Journal
JOURNAL OF ALLERGY AND CLINICAL IMMUNOLOGY
Volume 116, Issue 6, Pages 1364-1371Publisher
MOSBY, INC
DOI: 10.1016/j.jaci.2005.09.006
Keywords
WASP; IL-2 gene regulation; NF-kappa B; NF-AT; Erk; Jnk; c-fos; c-Jun
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Funding
- NHLBI NIH HHS [HL59561] Funding Source: Medline
- NIAID NIH HHS [AI35714, AI054933] Funding Source: Medline
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Background: Proliferation and IL-2 production in response to T-cell receptor ligation are impaired in patients with Wiskott-Aldrich syndrome (WAS). The transcription factors nuclear factor-kappa B (NF-kappa B), nuclear factor of activated T cells (NF-AT), and activating protein-1 (AP-1) play a critical role in IL-2 gene expression. Objective: To investigate the mechanisms of impaired IL-2 production after T-cell receptor ligation in T cells deficient in WAS protein (WASP). Methods: T cells from WASP(-/-) mice were stimulated with anti-CD3 and anti-CD28. Nuclear NF-kappa B, NF-AT, and AP-1 DNA-binding activity was examined by electroshift mobility assay. NF-ATp dephosphorylation and nuclear localization were examined by Western blot and indirect immunofluorescence. Phosphorylation of the mitogen-activated protein kinases Erk and Jnk, and of their nuclear substrates Elk-1 and c-Jun, was examined by Western blot. Expression of mRNA for IL-2 and the NF-kappa B-dependent gene A20 and of the AP-1 components c-fos and c-Jun was examined by quantitative RT-PCR. Results: Nuclear translocation and activity of NF-kappa B were normal in T cells from WASP(-/-) mice. In contrast, NF-ATp dephosphorylation and nuclear localization, nuclear AP-1 binding activity, and expression of c-fos, but not c-Jun, were all impaired. Phosphorylation of Jnk, c-Jun, and Erk were normal. However, nuclear translocation of phosphorylated Erk and phosphorylation of its nuclear substrate Elk1, which activates the c-fos promoter, were impaired. Conclusion: These results suggest that WASP is essential for NF-ATp activation, and for nuclear translocation of p-Erk, Elk1 phosphorylation, and c-fos gene expression in T cells. These defects underlie defective IL-2 expression and T-cell proliferation in WAS.
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