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.