ScIeNtIfIc RepoRts | 7: 16547 | DOI:10.1038/s41598-017-16702-w
IL-27, but not IL-35, inhibits
modulating GM-CSF expression
, Annamaria Finardi
, Hélène Descamps
, Federico Colombo
, Francesca Runi
, Marco Patrone
, Massimo Degano
, Gianvito Martino
, Burkhard Becher
& Roberto Furlan
IL-27 and IL-35 are heterodimeric cytokines, members of the IL-12 family and considered to have
immunomodulatory properties. Their role during neuroinammation had been investigated using
mutant mice devoid of either one of their subunits or lacking components of their receptors, yielding
conicting results. We sought to understand the therapeutic potential of IL-27 and IL-35 delivered by
gene therapy in neuroinammation. We constructed lentiviral vectors expressing IL-27 and IL-35 from
a single polypeptide chain, and we validated in vitro their biological activity. We injected IL-27 and
IL-35-expressing lentiviral vectors into the cerebrospinal uid (CSF) of mice aected by experimental
neuroinammation (EAE), and performed clinical, neuropathological and immunological analyses.
Both cytokines interfere with neuroinammation, but only IL-27 signicantly modulates disease
development, both clinically and neuropathologically. IL-27 protects from autoimmune inammation
by inhibiting granulocyte macrophages colony-stimulating factor (GM-CSF) expression in CD4
and by inducing program death-ligand 1 (PD-L1) expression in both CNS-resident and CNS-inltrating
myeloid cells. We demonstrate here that IL-27 holds therapeutic potential during neuroinammation
and that IL-27 inhibits GM-CSF and induces pd-l1 mRNA in vivo.
e interleukin-12 family of heterodimeric cytokines is characterized by three alpha subunits (p19, p28, p35)
and two beta subunits (p40 and EBI3), allowing six theoretical dierent pairings
. While for IL-12 (p35/p40),
IL-23 (p19/p40) and IL-27 (p28/EBI3) there is concluding evidence that the pairing occurs in vivo, the existence
and biological relevance of IL-35 (p35/EBI3), IL-39 (p10/EBI3), and IL-Y (p28/p40) are questioned by some
. Structure homology within the IL-12 family leads, surprisingly, to very dierent biological properties.
In general, IL-12 and IL-23 are considered pro-inammatory cytokines whereas IL-27 and IL-35 are mainly
anti-inammatory or immunoregulatory cytokines
IL-27 is a pleiotropic cytokine mainly released by antigen-presenting cells (APC), modulating several immune
cells, including myeloid cells and T cells
. IL-27 signals through a heterodimer composed by IL-27R alpha (also
called WSX-1) and gp130, that can be found on both innate- and acquired-immune cells and that induces STAT1/
. IL-27, initially thought to be a pro-inammatory, 1-promoting, cytokine
presses 1, 17 responses and limits CNS inammation in several experimental models
. In fact, in exper-
imental autoimmune encephalomyelitis (EAE), recombinant IL-27 peripheral administration inhibits disease
, while interference with IL-27 signaling results in exaggerated 17 responses and the worsening
. IL-27 has been shown to inhibit the development of 17 cells and to promote the dierentiation of
IL-10 producing type 1 regulatory T cells (Tr1 cells)
. e suppressive eect of IL-27 on GM-CSF, a cytokine
considered crucial for the development of autoimmune neuroinammation
, has been suggested in vivo using
deletion mutants for one of the subunits composing either the cytokine or its receptor
. However, direct evi-
dence of IL-27 inhibitory activity on GM-CSF in neuroinammation is lacking.
Clinical Neuroimmunology Unit, Department of Neuroscience, Institute for Experimental Neurology, San Raaele
Scientific Institute, 20132, Milan, Italy.
Neuroimmunology Unit, Department of Neuroscience, Institute for
Experimental Neurology, San Raaele Scientic Institute, 20132, Milan, Italy.
Biocrystallography Unit, Department
of Immunology, Transplantation and Infectious Diseases, San Raaele Scientic Institute, 20132, Milano, Italy.
Inammation Research, Institute of Experimental Immunology, University of Zurich, 8057, Zurich, Switzerland.
Annamaria Finardi and Hélène Decamps contributed equally to this work. Correspondence and requests for materials
should be addressed to R.F. (email: email@example.com)
Received: 9 May 2017
Accepted: 13 November 2017
Published: xx xx xxxx