IL-31 in Mucosal Airway and Intestine
Recently, IL-31 signaling has been detected in mucosal sites of the
human lung, nasal sinus and intestine (Figure
3).81–83 Lung epithelial cells express IL31RA, OSMRβ
and gp130. Although both, OSM and IL-31, engage with equal affinities to
IL31RA/OSMRβ of lung epithelium and activate common signal transduction
pathways, each agonist can activate distinct downstream signaling
cascades.81 For instance, OSM activation leads to
balanced phosphorylation of STAT3, ERK and STAT5, whereas IL-31
increases STAT3 phosphorylation, while attenuating STAT5 responses and
leaving pERK levels unaffected.81 Neither OSM nor
IL-31 initiate the expression of any of the other “classical” IL-6
targets such as STAT1.81 STAT3 signaling has been
linked to both proinflammatory and anti-inflammatory responses and is
involved in regenerative processes, such as proliferation and inhibition
of apoptosis.84,85 As to whether IL-31 is implicated
in these functional roles within intestinal epithelium via STAT3
activation has yet to be determined.
In the epithelial-like human lung adenocarcinoma cell line (A549), IL-31
induces morphological changes characterized by formation of podosomal
extensions and a reduction in cell-cell
interactions.81 Furthermore, IL-31 activation induces
cell-cycle arrest and an impaired regulation and expression of cell
cycle proteins such as cyclin B1, CDK6 and CDK1 (CDC2), and suppressing
proliferation. This indicates a profound role of IL-31 in tissue
homeostasis.81 Of note, the responses of lung
epithelial cells to IL-31 activation can vary due to the inducible
expression of IL31RA and differences in receptor abundance between
donors. For example, the expression of IL31RA is transiently
downregulated after engagement of its ligand by downstream signaling
effects.81
In TH2-dominated asthmatic or non-asthmatic airway
inflammation changes in IL31RA abundance could be essential, since IL-31
was found to support the progression of the asthmatic phenotype leading
to the notion by some that IL-31 might serve as a marker of allergic
asthma.51,86,87 Contrary to findings in the skin, this
study suggests that the culprit IL-31 would not be exclusively expressed
by T cells but rather stems from unidentified cells in the lung that
respond to IL-4. Interestingly, IL-33 is secreted continuously by lung
epithelial cells during asthmatic inflammatory reactions as an alarm
signal against invading pathogens and allergens 88 but
appears to fail to signal in pulmonary TH2 cells to
up-regulate IL-31 release levels in an allergic
situation.11 Interestingly, asthma was found as one of
the dose-dependent side effects in clinical trials with
nemolizumab.80 The asthmatic events have exclusively
been observed in patients with a pre-existing asthma, probably due to
improved health and increased activity levels that triggered asthma.
In human bronchial epithelial cells and co-cultures with eosinophils,
IL-31 alone or in cooperation with TH2 cytokines (IL-4
or IL-13) was shown to alter the production of inflammatory cytokines
(IL-6, IL-8), chemokines (CCL2) and growth factors (vascular endothelial
growth factor (VEGF), endothelial growth factor (EGF)). CCL2, VEGF and
EGF are involved in the recruitment of inflammatory cells, and the
autocrine remodelling of epithelial cells,89indicating an overall pro-inflammatory role for IL-31 in pulmonary
inflammation. Subsequent studies, however, describe IL-31 as a
regulatory rather than an inflammatory cytokine in the lung, suggesting
a dual role for IL-31 in airway function. Perrigoue et al. described
ameliorating effects of the IL-31/IL31RA axis in a murine model of
pulmonary type 2 inflammation.90 Mice infected withS. mansoni eggs, lodging in the small blood vessels of the lung,
develop pulmonary granulomas, due to IL-4/IL-13 signaling, but displayed
intensified inflammation of the parenchymal lung tissue when IL31RA was
absent.90 In this model, IL31RA-/-mice showed an increased production of type-2 cytokines (IL-4, IL-5,
IL-13) upon secondary challenge of isolated lymph node cells withS. mansoni egg antigen . Contrary to initial studies in lung
inflammation models, these findings suggest a stronger anti-inflammatory
function of IL31RA signaling in the parasite-affected lung tissue.
