期刊
JOURNAL OF CLINICAL INVESTIGATION
卷 107, 期 7, 页码 861-869出版社
AMER SOC CLINICAL INVESTIGATION INC
DOI: 10.1172/JCI11783
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资金
- NIDDK NIH HHS [DK-35932, DK-47662, K08 DK-02802, R37 DK035932, K08 DK002802, K01 DK-02792, R01 DK047662] Funding Source: Medline
Adenosine is formed in the intestinal lumen during active inflammation from neutrophil-derived 5 ' AMP. Using intestinal epithelial cell line T84, we studied the effect of adenosine on the secretion of IL-6, a proinflammatory cytokine involved in neutrophil degranulation and lymphocyte differentiation. Stimulation of T84 monolayers with either apical or basolateral adenosine induces A2b receptor-mediated increase in IL-6 secretion, which is polarized to the apical (luminal) compartment. In addition, Salmonella typhimurium, TNF-a, and forskolin, known inducers of IL-6 secretion in intestinal epithelial cells, also stimulate IL-G secretion into the apical compartment. We show that IL6 promoter induction by adenosine occurs through cAMP-mediated activation of nuclear cAMP-responsive element-binding protein (CREB). We also show that IL-6 released in the luminal (apical) compartment achieves a sufficient concentration to activate neutrophils (from which the adenosine signal originates), since such IL-6 is found to induce an intracellular [Ca++] flux in neutrophils. We conclude that adenosine released in the intestinal lumen during active inflammation may induce IL-6 secretion, which is mediated by cAMP/CREB activation and occurs in an apically polarized fashion. This would allow sequential activation of neutrophil degranulation in the lumen - a flow of events that would, in an epithelium-dependent fashion, enhance microbicidal activity of neutrophils as they arrive in the intestinal lumen.
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