NF-kappa B-inducing kinase is a common mediator of IL-17-, TNF-alpha-, and IL-1 beta-induced chemokine promoter activation in intestinal epithelial cells.
IL-17 expression is restricted to activated T cells, whereas the IL-17R is expressed in a variety of cell types including intestinal epithelial cells. However, the functional responses of intestinal epithelial cells to stimulation with IL-17 are unknown. Moreover, the signal transduction pathways activated by the IL-17R have not been characterized. IL-17 induced NF-kappa B protein-DNA complexes consisting of p65/p50 heterodimers in the rat intestinal epithelial cell line IEC-6. The induction of NF-kappa B correlated with the induction of CXC and CC chemokine mRNA expression in IEC-6 cells. IL-17 acted in a synergistic fashion with IL-1 beta to induce the NF-kappa B site-dependent CINC promoter. Induction of the CINC promoter by IL-17 in IEC-6 cells was TNF receptor-associated factor-6 (TRAF6), but not TRAF2, dependent. Furthermore, IL-17 induction of the CINC promoter could be inhibited by kinase-negative mutants of NF-kappa B-inducing kinase and I kappa B kinase-alpha. In addition to activation of the NF-kappa B, IL-17 regulated the activities of extracellular regulated kinase, c-Jun N-terminal kinase, and p38 mitogen-activated protein kinases in IEC-6 cells. Whereas the IL-17-mediated activation of extracellular regulated kinase mitogen-activated protein kinases was mediated through ras, c-Jun N-terminal kinase activation was dependent on functional TRAF6. These data suggest that NF-kappa B-inducing kinase serves as the common mediator in the NF-kappa B signaling cascades triggered by IL-17, TNF-alpha, and IL-1 beta in intestinal epithelial cells.
Awane
M
M
Gastrointestinal Unit, Department of Medicine, Center for the Study of Inflammatory Bowel Disease, Massachusetts General Hospital, Boston, MA 02114, USA.
Andres
P G
PG
Li
D J
DJ
Reinecker
H C
HC
D000818:Animals; D001692:Biological Transport; D017871:Calcium-Calmodulin-Dependent Protein Kinases / Q000378:metabolism; D002455:Cell Division / Q000276:immunology; D002460:Cell Line; D002467:Cell Nucleus / Q000235:genetics / Q000378:metabolism; D054360:Chemokine CXCL1; D018925:Chemokines / Q000096:biosynthesis / Q000235:genetics*; D019742:Chemokines, CC / Q000096:biosynthesis / Q000235:genetics; D019743:Chemokines, CXC / Q000096:biosynthesis / Q000235:genetics; D002630:Chemotactic Factors / Q000096:biosynthesis / Q000235:genetics; D004268:DNA-Binding Proteins; D004357:Drug Synergism; D004789:Enzyme Activation / Q000276:immunology; D005786:Gene Expression Regulation / Q000276:immunology; D006131:Growth Inhibitors / Q000502:physiology; D006133:Growth Substances / Q000096:biosynthesis / Q000235:genetics; D006801:Humans; D051550:I-kappa B Kinase; D036341:Intercellular Signaling Peptides and Proteins; D007375:Interleukin-1 / Q000502:physiology*; D020381:Interleukin-17 / Q000378:metabolism*; D007413:Intestinal Mucosa / Q000166:cytology / Q000201:enzymology / Q000276:immunology* / Q000378:metabolism; D048031:JNK Mitogen-Activated Protein Kinases; D020928:Mitogen-Activated Protein Kinases; D016328:NF-kappa B / Q000096:biosynthesis* / Q000378:metabolism; D052002:NF-kappa B p50 Subunit; D011401:Promoter Regions, Genetic / Q000276:immunology*; D017346:Protein Serine-Threonine Kinases / Q000502:physiology*; D011506:Proteins / Q000502:physiology; D011518:Proto-Oncogene Proteins / Q000378:metabolism; D012333:RNA, Messenger / Q000096:biosynthesis; D051381:Rats; D015398:Signal Transduction / Q000276:immunology; D048029:TNF Receptor-Associated Factor 6; D051996:Transcription Factor RelA; D014157:Transcription Factors; D015533:Transcriptional Activation / Q000276:immunology; D014409:Tumor Necrosis Factor-alpha / Q000378:metabolism*; D050807:ets-Domain Protein Elk-1; D018631:ras Proteins / Q000502:physiology; D000097782:NF-kappaB-Inducing Kinase
D017871:Calcium-Calmodulin-Dependent Protein Kinases; D054360:Chemokine CXCL1; D018925:Chemokines; D019742:Chemokines, CC; D019743:Chemokines, CXC; D002630:Chemotactic Factors; D004268:DNA-Binding Proteins; D006131:Growth Inhibitors; D006133:Growth Substances; D051550:I-kappa B Kinase; D036341:Intercellular Signaling Peptides and Proteins; D007375:Interleukin-1; D020381:Interleukin-17; D048031:JNK Mitogen-Activated Protein Kinases; D020928:Mitogen-Activated Protein Kinases; D016328:NF-kappa B; D052002:NF-kappa B p50 Subunit; D017346:Protein Serine-Threonine Kinases; D011506:Proteins; D011518:Proto-Oncogene Proteins; D012333:RNA, Messenger; D048029:TNF Receptor-Associated Factor 6; D051996:Transcription Factor RelA; D014157:Transcription Factors; D014409:Tumor Necrosis Factor-alpha; D050807:ets-Domain Protein Elk-1; D018631:ras Proteins; D000097782:NF-kappaB-Inducing Kinase; C475829:CXCL1 protein, human; C513297:Cxcl1 protein, rat; C494114:Elk1 protein, rat; C496559:CHUK protein, human; C496560:IKBKB protein, human; C496565:IKBKE protein, human