Article Text
Abstract
Background/aim: Interleukin 31 (IL31), primarily expressed in activated lymphocytes, signals through a heterodimeric receptor complex consisting of the IL31 receptor alpha (IL31Rα) 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-α, IL1β, IFN-γ, and sodium butyrate stimulation increased IL31, IL31Rα, 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 TNFΔARE 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.
- CD, Crohn’s disease
- ERK, extracellular signal regulated kinase
- ELISA, enzyme linked immunosorbent assay
- FCS, fetal calf serum
- GAPDH, glyceraldehyde-3-phosphate dehydrogenase
- GPL, gp130-like receptor
- IBD, inflammatory bowel disease
- IEC, intestinal epithelial cell
- IFN, interferon
- IL, interleukin
- IL31Rα, interleukin 31 receptor alpha
- LIF, leukaemia inhibitory factor
- LIFR, leukaemia inhibitory factor receptor
- LPS, lipopolysaccharide
- MAP kinase, mitogen activated protein kinase
- MCMV, murine cytomegalovirus
- MEK, mitogen activated protein kinase kinase
- MTS, 3-(4,5-dimethylthiazol-2-yl)-5-(3-carboxymethoxyphenyl)-2-(4-sulfophenyl)-2H-tetrazolium
- OSM, oncostatin M
- OSMR, oncostatin M receptor
- PCR, polymerase chain reaction
- PI, phosphatidyl-inositol
- RT-PCR, reverse transcriptase polymerase chain reaction
- SOCS, suppressor of cytokine signalling
- STAT, signal transducer and activator of transcription
- TNF-α, tumour necrosis factor alpha
- UC, ulcerative colitis
- interleukin
- Crohn’s disease
- ulcerative colitis
- inflammatory bowel disease
- intestinal epithelial cell
Statistics from Altmetric.com
- CD, Crohn’s disease
- ERK, extracellular signal regulated kinase
- ELISA, enzyme linked immunosorbent assay
- FCS, fetal calf serum
- GAPDH, glyceraldehyde-3-phosphate dehydrogenase
- GPL, gp130-like receptor
- IBD, inflammatory bowel disease
- IEC, intestinal epithelial cell
- IFN, interferon
- IL, interleukin
- IL31Rα, interleukin 31 receptor alpha
- LIF, leukaemia inhibitory factor
- LIFR, leukaemia inhibitory factor receptor
- LPS, lipopolysaccharide
- MAP kinase, mitogen activated protein kinase
- MCMV, murine cytomegalovirus
- MEK, mitogen activated protein kinase kinase
- MTS, 3-(4,5-dimethylthiazol-2-yl)-5-(3-carboxymethoxyphenyl)-2-(4-sulfophenyl)-2H-tetrazolium
- OSM, oncostatin M
- OSMR, oncostatin M receptor
- PCR, polymerase chain reaction
- PI, phosphatidyl-inositol
- RT-PCR, reverse transcriptase polymerase chain reaction
- SOCS, suppressor of cytokine signalling
- STAT, signal transducer and activator of transcription
- TNF-α, tumour necrosis factor alpha
- UC, ulcerative colitis
Footnotes
-
Published Online First 20 April 2007
-
Competing interests: None.