Interleukin 27 balances the immune response to influenza and reduces lung damage

Interleukin 27 balances the immune response to influenza and reduces lung damage

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The recent identification of Interleukin-27 (IL-27p28/EBV-induced gene 3) and IL-27R(WSX-1/gp130) has provided new insights for the biology of IL-6/IL-12 family cytokines.Interleukin-27 (IL-27) is a heterodimeric cytokine belonging to the IL-12 family that is composed of two subunits; Epstein-Barr virus (EBV)-induced gene 3 (EBI3) (also known as IL-27B) and IL27-p28 (known as IL-30). IL-27 is produced by antigen-presenting cells. Initial studies indicated that IL-27 can directly regulate T and B-lymphocytes functions and suggested an important role for it in promoting Th1 type responses. The effects of IL-27 are eliciting by its interaction with a specific cell-surface receptor complex composed of two proteins known as IL27R and gp130.
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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