Differential regulation of interleukin-8 gene transcription by death receptor 3 (DR3) and type I TNF receptor (TNFRI).
TL1A induces interleukin-8 (IL-8) secretion in human peripheral blood monocyte-derived macrophage in a dose- and time-dependent manner. Overexpression of its cognate receptor DR3 can induce a higher amount of IL-8 protein secretion than that induced by TNFRI even though both receptors activate IL-8 gene transcription in a similar fashion. The underlying mechanism for the regulation of the IL-8 gene transcription by DR3 has not been investigated yet. Here, we used HEK293 cells as a model system to dissect the possible signaling components that are involved in the regulation of DR3-mediated IL-8 gene expression. Although both DR3 and TNFRI activated TRAF2 and NF-kappaB to induce IL-8 gene transcription, the kinase cascades that transduce signals for DR3- and TNFRI-induced IL-8 gene transcription are different. The axis TAK1/ASK1-MKK4/MKK7-JNK2 is responsible for DR3-mediated IL-8 gene expression whereas the axis ASK1-MKK4-JNK1/JNK2/p38MAPK is the choice for TNFRI-mediated activation of IL-8 gene expression. This indicates that the downstream signaling pathways of DR3 and TNFRI for IL-8 secretion are divergent even though both receptors contain death-domain and induce IL-8 secretion via TRAF2.
Su
Wenlynn B
WB
Institute of Microbiology and Immunology, National Yang-Ming University, Taipei, Taiwan.
Chang
Ying-Hsin
YH
Lin
Wan-Wan
WW
Hsieh
Shie-Liang
SL
D002460:Cell Line; D005786:Gene Expression Regulation; D006801:Humans; D016209:Interleukin-8 / Q000235:genetics* / Q000378:metabolism; D007668:Kidney / Q000166:cytology / Q000378:metabolism; D048670:MAP Kinase Kinase 4 / Q000378:metabolism; D020930:MAP Kinase Kinase Kinases / Q000378:metabolism; D020935:MAP Kinase Signaling System; D016328:NF-kappa B / Q000378:metabolism*; D018124:Receptors, Tumor Necrosis Factor / Q000378:metabolism*; D053219:Receptors, Tumor Necrosis Factor, Member 25; D047888:Receptors, Tumor Necrosis Factor, Type I / Q000378:metabolism*; D047992:TNF Receptor-Associated Factor 2 / Q000378:metabolism; D018808:Transcription Factor AP-1 / Q000378:metabolism; D015533:Transcriptional Activation; D053380:Tumor Necrosis Factor Ligand Superfamily Member 15; D014409:Tumor Necrosis Factor-alpha; D048051:p38 Mitogen-Activated Protein Kinases / Q000378:metabolism; D000099151:MAP Kinase Kinase Kinase 7
D016209:Interleukin-8; D048670:MAP Kinase Kinase 4; D020930:MAP Kinase Kinase Kinases; D016328:NF-kappa B; D018124:Receptors, Tumor Necrosis Factor; D053219:Receptors, Tumor Necrosis Factor, Member 25; D047888:Receptors, Tumor Necrosis Factor, Type I; D047992:TNF Receptor-Associated Factor 2; D018808:Transcription Factor AP-1; D053380:Tumor Necrosis Factor Ligand Superfamily Member 15; D014409:Tumor Necrosis Factor-alpha; D048051:p38 Mitogen-Activated Protein Kinases; D000099151:MAP Kinase Kinase Kinase 7; C506033:TNFRSF25 protein, human; C117026:TNFSF15 protein, human