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Overexpression of IL-9 and its receptor by leukocytes contributes to the pathogenesis of ulcerative colitis
Introduction: IL-9 and its receptor have been historically linked to the pathogenesis of asthma. More recently, a subpopulation of lymphocytes so called Th9 cells were identified to produce large amounts of IL-9. However, the role of this cytokine and its receptor in ulcerative colitis, a disease characterized by high granulocyte accumulation resulting in crypt abscess, has not been addressed so far.
Methods: The capacity of peripheral blood lymphocytes to produce IL-9 upon stimulation with anti-CD3/anti-CD28 has been investigated by ELISA whereas the expression of the IL-9 receptor by peripheral blood cells was monitored by flow cytometry and immunofluorescence. The effect of IL-9 stimulation on granulocyte's life-span has been addressed by flow cytometry. Furthermore, IL-9 receptor expression was analysed using immunofluorescence staining on gut biopsies, including double stainings with the neutrophils marker myeloperoxidase.
Results: Upon stimulation, peripheral blood lymphocytes from ulcerative colitis patients produced significantly more IL-9 compared to cells from healthy control donors whereas non-stimulated cells produced solely negligible IL-9. There was a good correlation between the IL-9 levels and the general inflammatory status of patients as measured by the C reactive protein values. The expression of the IL-9 receptor on peripheral blood cells was largely restricted to the granulocytes with cells from ulcerative colitis patients expressing significantly more receptors compared to control cells. Functionally, IL-9 addition prolonged the life-span of GM-CSF-stimulated granulocytes from ulcerative colitis patients. Nevertheless, neutrophils from ulcerative colitis biopsies also stained positive for the IL-9 receptor suggesting a possibly relevant pathogenic role of these cells in the context of gut inflammation.
Conclusion: Our present results indicate that IL-9 play an important pathogenic role in ulcerative colitis by activating granulocytes and suggest that levels of IL-9 production and/or IL-9 receptor expression by peripheral blood cells might represent useful markers for monitoring disease course.
Key words: Granulocytes, IL-9, inflammatory bowel disease, ulcerative colitis