Enhanced secretion of IFN-gamma by activated Th1 cells occurs via reverse signaling through TNF-related activation-induced cytokine.
Growing evidence has demonstrated that members of TNF superfamily transduce signals after engagement with their receptors. TNF-related activation-induced cytokine (TRANCE), a member of TNF superfamily, is preferentially expressed on the surface of activated CD4(+) Th1 cells. The soluble receptor activator of NF-kappaB (RANK).Fc fusion protein suppresses IFN-gamma secretion by activated Th1 cells, but does not affect IL-4 secretion by Th2 cells. The suppressive effect on IFN-gamma secretion is observed when Th1 cells are activated by APCs, but not by immobilized anti-TCR beta mAb. In contrast, immobilized RANK.Fc fusion protein augments IFN-gamma secretion by Th1 cells, indicating the occurrence of reverse signaling through TRANCE during T cell/APC interaction. The enhanced secretion of IFN-gamma mediated via TRANCE correlates with the activation of p38 mitogen-activated protein kinase and is blocked by SB203580, a p38 mitogen-activated protein kinase-specific inhibitor. Thus, in addition to its role in activating dendritic cells by binding to the receptor RANK, TRANCE itself can signal the augmentation of IFN-gamma secretion via a p38-dependent pathway, and this provides yet another example of reverse signaling by a member of TNF superfamily.
Chen
N J
NJ
Department of Microbiology and Immunology, National Yang-Ming University, Taipei, Taiwan.
Huang
M W
MW
Hsieh
S L
SL
D000818:Animals; D002352:Carrier Proteins / Q000096:biosynthesis / Q000235:genetics / Q000378:metabolism / Q000502:physiology*; D002454:Cell Differentiation / Q000235:genetics / Q000276:immunology; D016207:Cytokines / Q000096:biosynthesis / Q000235:genetics / Q000378:metabolism / Q000502:physiology*; D004789:Enzyme Activation / Q000235:genetics / Q000276:immunology; D004791:Enzyme Inhibitors / Q000494:pharmacology; D006801:Humans; D007371:Interferon-gamma / Q000037:antagonists & inhibitors / Q000378:metabolism*; D008213:Lymphocyte Activation / Q000235:genetics; D008562:Membrane Glycoproteins / Q000096:biosynthesis / Q000235:genetics / Q000378:metabolism / Q000502:physiology*; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D008822:Mice, Transgenic; D020928:Mitogen-Activated Protein Kinases / Q000037:antagonists & inhibitors / Q000378:metabolism; D016328:NF-kappa B / Q000378:metabolism; D053245:RANK Ligand; D053246:Receptor Activator of Nuclear Factor-kappa B; D018124:Receptors, Tumor Necrosis Factor / Q000235:genetics / Q000378:metabolism / Q000502:physiology; D011993:Recombinant Fusion Proteins / Q000276:immunology / Q000378:metabolism / Q000494:pharmacology; D015398:Signal Transduction / Q000235:genetics / Q000276:immunology*; D018417:Th1 Cells / Q000166:cytology / Q000276:immunology / Q000378:metabolism*; D018418:Th2 Cells / Q000166:cytology / Q000378:metabolism; D015854:Up-Regulation / Q000187:drug effects / Q000235:genetics / Q000276:immunology; D048051:p38 Mitogen-Activated Protein Kinases
D002352:Carrier Proteins; D016207:Cytokines; D004791:Enzyme Inhibitors; D008562:Membrane Glycoproteins; D016328:NF-kappa B; D053245:RANK Ligand; D053246:Receptor Activator of Nuclear Factor-kappa B; D018124:Receptors, Tumor Necrosis Factor; D011993:Recombinant Fusion Proteins; C505686:TNFRSF11A protein, human; C505688:TNFSF11 protein, human; C505687:Tnfrsf11a protein, mouse; C505689:Tnfsf11 protein, mouse; D007371:Interferon-gamma; D020928:Mitogen-Activated Protein Kinases; D048051:p38 Mitogen-Activated Protein Kinases