TCR-independent CD30 signaling selectively induces IL-13 production via a TNF receptor-associated factor/p38 mitogen-activated protein kinase-dependent mechanism.

Harlin H, Podack E, Boothby M, Alegre ML
J Immunol. 2002 169 (5): 2451-9

PMID: 12193714 · DOI:10.4049/jimmunol.169.5.2451

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.

MeSH Terms (28)

Active Transport, Cell Nucleus Animals Cells, Cultured Cross-Linking Reagents Cytokines Enzyme Activation Gene Expression Regulation Interleukin-13 JNK Mitogen-Activated Protein Kinases Ki-1 Antigen Ligands Lymphocyte Activation MAP Kinase Signaling System Mice Mice, Inbred BALB C Mice, Transgenic Mitogen-Activated Protein Kinases NF-kappa B p38 Mitogen-Activated Protein Kinases Proteins Receptors, Antigen, T-Cell Receptors, Tumor Necrosis Factor T-Lymphocyte Subsets Th1 Cells Th2 Cells TNF Receptor-Associated Factor 2 Transgenes Tumor Cells, Cultured

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