TCR-independent CD30 signaling selectively induces IL-13 production via a TNF receptor-associated factor/p38 mitogen-activated protein kinase-dependent mechanism.
Initiation of T lymphocyte responses to most Ags requires concurrent stimulation through the TCR and costimulatory receptors such as CD28. Following initial activation, secondary receptors are up-regulated that can costimulate T cells in concert with TCR engagement. One such receptor is the TNFR family member CD30. In this study, we report that unlike CD28, ligation of CD30 on normal effector T cells induces IL-13 production in the absence of concurrent TCR engagement. TCR-independent CD30-mediated IL-13 release correlated with activation of c-Jun N-terminal kinase, p38 mitogen-activated protein kinase (MAPK), and NF-kappaB, and was completely inhibited by the expression of a TNFR-associated factor 2 (TRAF2) dominant-negative transgene (TRAF2.DN-Tg), but not by that of an I-kappaBalpha dominant-negative transgene. In parallel, expression of the TRAF2.DN-Tg selectively prevented the induction of c-Jun N-terminal kinase and p38 MAPK, but not that of NF-kappaB. Furthermore, IL-13 production was reduced in a dose-dependent manner by the p38 MAPK inhibitor SB203580. Together, these results suggest that TCR-independent CD30-mediated production of IL-13 is triggered by association of CD30 with TRAF family members and subsequent activation of p38 MAPK. Inasmuch as IL-13 can promote airway inflammation and cancer progression, production of IL-13 in a TCR-independent manner has important pathological implications in vivo.
Committee on Immunology and Department of Medicine, Section of Rheumatology, University of Chicago, IL 60637, USA.
Helena
H
Harlin
Eckhard
E
Podack
Mark
M
Boothby
Maria-Luisa
ML
Alegre
D021581:Active Transport, Cell Nucleus / Q000276:immunology; D000818:Animals; D002478:Cells, Cultured; D003432:Cross-Linking Reagents / Q000378:metabolism; D016207:Cytokines / Q000378:metabolism; D004789:Enzyme Activation / Q000235:genetics / Q000276:immunology; D005786:Gene Expression Regulation / Q000276:immunology; D018793:Interleukin-13 / Q000096:biosynthesis*; D048031:JNK Mitogen-Activated Protein Kinases; D017730:Ki-1 Antigen / Q000096:biosynthesis / Q000276:immunology / Q000378:metabolism / Q000502:physiology*; D008024:Ligands; D008213:Lymphocyte Activation / Q000235:genetics; D020935:MAP Kinase Signaling System / Q000235:genetics / Q000276:immunology*; D051379:Mice; D008807:Mice, Inbred BALB C; D008822:Mice, Transgenic; D020928:Mitogen-Activated Protein Kinases / Q000037:antagonists & inhibitors / Q000378:metabolism / Q000502:physiology*; D016328:NF-kappa B / Q000378:metabolism; D011506:Proteins / Q000502:physiology*; D011948:Receptors, Antigen, T-Cell / Q000502:physiology*; D018124:Receptors, Tumor Necrosis Factor / Q000378:metabolism*; D016176:T-Lymphocyte Subsets / Q000276:immunology / Q000378:metabolism; D047992:TNF Receptor-Associated Factor 2; D018417:Th1 Cells / Q000276:immunology / Q000378:metabolism; D018418:Th2 Cells / Q000276:immunology / Q000378:metabolism; D019076:Transgenes / Q000276:immunology; D014407:Tumor Cells, Cultured; D048051:p38 Mitogen-Activated Protein Kinases
D003432:Cross-Linking Reagents; D016207:Cytokines; D018793:Interleukin-13; D017730:Ki-1 Antigen; D008024:Ligands; D016328:NF-kappa B; D011506:Proteins; D011948:Receptors, Antigen, T-Cell; D018124:Receptors, Tumor Necrosis Factor; D047992:TNF Receptor-Associated Factor 2; D048031:JNK Mitogen-Activated Protein Kinases; D020928:Mitogen-Activated Protein Kinases; D048051:p38 Mitogen-Activated Protein Kinases