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Article: Impaired CD28-mediated interleukin 2 production and proliferation in stress kinase SAPK/ERK1 kinase (SEK1)/mitogen-activated protein kinase kinase 4 (MKK4)-deficient T lymphocytes

TitleImpaired CD28-mediated interleukin 2 production and proliferation in stress kinase SAPK/ERK1 kinase (SEK1)/mitogen-activated protein kinase kinase 4 (MKK4)-deficient T lymphocytes
Authors
Issue Date1997
Citation
Journal of Experimental Medicine, 1997, v. 186, n. 6, p. 941-953 How to Cite?
AbstractThe dual specific kinase SAPK/ERK1 kinase (SEK1; mitogen-activated protein kinase kinase 4/Jun NH 2 terminal kinase [JNK] kinase) is a direct activator of stress-activated protein kinases ([SAPKs]/JNKs) in response to CD28 costimulation, CD40 signaling, or activation of the germinal center kinase. Here we show that SEK1(-/-) recombination-activating gene (RAG)2(-/- ) chimeric mice have a partial block in B cell maturation. However, peripheral B cells displayed normal responses to IL-4, IgM, and CD40 cross- linking. SEK1(-/-) peripheral T cells showed decreased proliferation and IL- 2 production after CD28 costimulation and PMA/Ca 2+ ionophore activation. Although CD28 expression was absolutely crucial to generate vesicular stomatitis virus (VSV)-specific germinal centers, SEK1(-/-)RAG2(-/-) chimeras mounted a protective antiviral B cell response, exhibited normal IgG class switching, and made germinal centers in response to VSV. Interestingly, PMA/Ca 2+ ionophore stimulation, which mimics TCR-CD3 and CD28-mediated signal transduction, induced SAPK/JNK activation in peripheral T cells, but not in thymocytes, from SEK1(-/-) mice. These results show that signaling pathways for SAPK activation are developmentally regulated in T cells. Although SEK1(-/-) thymocytes failed to induce SAPK/JNK in response to PMA/Ca 2+ ionophore, SEK1(-/-)RAG2(-/-) thymocytes proliferated and made IL- 2 after PMA/Ca 2+ ionophore and CD3/CD28 stimulation, albeit at significantly lower levels compared to SEK1(+/+)RAG2(-/-) thymocytes, implying that CD28 costimulation and PMA/Ca 2+ ionophore-triggered signaling pathways exist that can mediate proliferation and IL-2 production independently of SAPK activation. Our data provide the first genetic evidence that SEK1 is an important effector molecule that relays CD28 signaling to IL- 2 production and T cell proliferation.
Persistent Identifierhttp://hdl.handle.net/10722/291413
ISSN
2020 Impact Factor: 14.307
2020 SCImago Journal Rankings: 8.483
PubMed Central ID
ISI Accession Number ID

 

DC FieldValueLanguage
dc.contributor.authorNishina, Hiroshi-
dc.contributor.authorBachmann, Martin-
dc.contributor.authorOliveira-dos-Santos, Antonio J.-
dc.contributor.authorKozieradzki, Ivona-
dc.contributor.authorFischer, Klaus D.-
dc.contributor.authorOdermatt, Bernhard-
dc.contributor.authorWakeham, Andrew-
dc.contributor.authorShahinian, Arda-
dc.contributor.authorTakimoto, Hiroaki-
dc.contributor.authorBernstein, Alan-
dc.contributor.authorMak, Tak W.-
dc.contributor.authorWoodgett, James R.-
dc.contributor.authorOhashi, Pamela S.-
dc.contributor.authorPenninger, Josef M.-
dc.date.accessioned2020-11-17T14:54:19Z-
dc.date.available2020-11-17T14:54:19Z-
dc.date.issued1997-
dc.identifier.citationJournal of Experimental Medicine, 1997, v. 186, n. 6, p. 941-953-
dc.identifier.issn0022-1007-
dc.identifier.urihttp://hdl.handle.net/10722/291413-
dc.description.abstractThe dual specific kinase SAPK/ERK1 kinase (SEK1; mitogen-activated protein kinase kinase 4/Jun NH 2 terminal kinase [JNK] kinase) is a direct activator of stress-activated protein kinases ([SAPKs]/JNKs) in response to CD28 costimulation, CD40 signaling, or activation of the germinal center kinase. Here we show that SEK1(-/-) recombination-activating gene (RAG)2(-/- ) chimeric mice have a partial block in B cell maturation. However, peripheral B cells displayed normal responses to IL-4, IgM, and CD40 cross- linking. SEK1(-/-) peripheral T cells showed decreased proliferation and IL- 2 production after CD28 costimulation and PMA/Ca 2+ ionophore activation. Although CD28 expression was absolutely crucial to generate vesicular stomatitis virus (VSV)-specific germinal centers, SEK1(-/-)RAG2(-/-) chimeras mounted a protective antiviral B cell response, exhibited normal IgG class switching, and made germinal centers in response to VSV. Interestingly, PMA/Ca 2+ ionophore stimulation, which mimics TCR-CD3 and CD28-mediated signal transduction, induced SAPK/JNK activation in peripheral T cells, but not in thymocytes, from SEK1(-/-) mice. These results show that signaling pathways for SAPK activation are developmentally regulated in T cells. Although SEK1(-/-) thymocytes failed to induce SAPK/JNK in response to PMA/Ca 2+ ionophore, SEK1(-/-)RAG2(-/-) thymocytes proliferated and made IL- 2 after PMA/Ca 2+ ionophore and CD3/CD28 stimulation, albeit at significantly lower levels compared to SEK1(+/+)RAG2(-/-) thymocytes, implying that CD28 costimulation and PMA/Ca 2+ ionophore-triggered signaling pathways exist that can mediate proliferation and IL-2 production independently of SAPK activation. Our data provide the first genetic evidence that SEK1 is an important effector molecule that relays CD28 signaling to IL- 2 production and T cell proliferation.-
dc.languageeng-
dc.relation.ispartofJournal of Experimental Medicine-
dc.titleImpaired CD28-mediated interleukin 2 production and proliferation in stress kinase SAPK/ERK1 kinase (SEK1)/mitogen-activated protein kinase kinase 4 (MKK4)-deficient T lymphocytes-
dc.typeArticle-
dc.description.naturelink_to_OA_fulltext-
dc.identifier.doi10.1084/jem.186.6.941-
dc.identifier.pmid9294148-
dc.identifier.pmcidPMC2199046-
dc.identifier.scopuseid_2-s2.0-0030931125-
dc.identifier.volume186-
dc.identifier.issue6-
dc.identifier.spage941-
dc.identifier.epage953-
dc.identifier.isiWOS:A1997XX67800015-
dc.identifier.issnl0022-1007-

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