Abstract
The transcription factor NF-κB plays an important role in the regulated expression of cytokines in human monocytes. A p100 subunit of NF-κB has IκB-like properties by sequestering the p65 transactivating subunit in the cytosol of cells. In transient transfection assays we demonstrated that p100 has an inhibitory effect on the NF-κB-dependent IL-6 promoter activity. In view of this finding, we studied the regulation of the p100 subunit in human monocytes in response to LPS, the inflammatory cytokines IL-1β and TNF-α and lymphokines. The results demonstrate that LPS, IL-1β, and TNF-α induce p100 expression at mRNA and protein level while IFN-γ, IL-3 and IL-4/IL-10 have no effect. The induction of p100 expression was shown to be mediated by a two-fold increase in the p100 transcription rate and a two-fold increase in p100 mRNA stability. Furthermore the p100 mediated upregulation was dependent on a tyrosine kinase dependent pathway rather than the protein kinase C pathway. NF-κB is a complex of either p50 homodimers or a p50/p65 heterodimer. The latter is known to strongly autoregulate p100 transcription. We therefore examined the composition of NF-κB induced by LPS vs the different lymphokines. LPS-induced NF-κB showed a distinct p65 supershift whereas the composition of NF-κB induced by different lymphokines did not show a change in p65. We conclude that the p100 subunit of the transcription factor NF-κB is induced by different inflammatory mediators while lymphokines fail to induce p100 expression which may be caused by the induction of NF-κB predominantly consisting of p50 homodimers.
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de Wit, H., Dokter, W., Koopmans, S. et al. Regulation of p100 (NFKB2) expression in human monocytes in response to inflammatory mediators and lymphokines. Leukemia 12, 363–370 (1998). https://doi.org/10.1038/sj.leu.2400950
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DOI: https://doi.org/10.1038/sj.leu.2400950
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