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J Biol Chem. 2017 Apr 21;292(16):6644-6656. doi: 10.1074/jbc.M116.762021. Epub 2017 Mar 9.

Epstein-Barr virus-induced gene 3 (EBI3) can mediate IL-6 trans-signaling.

Author information

1
From the Départements de Pharmacologie and.
2
Chimie, Université de Montréal, Montréal, Québec H3T 1J4, Canada.
3
the Laboratory of Pharmacology and Toxicology, Faculty of Medicine and Pharmacy, University Mohammed V, Rabat, Morocco.
4
NovImmune, 1228-Plan-les-Ouates, Switzerland, and.
5
the Research Service, Kansas City Veterans Affairs Medical Center and Midwest Biomedical Research Foundation, Kansas City, Missouri 64128-2226.
6
From the Départements de Pharmacologie and jf.gauchat@umontreal.ca.

Abstract

Epstein-Barr virus-induced gene 3 (EBI3) is a subunit of the composite cytokines IL-27 and IL-35. Both have beneficial functions or effects in models of infectious and autoimmune diseases. This suggests that administration of EBI3 could be therapeutically useful by binding free p28 and p35 to generate IL-27 and IL-35. IL-27- and IL-35-independent functions of EBI3 could compromise its therapeutic uses. We therefore assessed the effects of EBI3 on cytokine receptor-expressing cells. We observed that EBI3 activates STAT3 and induces the proliferation of the IL-6-dependent B9 mouse plasmacytoma cell line. Analyses using blocking mAbs and Ba/F3 transfectants expressing gp130 indicate that EBI3 activity was linked to its capacity to mediate IL-6 trans-signaling, albeit less efficiently than soluble IL-6Rα. In line with this interpretation, co-immunoprecipitation and SPR experiments indicated that EBI3 binds IL-6. An important pro-inflammatory function of IL-6 trans-signaling is to activate blood vessel endothelial cells. We observed that EBI3 in combination with IL-6 could induce the expression of chemokines by human venal endothelial cells. Our results indicate that EBI3 can promote pro-inflammatory IL-6 functions by mediating trans-signaling. These unexpected observations suggest that use of EBI3 as a therapeutic biologic for autoimmune diseases will likely require co-administration of soluble gp130 to prevent the side effects associated with IL-6 trans-signaling. Together with previous studies that demonstrated activation of IL-6R by p28 (IL-30), new findings further suggest a complex interrelation between IL-27 and IL-6.

KEYWORDS:

cytokine; endothelial cell; inflammation; interleukin 6 (IL-6); interleukin 6 receptor (IL6R)

PMID:
28280243
PMCID:
PMC5399113
DOI:
10.1074/jbc.M116.762021
[Indexed for MEDLINE]
Free PMC Article

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