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Clinical and Diagnostic Laboratory Immunology, May 2003, p. 376-382, Vol. 10, No. 3
1071-412X/03/$08.00+0     DOI: 10.1128/CDLI.10.3.376-382.2003
Copyright © 2003, American Society for Microbiology. All Rights Reserved.

NF-B Is Involved in Regulation of CD40 Ligand Expression on Mycobacterium bovis Bacillus Calmette-Guérin-Activated Human T Cells

Departamento de Inmunología, Escuela Nacional de Ciencias Biológicas, IPN, Carpio y Plan de Ayala, México D. F. 11340, México

Received 3 December 2002/ Returned for modification 7 January 2003/ Accepted 20 February 2003

Interaction between CD40L (CD154) on activated T cells and its receptor CD40 on antigen-presenting cells has been reported to be important in the resolution of infection by mycobacteria. However, the mechanism(s) by which Mycobacterium bovis bacillus Calmette-Guérin (BCG) up-regulates membrane expression of CD40L molecules is poorly understood. This study was done to investigate the role of the nuclear factor B (NF-B) signaling pathway in the regulation of CD40L expression in human CD4⁺ T cells stimulated with BCG. Specific pharmacologic inhibition of the NF-B pathway revealed that this signaling cascade was required in the regulation of CD40L expression on the surface of BCG-activated CD4⁺ T cells. These results were further supported by the fact that treatment of BCG-activated CD4⁺ T cells with these pharmacological inhibitors significantly down-regulated CD40L mRNA. In this study, inhibitor B (IB) and IBß protein production was not affected by the chemical protease inhibitors and, more importantly, BCG led to the rapid but transient induction of NF-B activity. Our results also indicated that CD40L expression on BCG-activated CD4⁺ T cells resulted from transcriptional up-regulation of the CD40L gene by a mechanism which is independent of de novo protein synthesis. Interestingly, BCG-induced activation of NF-B and the increased CD40L cell surface expression were blocked by the protein kinase C (PKC) inhibitors 1-[5-isoquinolinesulfonyl]-2-methylpiperazine and salicylate, both of which block phosphorylation of IB. Moreover, rottlerin a Ca²⁺-independent PKC isoform inhibitor, significantly down-regulated CD40L mRNA in BCG-activated CD4⁺ T cells. These data strongly suggest that CD40L expression by BCG-activated CD4⁺ T cells is regulated via the PKC pathway and by NF-B DNA binding activity.

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