title: Differential Expression of the Activator Protein 1 Transcription Factor Regulates Interleukin-1ß Induction of Interleukin 6 in the Developing Enterocyte.
abstract: The innate immune response is characterized by activation of transcription factors, nuclear factor kappa B and activator protein-1 and their downstream targets, the pro-inflammatory cytokines including interleukin 1β and interleukin 6. Normal development of this response in the intestine is critical to survival of the human neonate and delays can cause the onset of devastating inflammatory diseases such as necrotizing enterocolitis. Previous studies have addressed the role of nuclear factor kappa B in the development of the innate immune response in the enterocyte, however despite its central role in the control of multiple pro-inflammatory cytokine genes, little is known on the role of Activator Protein 1 in this response in the enterocyte. Here we show that the canonical Activator Protein 1 members, cJun and cFos and their upstream kinases JNK and p38 play an essential role in the regulation of interleukin 6 in the immature enterocyte. Our data supports a model whereby the cFos/cJun heterodimer and the more potent cJun homodimer downstream of JNK are replaced by less efficient JunD containing dimers, contributing to the decreased responsiveness to interleukin 1β and decreased interleukin 6 secretion observed in the mature enterocyte. The tissue specific expression of JunB in colonocytes and colon derived tissues together with its ability to repress Interleukin-1β induction of an Interleukin-6 gene reporter in the NCM-460 colonocyte suggests that induction of JunB containing dimers may offer an attractive therapeutic strategy for the control of IL-6 secretion during inflammatory episodes in this area of the intestine.
authors.affiliation: Neurochemistry Laboratory, Department of Psychiatry, Massachusetts General Hospital, and Harvard Medical School, Charlestown, Massachusetts, United States of America.
authors.forename: Catherine M
authors.initials: CM
authors.lastname: Cahill
authors.affiliation: Mucosal Immunology and Biology Research Center, Department of Pediatrics, Massachusetts General Hospital for Children, and Harvard Medical School, Charlestown, Massachusetts, United States of America.
authors.forename: Weishu
authors.initials: W
authors.lastname: Zhu
authors.affiliation: Department. of Environmental Science, Baylor University One Bear Place #97266, Waco, Texas, United States of America.
authors.forename: Elias
authors.initials: E
authors.lastname: Oziolor
authors.affiliation: Departments of Pediatrics and Internal Medicine, National Cheng Kung University, Tainan, Taiwan.
authors.forename: Yao-Jong
authors.initials: YJ
authors.lastname: Yang
authors.affiliation: Neurochemistry Laboratory, Department of Psychiatry, Massachusetts General Hospital, and Harvard Medical School, Charlestown, Massachusetts, United States of America.
authors.forename: Bosco
authors.initials: B
authors.lastname: Tam
authors.affiliation: Neurochemistry Laboratory, Department of Psychiatry, Massachusetts General Hospital, and Harvard Medical School, Charlestown, Massachusetts, United States of America.
authors.forename: Susruthi
authors.initials: S
authors.lastname: Rajanala
authors.affiliation: Neurochemistry Laboratory, Department of Psychiatry, Massachusetts General Hospital, and Harvard Medical School, Charlestown, Massachusetts, United States of America.
authors.forename: Jack T
authors.initials: JT
authors.lastname: Rogers
authors.affiliation: Mucosal Immunology and Biology Research Center, Department of Pediatrics, Massachusetts General Hospital for Children, and Harvard Medical School, Charlestown, Massachusetts, United States of America.
authors.forename: W Allan
authors.initials: WA
authors.lastname: Walker
mesh_terms: D000818:Animals; D002460:Cell Line; D020895:Enterocytes / Q000166:cytology / Q000187:drug effects / Q000502:physiology*; D064593:Heterografts; D006801:Humans; D053583:Interleukin-1beta / Q000378:metabolism* / Q000494:pharmacology; D015850:Interleukin-6 / Q000235:genetics / Q000378:metabolism*; D007422:Intestines / Q000166:cytology / Q000196:embryology; D048031:JNK Mitogen-Activated Protein Kinases / Q000378:metabolism; D016513:Mice, SCID; D048055:Mitogen-Activated Protein Kinase 8 / Q000378:metabolism; D016328:NF-kappa B / Q000378:metabolism; D009924:Organ Culture Techniques; D010766:Phosphorylation; D020218:Response Elements; D015398:Signal Transduction; D018808:Transcription Factor AP-1 / Q000235:genetics / Q000378:metabolism*; D014157:Transcription Factors / Q000235:genetics / Q000378:metabolism; D048051:p38 Mitogen-Activated Protein Kinases / Q000378:metabolism
chemical_list: C508600:IL6 protein, human; D053583:Interleukin-1beta; D015850:Interleukin-6; C581727:JunB protein, human; D016328:NF-kappa B; D018808:Transcription Factor AP-1; D014157:Transcription Factors; D048031:JNK Mitogen-Activated Protein Kinases; D048055:Mitogen-Activated Protein Kinase 8; D048051:p38 Mitogen-Activated Protein Kinases