Inhibition of natural killer cell cytotoxicity by interleukin-6: Implications for the pathogenesis of macrophage activation syndrome

Research output: Contribution to journalArticle

44 Citations (Scopus)

Abstract

Objective Systemic juvenile idiopathic arthritis (JIA) is associated with high levels of interleukin-6 (IL-6) in the serum and synovial fluid, and impairment of natural killer (NK) cell function is often observed. This study was undertaken to evaluate a possible link between these 2 biologic findings and whether they may be associated with the development of macrophage activation syndrome, a condition frequently observed in systemic JIA. Methods Splenocytes from wild-type (WT) or IL-6-transgenic (Tg) mice were evaluated for NK cell cytotoxicity using a 51Cr-release assay. Numbers of NK cells and expression of perforin, granzyme B, CD69, and CD107a were evaluated by flow cytometry. Human peripheral blood mononuclear cells (PBMCs) isolated from healthy donors were treated with IL-6 and cultured in the presence or absence of tocilizumab (TCZ), an IL-6 receptor blocker. Human polyclonal NK cells from healthy donor PBMCs were evaluated for cell cytotoxicity and expression of perforin, granzyme B, and CD107a. PBMCs harvested from patients with systemic JIA during periods of active or inactive disease were left untreated or treated with IL-6 in combination with soluble IL-6 receptor and analyzed for the expression of perforin and granzyme B. Results Splenic NK cell cytotoxicity was reduced in IL-6-Tg mice compared to WT mice. Levels of CD69 and CD107a showed no significant differences, whereas expression of perforin and granzyme B was impaired in NK cells from IL-6-Tg mice. Exposure of human peripheral blood NK cells to IL-6 led to reduced expression of perforin and granzyme B. Culturing human polyclonal NK cells in the presence of TCZ significantly increased cell cytotoxicity, and also increased expression of perforin and granzyme B. In patients with systemic JIA, a reduction in IL-6 plasma levels during disease remission correlated with the rescue of perforin and granzyme B expression in NK cells from these patients. Conclusion In both mice and humans, IL-6 down-modulated the cytotoxic activity of NK cells. This decrease was associated with reduced perforin and granzyme B levels in the absence of altered granule exocytosis.

Original languageEnglish
Pages (from-to)3037-3046
Number of pages10
JournalArthritis and Rheumatology
Volume67
Issue number11
DOIs
Publication statusPublished - Nov 1 2015

Fingerprint

Macrophage Activation Syndrome
Natural Killer Cells
Interleukin-6
Juvenile Arthritis
Blood Cells
Interleukin-6 Receptors
Tissue Donors
perforin-granzyme B
Synovial Fluid
Exocytosis
Transgenic Mice
Flow Cytometry

ASJC Scopus subject areas

  • Immunology
  • Immunology and Allergy
  • Rheumatology
  • Medicine(all)

Cite this

@article{cb77e072cc784c1fbd07243e994709e7,
title = "Inhibition of natural killer cell cytotoxicity by interleukin-6: Implications for the pathogenesis of macrophage activation syndrome",
abstract = "Objective Systemic juvenile idiopathic arthritis (JIA) is associated with high levels of interleukin-6 (IL-6) in the serum and synovial fluid, and impairment of natural killer (NK) cell function is often observed. This study was undertaken to evaluate a possible link between these 2 biologic findings and whether they may be associated with the development of macrophage activation syndrome, a condition frequently observed in systemic JIA. Methods Splenocytes from wild-type (WT) or IL-6-transgenic (Tg) mice were evaluated for NK cell cytotoxicity using a 51Cr-release assay. Numbers of NK cells and expression of perforin, granzyme B, CD69, and CD107a were evaluated by flow cytometry. Human peripheral blood mononuclear cells (PBMCs) isolated from healthy donors were treated with IL-6 and cultured in the presence or absence of tocilizumab (TCZ), an IL-6 receptor blocker. Human polyclonal NK cells from healthy donor PBMCs were evaluated for cell cytotoxicity and expression of perforin, granzyme B, and CD107a. PBMCs harvested from patients with systemic JIA during periods of active or inactive disease were left untreated or treated with IL-6 in combination with soluble IL-6 receptor and analyzed for the expression of perforin and granzyme B. Results Splenic NK cell cytotoxicity was reduced in IL-6-Tg mice compared to WT mice. Levels of CD69 and CD107a showed no significant differences, whereas expression of perforin and granzyme B was impaired in NK cells from IL-6-Tg mice. Exposure of human peripheral blood NK cells to IL-6 led to reduced expression of perforin and granzyme B. Culturing human polyclonal NK cells in the presence of TCZ significantly increased cell cytotoxicity, and also increased expression of perforin and granzyme B. In patients with systemic JIA, a reduction in IL-6 plasma levels during disease remission correlated with the rescue of perforin and granzyme B expression in NK cells from these patients. Conclusion In both mice and humans, IL-6 down-modulated the cytotoxic activity of NK cells. This decrease was associated with reduced perforin and granzyme B levels in the absence of altered granule exocytosis.",
author = "Loredana Cifaldi and Giusi Prencipe and Ivan Caiello and Claudia Bracaglia and Franco Locatelli and {De Benedetti}, Fabrizio and Raffaele Strippoli",
year = "2015",
month = "11",
day = "1",
doi = "10.1002/art.39295",
language = "English",
volume = "67",
pages = "3037--3046",
journal = "Arthritis and Rheumatology",
issn = "2326-5191",
publisher = "John Wiley and Sons Ltd",
number = "11",

