and CD11b expression revealed that immature NK cells were increased in abundance, while the mature population of NK cells was reduced. Also, NK cells were polarized to greater production of TNF-α, while dedicated IFN-γ producers were reduced. A novel subset of IL-18 receptor α NK cells contributed to the expansion of immature NK cells in IL-18BPKO mice. Splenocytes cultured with IL-18 resulted in alterations similar to those observed in IL-18BP deficiency. NK cell changes were associated with significantly reduced levels of circulating plasma IL-18. However, IL-18BPKO mice exhibited normal weight gain and responded to LPS challenge with a >10-fold increase in IFN-γ compared to wild type. Finally, we identified that the source of splenic IL-18BP was among dendritic cells/macrophage localized to the T cell-rich regions of the spleen. Our results demonstrate that IL-18BP is required for normal NK cell abundance and function and also contributes to maintaining steady-state levels of circulating IL-18. Thus, IL-18BP appears to have functions suggestive of a carrier protein, not just an inhibitor.

Original languageEnglish (US)
Article number1020
JournalFrontiers in immunology
Volume8
Issue numberAUG
DOIs
StatePublished - Aug 28 2017

Fingerprint

Protein Deficiency
Interleukin-18
Natural Killer Cells
Interleukins
Interleukin-18 Receptors
interleukin-18 binding protein
Spleen
Dendritic Cells
Weight Gain
Carrier Proteins
Bone Marrow
Macrophages

Keywords

  • Cytokines
  • Inflammation
  • Innate immunity
  • Interleukin-18
  • Interleukin-18 binding protein
  • Mouse models
  • Natural killer cells
  • Spleen

ASJC Scopus subject areas

  • Immunology and Allergy
  • Immunology

Cite this

Interleukin (il)-18 binding protein deficiency disrupts natural killer cell maturation and diminishes circulating il-18. / Harms, Robert Z.; Creer, Austin J.; Lorenzo-Arteaga, Kristina M.; Ostlund, Katie R.; Sarvetnick, Nora E.

In: Frontiers in immunology, Vol. 8, No. AUG, 1020, 28.08.2017.

Research output: Contribution to journalArticle

Harms, Robert Z. ; Creer, Austin J. ; Lorenzo-Arteaga, Kristina M. ; Ostlund, Katie R. ; Sarvetnick, Nora E. / Interleukin (il)-18 binding protein deficiency disrupts natural killer cell maturation and diminishes circulating il-18. In: Frontiers in immunology. 2017 ; Vol. 8, No. AUG.
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abstract = "The cytokine interleukin (IL)-18 is a crucial amplifier of natural killer (NK) cell function. IL-18 signaling is regulated by the inhibitory effects of IL-18 binding protein (IL-18BP). Using mice deficient in IL-18BP (IL-18BPKO), we investigated the impact of mismanaged IL-18 signaling on NK cells. We found an overall reduced abundance of splenic NK cells in the absence of IL-18BP. Closer examination of NK cell subsets in spleen and bone marrow using CD27 and CD11b expression revealed that immature NK cells were increased in abundance, while the mature population of NK cells was reduced. Also, NK cells were polarized to greater production of TNF-α, while dedicated IFN-γ producers were reduced. A novel subset of IL-18 receptor α− NK cells contributed to the expansion of immature NK cells in IL-18BPKO mice. Splenocytes cultured with IL-18 resulted in alterations similar to those observed in IL-18BP deficiency. NK cell changes were associated with significantly reduced levels of circulating plasma IL-18. However, IL-18BPKO mice exhibited normal weight gain and responded to LPS challenge with a >10-fold increase in IFN-γ compared to wild type. Finally, we identified that the source of splenic IL-18BP was among dendritic cells/macrophage localized to the T cell-rich regions of the spleen. Our results demonstrate that IL-18BP is required for normal NK cell abundance and function and also contributes to maintaining steady-state levels of circulating IL-18. Thus, IL-18BP appears to have functions suggestive of a carrier protein, not just an inhibitor.",
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