However, the increase in cytokine production in
IL31RA-/- mice leads to an elevated frequency of
alternatively activated macrophages (AAMs) resulting in pulmonary tissue
remodeling and fibrosis. Naïve CD4+ T cells from
IL31RA-/- mice demonstrated an augmented proliferative
capacity and elevated TH2-cytokine production without
differentiation into TH2 polarized cells. These findings
indicate a regulatory engagement of the IL-31/IL31RA axis with GATA-3 in
undifferentiated T cells, resulting in a refined control of cytokine
production. However, these effects were absent in fully differentiated
effector TH2 cells. Thus, IL-31 activation of
antigen-presenting cells (e.g. macrophages) appears to restrict the
proliferation of naïve and TH2 differentiated cells
without impairing their antigen-presenting capacity in lung
cells.90 Therefore, IL-31 may suppress some innate
immune cells, thereby regulating activation of the adaptive immune
system during airway inflammation.
IL-31 has recently been implicated in the pathogenesis of nasal polyps
(NP) of the sinus mucosa.82 Nasal polyps are similar
to AD histologically characterized by an infiltration of lymphocytes,
especially TH2 cells, and eosinophils, considered now as
a type-2 inflammation. The expression of IL-31 is elevated in NPs and
IL-31 protein levels correlated with clinical outcome, probably due to
the IL-31-amplified TH2-skewed inflammation
profile.82
Expression levels of IL-31 and IL31RA were further found upregulated in
the inferior turbinate of patients with allergic
rhinitis.91 IL31RA primarily localized to submucosal
glands and stimulation of A549 cells induced expression of themucin 5AC (MUC5AC ) gene suggesting a role for IL-31 in
mucus overproduction during nasal allergic
inflammation.91
In the intestine, IL-31 imbalance seems to be associated with
inflammatory bowel disease (IBD). IBD is a frequent autoimmune disorder
of the gastrointestinal tract presenting with mucosal inflammation and
ulceration due to an imbalance in effector and regulatory T
cells.92,93 Two major types of IBD have been
described, ulcerative colitis (UC) and Crohn’s disease (CD). Expression
analysis revealed elevated levels of IL-31, IL31RA and OSMR mRNA in
inflamed colonic lesions of CD and UC patients which correlated with
lesional IL-8 expression.94 Beyond this descriptive
finding, an IL-31-specific impact on cellular mechanisms in CD or UC are
still missing. In colorectal HCT116 cells, however, pro-inflammatory
cytokines (TNFα, IL-1β) and bacterial lipopolysaccharide (LPS) induced
IL-31, IL31RA, and OSMRβ mRNA expression, suggesting involvement of the
IL-31 axis in intestinal inflammation.94
A pro-inflammatory effect of IL-31 has further been revealed in human
colonic subepithelial myofibroblasts. IL-31 dependent activation led toin vitro production of IL-8 (CXCL8), growth-related oncogene-α
(GRO-α), CXCL1, monocyte chemoattractant protein-3 (MCP-3), CXCL3
(GRO-3), IL-6 and various metalloproteinases.95 The
inflammatory impact of IL-31 in vivo on the intestinal epithelial
layer has not been shown so far. To elucidate the function of
IL-31/IL31RA in chronic intestinal inflammation in humans will
necessitate detailed assessments of IL-31-induced signaling traits in
disease- promoting cell types, including intestinal epithelial cells,
effector/regulatory T cells, nerves and DCs.
Similar to the role of IL-31 signaling in S. mansoni -induced
airway inflammation, IL-31-/L31RA has been associated with immunological
responses in a murine model of parasitic infection.83Infection of mice with Trichuris muris initiates priming of
TH2 cells and subsequent production of
TH2 effector cytokines in the early infection stage and
to a conversion of the immune response to a
TH1-dominated phenotype including
IFNγ.83 Perrigoue et al. demonstrated that IL-31
expression increased under inflammatory conditions when IL-4 was present
to skew naïve T cells towards a TH2 phenotype. Like
their results on the role of IL-31/IL31RA in inflamed lung tissue, the
group demonstrated an enhanced production of type-2 cytokines in the
absence of IL31RA, implying an immuno-regulatory function of IL-31 in
the inflamed intestine.83 Nevertheless, although these
observations are consistent in lung and intestine, the results await
confirmation by additional studies since observations in the skin reveal
a rather pro-inflammatory role of IL-31.