title: Neutrophil-epithelial crosstalk at the intestinal lumenal surface mediated by reciprocal secretion of adenosine and IL-6.
abstract: 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-alpha, and forskolin, known inducers of IL-6 secretion in intestinal epithelial cells, also stimulate IL-6 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.
authors: Epithelial Pathobiology Unit, Department of Pathology, Emory University, Atlanta, Georgia, USA. ssitar2@emory.edu
authors: S V
authors: SV
authors: Sitaraman
authors: D
authors: D
authors: Merlin
authors: L
authors: L
authors: Wang
authors: M
authors: M
authors: Wong
authors: A T
authors: AT
authors: Gewirtz
authors: M
authors: M
authors: Si-Tahar
authors: J L
authors: JL
authors: Madara
mesh_terms: D051696:Activating Transcription Factors; D000241:Adenosine / Q000378:metabolism* / Q000494:pharmacology; D000818:Animals; D001798:Blood Proteins / Q000378:metabolism; D019556:COS Cells; D002460:Cell Line; D002522:Chlorocebus aethiops; D005576:Colforsin / Q000378:metabolism / Q000494:pharmacology; D017362:Cyclic AMP Response Element-Binding Protein / Q000378:metabolism; D004305:Dose-Response Relationship, Drug; D004847:Epithelial Cells / Q000166:cytology / Q000378:metabolism; D015850:Interleukin-6 / Q000378:metabolism*; D007413:Intestinal Mucosa / Q000166:cytology / Q000378:metabolism*; D009504:Neutrophils / Q000378:metabolism*; D058915:Purinergic P1 Receptor Antagonists; D043704:Receptor, Adenosine A2B; D018047:Receptors, Purinergic P1 / Q000378:metabolism; D012486:Salmonella typhimurium / Q000378:metabolism; D015398:Signal Transduction / Q000502:physiology*; D013997:Time Factors; D014157:Transcription Factors / Q000378:metabolism; D014158:Transcription, Genetic; D014409:Tumor Necrosis Factor-alpha / Q000378:metabolism / Q000494:pharmacology
chemical_list: D051696:Activating Transcription Factors; D001798:Blood Proteins; D017362:Cyclic AMP Response Element-Binding Protein; D015850:Interleukin-6; D058915:Purinergic P1 Receptor Antagonists; D043704:Receptor, Adenosine A2B; D018047:Receptors, Purinergic P1; D014157:Transcription Factors; D014409:Tumor Necrosis Factor-alpha; D005576:Colforsin; D000241:Adenosine