However, subsequent studies have
revealed that IL-27R signaling influences a variety of immune cell types and
can inhibit either Th1 or Th2 type responses. Though elucidation of the
Jak/STAT signaling pathways activated by IL-27R ligation has unveiled some of
the molecular mechanisms used by IL-27 to promote inflammation, little is known
about the anti-inflammatory activities of this cytokine. Thus, the aim of this
review is to discuss the pleotropic nature of the IL-27/IL-27R interaction and
attempt to reconcile the pro- and anti-inflammatory properties of this
immunomodulator.
Structure of IL-27
IL-27 is a
heterodimer composed of the Epstein-Barr virus induced gene 3 (EBI3) subunit
and p28 (also known as IL-30). EBI3 is a 34-kDa glycoprotein that was
first identified in B cells following Epstein-Barr virus infection, and is
homologous to the p40 subunit of IL-12 and IL-23. Studies indicate that
EBI3 can also be secreted independently of other subunits, possibly as a
homodimer. The p28 subunit is similar to p35, and has been shown to
function independently of EBI3. Studies demonstrate that IL-27 binds a unique
receptor subunit called WSX-1/TCCR (also known as IL-27Ra), which associates
with gp130, a common chain utilized by IL-6 family cytokines.
Function of IL-27
IL-27 is produced by
activated dendritic cells and macrophages in response to Toll-like receptor
ligands and pro-inflammatory cytokines. In addition to its role in
mediating pro- and anti-inflammatory effects, IL-27 promotes CD4+ T cell differentiation to the
Th1 lineage by inducing expression of the transcription factor T-bet and up
regulating IL-12Rβ2. In doing so, IL-27 suppresses Th2
and Th17 differentiation and proliferation. Binding to the IL-27R, which
is expressed most abundantly on activated T cells and NK cells with lower
expression on B cells and naïve T-cells,
leads to the phosphorylation and
activation of the JAK/STAT pathway, with STAT1 and STAT3 as the predominant
factors mediating the effects of IL-27.
In vitro-cultured human dendritic cells unstimulated (left) or
stimulated with Human IFN alpha 2 Recombinant Protein and LPS in the presence
of Protein
Transport Inhibitor Cocktail (right) and stained with Anti-Human
CD11c followed by fixation and intracellular staining with Anti-Human IL-27
EBI3. Total viable cells were used for analysis.
Interleukin 27 balances the immune
response to influenza and reduces lung damage
Highly pathogenic (dangerous) influenza strains elicit a
strong immune response which can lead to uncontrolled inflammation in the lung
and potentially fatal lung injury. A new study demonstrates the importance of
IL-27 for the control of immunopathology -- damage to the lung tissue caused by
the immune system -- and the therapeutic potential of well-timed IL-27
application to treat life-threatening inflammation during lung infection.
 |
| EM picture of a budding influenza virus in human lung tissue. |
Highly
pathogenic (dangerous) influenza strains elicit a strong immune response which
can lead to uncontrolled inflammation in the lung and potentially fatal lung
injury. A study published on May 8th in PLOS Pathogens demonstrates the
importance of IL-27 for the control of immunopathology -- damage to the lung
tissue caused by the immune system -- and the therapeutic potential of
well-timed IL-27 application to treat life-threatening inflammation during lung
infection.
Alf
Hamann, from Deutsches Rheuma-Forschungszentrum and Charité Universitätsmedizin
Berlin, Germany, and colleagues, did a comprehensive analysis of IL-27 function
in mice infected with a highly pathogenic influenza strain. They found that
IL-27 levels in infected lungs follow, with some delay, the level of virus:
they peak as viral levels are starting to decline and come down when
immunopathology has resolved. This is compatible with a role for IL-27 in dampening
uncontrolled inflammation at later stages of the infection, while initially
allowing for a rapid immune defense.
When
the researchers examined mice with disrupted IL-27 function, they found that
they were more likely than normal mice likely to die when infected with the
virus, and that they died as a consequence of rampant lung inflammation. This
was associated with a stronger immune response and stronger immunopathology.
Thus, IL-27 plays an important role in limiting destructive inflammation during
the advanced stages of infection.
Having
discovered the crucial role of IL-27 in regulating immunopathology, the
researchers wondered whether this could be exploited for therapeutic purposes.
To test the potential of IL-27 treatment, they administered recombinant IL-27
(rIL-27, that is, IL-27 produced by biotechnology) to normal mice at different
times after virus infection.
When
they matched the natural course of IL-27 (treatment starting at day 5 after
virus infection), they found that fewer mice died, that they lost less weight,
and recovered quicker than those without treatment. In contrast, mice treated
with IL-27 early (starting at the day of virus infection) were doing poorly and
did not recover from the infection. Although their lungs showed less extensive
damage, they were not able to control overall virus levels. This shows the
importance of timing, with IL-27 treatment being beneficial only during later
stages of infection but harmful when given too early.
The
scientists conclude that in mice "well-timed treatment with rIL-27
improved lung injury and accelerated recovery without affecting viral
clearance" and continue "these data demonstrate that IL-27 has a
unique role in controlling immunopathology without impacting on host defense,
and might therefore represent a promising candidate for immunomodulatory
therapy of viral pneumonia."
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