Interleukin-31 mediates MAP kinase and STAT1/3 activation in intestinal epithelial cells and its expression is up-regulated in inflammatory bowel disease

Abstract

Background/aim: Interleukin 31 (IL31), primarily expressed in activated lymphocytes, signals through a heterodimeric receptor complex consisting of the IL31 receptor alpha (IL31Ra) and the oncostatin M receptor (OSMR). The aim of this study was to analyse IL31 receptor expression, signal transduction, and specific biological functions of this cytokine system in intestinal inflammation. Methods: Expression studies were performed by RT-PCR, quantitative PCR, western blotting, and immunohistochemistry. Signal transduction was analysed by western blotting. Cell proliferation was measured by MTS assays, cell migration by restitution assays. Results: Colorectal cancer derived intestinal epithelial cell (IEC) lines express both IL31 receptor subunits, while their expression in unstimulated primary murine IEC was low. LPS and the proinflammatory cytokines TNF-a, IL1b, IFN-c, and sodium butyrate stimulation increased IL31, IL31Ra, and OSMR mRNA expression, while IL31 itself enhanced IL8 expression in IEC. IL31 mediates ERK-1/2, Akt, STAT1, and STAT3 activation in IEC resulting in enhanced IEC migration. However, at low cell density, IL31 had significant antiproliferative capacities (p,0.005). IL31 mRNA expression was not increased in the TNFDARE mouse model of ileitis but in inflamed colonic lesions compared to non-inflamed tissue in patients with Crohn's disease (CD; average 2.4-fold increase) and in patients with ulcerative colitis (UC; average 2.6-fold increase) and correlated with the IL-8 expression in these lesions (r = 0.564 for CD; r = 0.650 for UC; total number of biopsies analysed: n = 88). Conclusion: IEC express the functional IL31 receptor complex. IL31 modulates cell proliferation and migration suggesting a role in the regulation of intestinal barrier function particularly in intestinal inflammation.

Interleukin‐31 induces cytokine and chemokine production from human bronchial epithelial cells through activation of mitogen‐activated protein kinase signalling pathways: implications for the allergic response

“…14 In addition, Dambacher et al also demonstrated that IL-31 might mediate ERK-1,2, Akt, STAT-1 and STAT-3 activation in human intestine epithelial cells. 17 In concurrence with these recent findings, we demonstrated the activation of ERK1, JNK1,2 and p38 MAPK signalling molecules in IL-31-stimulated human bronchial epithelial cells (Fig. 5).…”

“…The expression of IL‐31RA and OSMR on human epidermal keratinocytes and the number of IL‐31‐expressing, skin‐infiltrating Th2 and CD45RO + (memory) cutaneous lymphocyte antigen (CLA) + T cells in atopic dermatitis patients was higher than in normal subjects 11 . Interleukin‐31 heterodimeric receptors are also present in many tissues including testis, brain, bone marrow, thymus, skin and intestine 10,12 , 15–17 . Target cells expressing IL‐31RA for IL‐31 in these tissues include activated monocytes, macrophages, myeloid progenitor cells, keratinocytes, eosinophils and epithelial cells 10–12,17 , 18 …”

“…11 Interleukin-31 heterodimeric receptors are also present in many tissues including testis, brain, bone marrow, thymus, skin and intestine. 10,12,[15][16][17] Target cells expressing IL-31RA for IL-31 in these tissues include activated monocytes, macrophages, myeloid progenitor cells, keratinocytes, eosinophils and epithelial cells. [10][11][12]17,18 Recent evidence has suggested that IL-31 might be involved in promoting allergic inflammation and an airway epithelial response that may characterize allergic asthma.…”

“…10,12,[15][16][17] Target cells expressing IL-31RA for IL-31 in these tissues include activated monocytes, macrophages, myeloid progenitor cells, keratinocytes, eosinophils and epithelial cells. [10][11][12]17,18 Recent evidence has suggested that IL-31 might be involved in promoting allergic inflammation and an airway epithelial response that may characterize allergic asthma. 14 Although the intracellular signalling pathways of IL-31RA in human alveolar epithelial cells have recently been characterized, the function of IL-31 in bronchial inflammation or allergic asthma is still not clear.…”

IL-31 Expression by Inflammatory Cells is Preferentially Elevated in Atopic Dermatitis

“…Expression of IL-31Ra and OSMRß mRNA can be induced in activated monocytes, while their expression is constitutive in skin, testis and thymus, arguing that these organs are probably responsive to IL-31 (1,9,10). IL-3 IRA and OSMRß are also found co-expressed in a subset of neurons of murine and human dorsal root ganglia (9,11 ), which represents the site where the soma of cutaneous sensory neurons are located, while their sensory fibres protrude directly into the skin.…”