Chapter 1 Introduction
1.5 Regulation of immunity and inflammation by the gp130 group of cytokines and
1.5.3 IL-31-IL-31 receptor signaling and function
The gp130-like monocyte receptor (GLMR), now known as IL-31Rα, is one of the most
recently identified members of the gp130 group and bears the closest homology to gp130. In fact, gp130 and IL-31Rα are located on the same chromosome and IL-31Rα
has been proposed to be the result of gene duplication of gp130. The IL-31Rα pairs with
oncostatin M receptor (OSMR) to form the signaling receptor for IL-31 (Fig. 6). Expression of IL-31Rα has been identified on monocyte/macrophage populations,
epithelial cells and T cells and its ligand, IL-31, is expressed by activated T cells, preferentially of the Th2 cell lineage, and has recently been reported to be expressed by some granulocyte populations associated with type 2 inflammation such as basophils and mast cells (Ishii et al., 2009; Sokol et al., 2008). The major pathways activated downstream of IL-31R signaling are STAT1, STAT3 and STAT5 as well as MAP kinase signaling and in vitro activation via IL-31R signaling can elicit production of cytokines
and chemokines from epithelial cells as well as influence cell proliferative responses. For example, IL-31 stimulation of lung epithelial cells results in activation of STAT3, ERK, JNK and Akt pathways and is associated with the inhibition of proliferation via alteration in expression of cell cycle proteins (Chattopadhyay et al., 2007). The signaling responsible for this alteration of cell cycle proteins was linked directly to IL-31Rα chain
signaling and could be disrupted by mutation of a single STAT3-recruitment site within the intracellular signaling domain. IL-31 treatment of human bronchial epithelial cells can also increase production of vascular endothelial growth factor (VEGF) and monocyte chemoattractant protein MCP-1/CCL2, supporting a potential role for IL-31 in recruitement of immune cells to the lung (Ip et al., 2007). While no known function has yet been assigned to it, there is a putative soluble IL-31Rα isoform (Dillon et al., 2004b)
and, given the close relationship between IL-31/IL-31Rα and IL-6/gp130, it remains a
possibility that trans signaling through this receptor may be an important factor in determing the functional biology of IL-31 signaling in vivo. Alternatively, this soluble receptor may function similarly to IL-13Rα2 in negatively regulating IL-31 function. In
support of this, administration of a soluble IL-31Rα-Fc protein partially blocked IL-31
signaling in vitro (Dillon et al., 2004b).
The first evidence supporting a role for IL-31 in inflammatory disease in vivo came from an overexpression study where IL-31 was expressed either under a ubiquitous or T cell- specific promoter. In both cases, IL-31 overexpression resulted in the development of inflammation in the skin resembling atopic dermatitis with thickening of the epidermis and dermis, granulocyte recruitment, alopecia and pruritis (Dillon et al., 2004b).
levels of IL-31 and human dermatitis patients compared to normal controls and, in animal studies, it appears that IL-31 may be responsible for prurutis associated with dermatitis as blockade of IL-31 significantly reduces scratching behaviour in affected mice (Grimstad et al., 2009). The development of skin inflammation resembling atopic dermatitis in mice overexpressing IL-31 coupled with the association of IL-31 with human dermatitis patients suggested that IL-31 may be a novel IL-6 family cytokine associated with the promotion of type 2 inflammation. However, no evaluation of cytokine expression was carried out in IL-31 transgenic mice and there was no detectable elevation in IgE observed during disease. The role of endogenous IL-31R signaling on the regulation of type 2 inflammation will be examined in Chapter 4 via the generation of IL-31Rα deficient mice and the use of two models of Th2 cytokine-dependent
Figure 1. Anatomy of the intestine. Illustration of the architecture of the small intestine highlighting the major lymphoid structures including the mesenteric lymph nodes (A), Peyer’s patches (B), isolated lymphoid follicles (C) and cryptopatches (D).
Figure 2. Antigen sampling in the intestine. Proposed mechansims for sampling antigens from the lumen of the intestine. (A) Antigen may gain access to the lamina propria (Lp) via a physical break in the intestinal barrier or by active transport by M cells located within the follicle associated epithelium and taken up by Lp dendritic cells. (B) Dendritic cell subsets within the small intestine Lp can extend their dendrites between tight cells junctions and directly sample antigens in the lumen. (C) In humans, neonatal Fc receptor expression on IEC is thought to facilitate uptake of antigen bound by IgG. (D) IEC can express MHC class II and may present antigens to T cells directly or indirectly.
Figure 3. Helper T cell fates. CD4+ T helper cell fates defined by mechanisms by
which they develop from naïve T cells, unique cytokine and transcription factor profiles and their functions. The cytokines that are produced by DCs and are known to promote the initiation and/or maintenance of Th cell differentiation are highlighted in blue font.
Figure 4. Coordinated initiation of type 2 immunity during helminth infection.
Recognition of some helminth-derived products by innate cells can be mediated by germline encoded pattern recognition receptors such as TLR and lectins in addition to other defined and undefined biochemical recognition mechanisms. Innate cell responses include secretion of effector molecules such as IL-4, IL-13, IL-25, IL-33, TSLP, and “alarmins” that contribute to CD4+ Th2 differentiation through influencing antigen
presenting cell function and/or directly acting on CD4+ T cells. DC conditioned with some helminth products can promote CD4+ Th2 differentiation through changes
mechanisms including expression of OX40L and CD40 and differential expression of Notch ligands.
Figure 5. Trichuris muris inhabits a partially intracellular niche within the large intestine. Light microscopy and scanning electron microscopy images of Trichuris
Figure 6. Selected members of the gp130 cytokine receptor family. Members of the gp130 family of cytokine receptors are grouped together on the basis of sequence and structural homology.