Regulation of p100 (NFKB2) expression in human monocytes in response to inflammatory mediators and lymphokines

Leukemia. 1998 Mar;12(3):363-70. doi: 10.1038/sj.leu.2400950.

Abstract

The transcription factor NF-kappaB plays an important role in the regulated expression of cytokines in human monocytes. A p100 subunit of NF-kappaB has IkappaB-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-kappaB-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-1beta and TNF-alpha and lymphokines. The results demonstrate that LPS, IL-1beta, and TNF-alpha induce p100 expression at mRNA and protein level while IFN-gamma, 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-kappaB 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-kappaB induced by LPS vs the different lymphokines. LPS-induced NF-kappaB showed a distinct p65 supershift whereas the composition of NF-kappaB induced by different lymphokines did not show a change in p65. We conclude that the p100 subunit of the transcription factor NF-kappaB is induced by different inflammatory mediators while lymphokines fail to induce p100 expression which may be caused by the induction of NF-kappaB predominantly consisting of p50 homodimers.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Cells, Cultured
  • Gene Expression Regulation / drug effects*
  • Humans
  • Inflammation
  • Interferon-gamma / pharmacology
  • Interleukin-1 / pharmacology*
  • Interleukin-10 / pharmacology
  • Interleukin-3 / pharmacology
  • Interleukin-4 / pharmacology
  • Lipopolysaccharides / pharmacology
  • Lymphokines / pharmacology*
  • Monocytes / cytology
  • Monocytes / drug effects
  • Monocytes / physiology*
  • NF-kappa B / biosynthesis*
  • NF-kappa B p52 Subunit
  • Protein Biosynthesis / drug effects
  • Proto-Oncogene Proteins / biosynthesis
  • Pseudomonas aeruginosa
  • RNA, Messenger / biosynthesis
  • Transcription, Genetic / drug effects
  • Tumor Necrosis Factor-alpha / pharmacology*

Substances

  • Interleukin-1
  • Interleukin-3
  • Lipopolysaccharides
  • Lymphokines
  • NF-kappa B
  • NF-kappa B p52 Subunit
  • Proto-Oncogene Proteins
  • RNA, Messenger
  • Tumor Necrosis Factor-alpha
  • Interleukin-10
  • Interleukin-4
  • Interferon-gamma