}

TY - JOUR

T1 - Inhibition of natural killer cell cytotoxicity by interleukin-6

T2 - Implications for the pathogenesis of macrophage activation syndrome

AU - Cifaldi, Loredana

AU - Prencipe, Giusi

AU - Caiello, Ivan

AU - Bracaglia, Claudia

AU - Locatelli, Franco

AU - De Benedetti, Fabrizio

AU - Strippoli, Raffaele

PY - 2015/11/1

Y1 - 2015/11/1

N2 - Objective Systemic juvenile idiopathic arthritis (JIA) is associated with high levels of interleukin-6 (IL-6) in the serum and synovial fluid, and impairment of natural killer (NK) cell function is often observed. This study was undertaken to evaluate a possible link between these 2 biologic findings and whether they may be associated with the development of macrophage activation syndrome, a condition frequently observed in systemic JIA. Methods Splenocytes from wild-type (WT) or IL-6-transgenic (Tg) mice were evaluated for NK cell cytotoxicity using a 51Cr-release assay. Numbers of NK cells and expression of perforin, granzyme B, CD69, and CD107a were evaluated by flow cytometry. Human peripheral blood mononuclear cells (PBMCs) isolated from healthy donors were treated with IL-6 and cultured in the presence or absence of tocilizumab (TCZ), an IL-6 receptor blocker. Human polyclonal NK cells from healthy donor PBMCs were evaluated for cell cytotoxicity and expression of perforin, granzyme B, and CD107a. PBMCs harvested from patients with systemic JIA during periods of active or inactive disease were left untreated or treated with IL-6 in combination with soluble IL-6 receptor and analyzed for the expression of perforin and granzyme B. Results Splenic NK cell cytotoxicity was reduced in IL-6-Tg mice compared to WT mice. Levels of CD69 and CD107a showed no significant differences, whereas expression of perforin and granzyme B was impaired in NK cells from IL-6-Tg mice. Exposure of human peripheral blood NK cells to IL-6 led to reduced expression of perforin and granzyme B. Culturing human polyclonal NK cells in the presence of TCZ significantly increased cell cytotoxicity, and also increased expression of perforin and granzyme B. In patients with systemic JIA, a reduction in IL-6 plasma levels during disease remission correlated with the rescue of perforin and granzyme B expression in NK cells from these patients. Conclusion In both mice and humans, IL-6 down-modulated the cytotoxic activity of NK cells. This decrease was associated with reduced perforin and granzyme B levels in the absence of altered granule exocytosis.

AB - Objective Systemic juvenile idiopathic arthritis (JIA) is associated with high levels of interleukin-6 (IL-6) in the serum and synovial fluid, and impairment of natural killer (NK) cell function is often observed. This study was undertaken to evaluate a possible link between these 2 biologic findings and whether they may be associated with the development of macrophage activation syndrome, a condition frequently observed in systemic JIA. Methods Splenocytes from wild-type (WT) or IL-6-transgenic (Tg) mice were evaluated for NK cell cytotoxicity using a 51Cr-release assay. Numbers of NK cells and expression of perforin, granzyme B, CD69, and CD107a were evaluated by flow cytometry. Human peripheral blood mononuclear cells (PBMCs) isolated from healthy donors were treated with IL-6 and cultured in the presence or absence of tocilizumab (TCZ), an IL-6 receptor blocker. Human polyclonal NK cells from healthy donor PBMCs were evaluated for cell cytotoxicity and expression of perforin, granzyme B, and CD107a. PBMCs harvested from patients with systemic JIA during periods of active or inactive disease were left untreated or treated with IL-6 in combination with soluble IL-6 receptor and analyzed for the expression of perforin and granzyme B. Results Splenic NK cell cytotoxicity was reduced in IL-6-Tg mice compared to WT mice. Levels of CD69 and CD107a showed no significant differences, whereas expression of perforin and granzyme B was impaired in NK cells from IL-6-Tg mice. Exposure of human peripheral blood NK cells to IL-6 led to reduced expression of perforin and granzyme B. Culturing human polyclonal NK cells in the presence of TCZ significantly increased cell cytotoxicity, and also increased expression of perforin and granzyme B. In patients with systemic JIA, a reduction in IL-6 plasma levels during disease remission correlated with the rescue of perforin and granzyme B expression in NK cells from these patients. Conclusion In both mice and humans, IL-6 down-modulated the cytotoxic activity of NK cells. This decrease was associated with reduced perforin and granzyme B levels in the absence of altered granule exocytosis.

UR - http://www.scopus.com/inward/record.url?scp=84946022428&partnerID=8YFLogxK

UR - http://www.scopus.com/inward/citedby.url?scp=84946022428&partnerID=8YFLogxK

U2 - 10.1002/art.39295

DO - 10.1002/art.39295

M3 - Article

C2 - 26251193

AN - SCOPUS:84946022428

VL - 67

SP - 3037

EP - 3046

JO - Arthritis and Rheumatology

JF - Arthritis and Rheumatology

SN - 2326-5191

IS - 11

ER -